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AIMS: Evidence is lacking on whether diabetes duration is associated with type 1 diabetes (T1D) self-management during late adolescence before transfer from paediatric to adult care. We examined associations of diabetes duration with dimensions of perceived comfort with diabetes self-management (self-efficacy, transition readiness, diabetes distress) and glycaemic control in late adolescence. METHODS: Using a cross-sectional design, we conducted a secondary analysis of baseline data of adolescents (ages 16-17 years) with T1D followed at paediatric diabetes academic hospitals in Montreal and enrolled in the Group Education Trial to Improve Transition (GET-IT-T1D). Participants completed validated questionnaires on self-efficacy (Self-Efficacy for Diabetes Self-Management Measure [SEDM], score 1 to 10), diabetes distress and transition readiness, as well as a haemoglobin (HbA1c) capillary blood test. Our primary outcome was self-efficacy. We examined associations of diabetes duration with self-efficacy, diabetes distress, transition readiness and HbA1c using linear and logistic regression models adjusted for sex, socioeconomic status, insulin pump use, glucose sensor use and psychiatric comorbidity. RESULTS: Of 203 adolescents with T1D, mean diabetes duration (SD) was 7.57 (4.44) years. Mean SEDM score was 6.83 (SD 1.62). Diabetes duration was not associated with self-efficacy, diabetes distress or transition readiness. Each additional year of diabetes duration was associated with 0.11% (95% CI, 0.05 to 0.16) higher HbA1c. CONCLUSIONS: Although diabetes duration is not associated with dimensions of perceived comfort with diabetes self-management, adolescents with longer diabetes duration are at risk for higher HbA1c and may need additional support to improve glycaemic control before transition to adult care.
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Diabetes Mellitus Tipo 1 , Autogestão , Transição para Assistência do Adulto , Adulto , Humanos , Adolescente , Criança , Estudos Transversais , Hemoglobinas Glicadas , Controle Glicêmico , GlicemiaRESUMO
OBJECTIVES: Adult cochlear implant (CI) recipients obtain varying levels of speech perception from their device. Adult CI users adapt quickly to their CI if they have no peripheral "bottom-up" or neurocognitive "top-down" limiting factors. Our objective here was to understand the influence of limiting factors on the progression of sentence understanding in quiet and in noise, initially and over time. We hypothesized that the presence of limiting factors, detected using a short test battery, would predictably influence sentence recognition with practical consequences. We aimed to validate the test battery by comparing the presence of limiting factors and the success criteria of >90% sentence understanding in quiet 1 month after activation. DESIGN: The study was a single-clinic, cross-sectional, retrospective design incorporating 32 adult unilateral Nucleus CI users aged 27 to 90 years (mean = 70, SD = 13.5). Postoperative outcome was assessed through sentence recognition scores in quiet and in varying signal to noise ratios at 1 day, 1 to 2 months, and up to 2 years. Our clinic's standard test battery comprises physiological and neurocognitive measures. Physiological measures included electrically evoked compound action potentials for recovery function, spread of excitation, and polarity effect. To evaluate general cognitive function, inhibition, and phonological awareness, the Montreal Cognitive Assessment screening test, the Stroop Color-Word Test, and tests 3 and 4 of the French Assessment of Reading Skills in Adults over 16 years of age, respectively were performed. Physiological scores were considered abnormal, and therefore limiting, when total neural recovery periods and polarity effects, for both apical and basal electrode positions, were >1.65 SDs from the population mean. A spread of excitation of >6 electrode units was also considered limiting. For the neurocognitive tests, scores poorer than 1.65 SDs from published normal population means were considered limiting. RESULTS: At 1 month, 13 out of 32 CI users scored ≥90% sentence recognition in quiet with no significant dependence on age. Subjects with no limiting peripheral or neurocognitive factors were 8.5 times more likely to achieve ≥90% score in quiet at 1 month after CI switch-on (p = 0.010). In our sample, we detected 4 out of 32 cases with peripheral limiting factors that related to neural health or poor electrode-neural interface at both apical and basal positions. In contrast, neurocognitive limiting factors were identified in 14 out of 32 subjects. Early sentence recognition scores were predictive of long-term sentence recognition thresholds in noise such that limiting factors appeared to be of continuous influence. CONCLUSIONS: Both peripheral and neurocognitive processing factors affect early sentence recognition after CI activation. Peripheral limiting factors may have been detected less often than neurocognitive limiting factors because they were defined using sample-based criteria versus normal population-based criteria. Early performance was generally predictive of long-term performance. Understanding the measurable covariables that limit CI performance may inform follow-up and improve counseling. A score of ≥90% for sentence recognition in quiet at 1 month may be used to define successful progress; whereas, lower scores indicate the need for diagnostic testing and ongoing rehabilitation. Our findings suggest that sentence test scores as early as 1 day after activation can provide vital information for the new CI user and indicate the need for rehabilitation follow-up.
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BACKGROUND: Since June 2017, oral pre-exposure prophylaxis (PrEP) has been reimbursed in Belgium for people at substantial risk of HIV. To inform the national PrEP programme, we described sociodemographic characteristics of PrEP users, PrEP dispensing practices, testing for HIV and sexually transmitted infections (STIs; gonorrhoea, chlamydia and syphilis), and incidence of HIV and STIs. METHODS: Analysis of routinely collected social health insurance claims data from all individuals who were dispensed at least one PrEP prescription between June 2017 and December 2019. Using logistic regression adjusted for age, we examined associations between sociodemographic characteristics and having been dispensed PrEP only once in the first six months of PrEP use. RESULTS: Overall, 4559 individuals were dispensed PrEP. Almost all PrEP users were male (99.2%, 4522/4559), with a median age of 37 years (IQR 30-45). A minority were entitled to an increased healthcare allowance (11.4%, 514/4559). 18% (657/3636) were dispensed PrEP only once in the first six months of PrEP use. PrEP users younger than 25 years, unemployed, entitled to an increased healthcare allowance, and who initiated PrEP between January 2019 and June 2019 were more likely to have had no PrEP dispensing after initiation compared to their counterparts. The testing rates for bacterial STIs and HIV were 4.2 tests per person-year (95% CI 4.1-4.2) and 3.6 tests per person-year (95% CI 3.5-3.6), respectively. Twelve individuals were identified to have seroconverted during the study period, resulting in an HIV incidence rate of 0.21/100 person-years (95% CI 0.12-0.36). The incidence of bacterial STIs was 81.2/100 person-years (95% CI 78.7-83.8). CONCLUSIONS: The study highlights challenges in PrEP persistence and a high incidence of bacterial STIs among individuals receiving PrEP. Tailored prevention support is crucial for individuals with ongoing HIV risk to optimise PrEP effectiveness. Integrated STI testing and prevention interventions within PrEP care are necessary to mitigate STI acquisition and transmission among PrEP users.
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Infecções por HIV , Profilaxia Pré-Exposição , Infecções Sexualmente Transmissíveis , Humanos , Profilaxia Pré-Exposição/estatística & dados numéricos , Bélgica/epidemiologia , Masculino , Adulto , Feminino , Incidência , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Pessoa de Meia-Idade , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Revisão da Utilização de Seguros , Estudos de Coortes , Adulto Jovem , AdolescenteRESUMO
Background: As the scope of pharmacy practice is expanding, a growing number of pharmacists perform physical examination (PE) to gather additional information to monitor the effectiveness and safety of their patients' therapy. This professional activity calls for the development of comprehensive and valuable PE training. We sought to determine by consensus which PE tests should be given teaching priority in pharmacy education. Methods: Using existing PE literature in pharmacy, we conducted an online Delphi survey from December 2021 to April 2022 with 16 pharmacists who practise in a variety of settings and/or who are considered experts in PE. Results: After 2 Delphi rounds, consensus was reached to either include or exclude 27 PE tests in entry-to-practice programs. One last round allowed prioritizing the agreed-upon PE tests in terms of educational needs. Clinicians agreed that measuring blood pressure is indispensable and should be given teaching priority, followed by pulse rate, weight and blood glucose measurements. Endocrine system and head and neck examinations should be included in pharmacy programs, but their clinical usefulness was considered less important. Discussion: We compared our results with PE literature in other health care disciplines. We found that only a few PE tests truly influence drug therapy management, that some examinations can be quite difficult to perform accurately and that without proper training and opportunities to retrain, skill decay can lead to dangerous misinterpretations. Pharmacy programs should consider focusing on teaching PE tests supported by evidence as having an impact on drug therapy management. Can Pharm J (Ott) 2024;157:xx-xx.
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The presence of virulent phages is closely monitored during cheese manufacturing, as these bacterial viruses can significantly slow down the milk fermentation process and lead to low-quality cheeses. From 2001 to 2020, whey samples from cheddar cheese production in a Canadian factory were monitored for the presence of virulent phages capable of infecting proprietary strains of Lactococcus cremoris and Lactococcus lactis used in starter cultures. Phages were successfully isolated from 932 whey samples using standard plaque assays and several industrial Lactococcus strains as hosts. A multiplex PCR assay assigned 97% of these phage isolates to the Skunavirus genus, 2% to the P335 group, and 1% to the Ceduovirus genus. DNA restriction profiles and a multilocus sequence typing (MLST) scheme distinguished at least 241 unique lactococcal phages from these isolates. While most phages were isolated only once, 93 of them (out of 241, 39%) were isolated multiple times. Phage GL7 was isolated 132 times from 2006 to 2020, demonstrating that phages can persist in a cheese factory for long periods of time. Phylogenetic analysis of MLST sequences showed that phages could be clustered based on their bacterial hosts rather than their year of isolation. Host range analysis showed that Skunavirus phages exhibited a very narrow host range, whereas some Ceduovirus and P335 phages had a broader host range. Overall, the host range information was useful in improving the starter culture rotation by identifying phage-unrelated strains and helped mitigating the risk of fermentation failure due to virulent phages. IMPORTANCE Although lactococcal phages have been observed in cheese production settings for almost a century, few longitudinal studies have been performed. This 20-year study describes the close monitoring of dairy lactococcal phages in a cheddar cheese factory. Routine monitoring was conducted by factory staff, and when whey samples were found to inhibit industrial starter cultures under laboratory conditions, they were sent to an academic research laboratory for phage isolation and characterization. This led to a collection of at least 241 unique lactococcal phages, which were characterized through PCR typing and MLST profiling. Phages of the Skunavirus genus were by far the most dominant. Most phages lysed a small subset of the Lactococcus strains. These findings guided the industrial partner in adapting the starter culture schedule by using phage-unrelated strains in starter cultures and removing some strains from the starter rotation. This phage control strategy could be adapted for other large-scale bacterial fermentation processes.
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Bacteriófagos , Queijo , Lactococcus lactis , Siphoviridae , Humanos , Queijo/microbiologia , Tipagem de Sequências Multilocus , Filogenia , Estudos Longitudinais , Canadá , Lactococcus lactis/genética , Siphoviridae/genética , Reação em Cadeia da Polimerase MultiplexRESUMO
Geographically isolated populations, specifically island-mainland counterparts, tend to exhibit phenotypic variation in many species. The so-called island syndrome occurs when different environmental pressures lead to insular divergence from mainland populations. This phenomenon can be seen in an island population of Nova Scotia masked shrews (Sorex cinereus), which have developed a specialized feeding habit and digestive enzyme compared to their mainland counterparts. Epigenetic modifications, such as DNA methylation (DNAm), can impact phenotypes by altering gene expression without changing the DNA sequence. Here, we used a de novo masked shrew genome assembly and a mammalian methylation array profiling 37 thousand conserved CpGs to investigate morphological and DNA methylation patterns between island and mainland populations. Island shrews were morphologically and epigenetically different than their mainland counterparts, exhibiting a smaller body size. A gene ontology enrichment analyses of differentially methylated CpGs implicated developmental and digestive system related pathways. Based on our shrew epigenetic clock, island shrews might also be aging faster than their mainland counterparts. This study provides novel insight on phenotypic and epigenetic divergence in island-mainland mammal populations and suggests an underlying role of methylation in island-mainland divergence.
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Epigênese Genética , Musaranhos , Animais , Musaranhos/genética , Tamanho Corporal , Sequência de Bases , Metilação de DNA/genéticaRESUMO
INTRODUCTION: When designing simulation for novices, educators aim to design tasks and environments that are complex enough to promote learning but not too complex to compromise task performance and cause cognitive overload. This study aimed to determine the impact of modulating task and environment complexity on novices' performance and cognitive load during simulation. METHODS: Second-year pharmacy students (N = 162) were randomly assigned to one of four conditions (2 × 2 factorial design) in simulation: simple task in simple environment, complex task in simple environment, simple task in complex environment and complex task in complex environment. Using video recordings, two raters assessed students' performance during the simulation. We measured intrinsic cognitive load (ICL) and extraneous cognitive load (ECL) with questionnaires after the task and tested knowledge after task and debriefing. RESULTS: Mean performance scores in simple environment were 28.2/32 (SD = 3.8) for simple task and 25.8/32 (SD = 4.2) for complex task. In complex environment, mean performance scores were 24.6/32 (SD = 5.2) for simple task and 25.6/32 (SD = 5.3) for complex task. We found significant interaction effects between task and environment complexity for performance. In simple environment, mean ICL scores were 4.2/10 (SD = 2.2) for simple task and 5.7/10 (SD = 1.5) for complex task. In complex environment, mean ICL scores were 4.9/10 (SD = 1.8) for simple task and 5.1/10 (SD = 1.9) for complex task. There was a main effect of task complexity on ICL. For ECL, we found neither an interaction effect nor main effects of task and environment complexity. There was a main effect of task complexity on knowledge test after task and main effects of both task and environment complexity on knowledge after debriefing. CONCLUSIONS: Performance was good, and cognitive load remained reasonable in all conditions, which suggests that, despite increased complexity, students seemed to strategically manage their own cognitive load and learn from the simulations. Our findings also indicate that environmental complexity contributes to ICL.
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Educação de Graduação em Medicina , Treinamento por Simulação , Estudantes de Farmácia , Humanos , Análise e Desempenho de Tarefas , CogniçãoRESUMO
OBJECTIVE: The "Marginal benefit from acoustic amplification" version 2 (MBAA2) sentence test has been used in France in the routine evaluation of cochlear implant (CI) users for 20 years. Here we present four studies that characterise and validate the test, and compare it with the French matrix sentence test. DESIGN AND SAMPLE: An analytic method was developed to obtain speech recognition threshold in noise (SNR50) from testing at a fixed signal to noise ratios (SNRs). Speech recognition was measured at several fixed SNRs in 18 normal-hearing listeners and 15 CI listeners. Then, the test-retest reliability of the MBAA2 was measured in an additional 15 CI listeners. Finally, list equivalence was evaluated in eight CI listeners. RESULTS: The MBAA2 test produced lower SNR50s and SNR50s were obtained in more CI listeners than with the French matrix test. For the MBAA2, the standard deviation of test-retest differences in CI listeners was around 1 dB SNR. Three lists had deviant difficulty and nine low item-to-total correlations. CONCLUSIONS: We propose to reduce the number of MBAA2 test lists to reduce variability. The MBAA2 test has high test-retest reliability for percent correct and SNR50, and is suitable for the assessment of cochlear implant patients.
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Implante Coclear , Implantes Cocleares , Percepção da Fala , Humanos , Reprodutibilidade dos Testes , Implante Coclear/métodos , AcústicaRESUMO
INTRODUCTION: Hypospadias is one of the most common congenital anomalies in men. Outpatient surgery has been proposed but is not widespread. The aim of this study was to evaluate our experience of outpatient surgery for penile hypospadias repair and to specify the constraints for a result similar to a conventional inpatient procedure. PATIENTS AND METHODS: Observational, retrospective and single-center study, including all the patients operated on hypospadias for the first time by one of the 3 senior surgeons, between January 2011 and March 2018. Peno-scrotal and perineal hypospadias were excluded because systematically hospitalized. RESULTS: One hundred sixty-six patients were included. 67 patients (40,4%) were treated on an outpatient basis. The mean age at the time of procedure was 15.6 (6-51) months. Forms with curvature were almost exclusively hospitalized (1 vs. 25, P<0.001). There was no significant difference for anterior penile forms (60 vs. 81, P=0.06). Middle and posterior hypospadias were more often hospitalized, although outpatient experience exists. There were no more complications in the outpatient group. CONCLUSION: Outpatient hypospadias surgery seems to be achievable in most of the cases, provided that medical care is standardized and multidisciplinary, the staff is trained and involved and a specific organization is put in place in the department. Evaluation of the socio-family environment is therefore fundamental.
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Hipospadia , Urologia , Criança , Humanos , Lactente , Masculino , Procedimentos Cirúrgicos Ambulatórios , Seguimentos , Hipospadia/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos Masculinos/métodosRESUMO
BACKGROUND: The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss. METHODS: We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238. FINDINGS: Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group. INTERPRETATION: Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis. FUNDING: F Hoffmann-La Roche and Genentech.
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Androstenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Piperazinas/uso terapêutico , Prednisolona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirimidinas/uso terapêutico , Idoso , Método Duplo-Cego , Humanos , Masculino , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/fisiopatologiaRESUMO
OBJECTIVES: The present study aimed to assess long-term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France. METHODS: Retrospective cross-sectional study of patients ages 6-30âyears that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups. RESULTS: Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR]â=â1.84 [1.31-2.57], Pâ<â0.001), or soiling (ORâ=â1.72 [1.31-2.25], Pâ<â0.001), which was also associated with the inability to discriminate between stool and gas (ORâ=â2.45 [1.28-4.67], Pâ=â0.007) and the presence of constipation (ORâ=â2.97 [1.74-5.08], Pâ<â0.001). Risk factors for constipation were sacral abnormalities [ORâ=â2.26 [1.23-4.25], Pâ=â0.01) and surgical procedures without an abdominal approach (ORâ=â2.98 [1.29-6.87], Pâ=â0.01). Only the holding of voluntary bowel movements and soiling rates improved with age. CONCLUSION: This cross-sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long-term follow-up of all patients to help them with supportive care.
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Malformações Anorretais , Adolescente , Adulto , Canal Anal/cirurgia , Malformações Anorretais/complicações , Malformações Anorretais/epidemiologia , Malformações Anorretais/cirurgia , Criança , Constipação Intestinal/complicações , Constipação Intestinal/etiologia , Estudos Transversais , Defecação , Feminino , Humanos , Masculino , Reto/cirurgia , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To identify the risk factors for early mortality and morbidity in a population with distal esophageal atresia (EA)-tracheoesophageal fistula. STUDY DESIGN: Cohort study from a national register. Main outcomes and measures included early mortality, hospital length of stay (LoS), need for nutritional support at 1 year of age as a proxy measure of morbidity, and complications during the first year of life. RESULTS: In total, 1008 patients with a lower esophageal fistula were included from January 1, 2008, to December 31, 2014. The survival rate at 3 months was 94.9%. The cumulative hospital LoS was 31.0 (17.0-64.0) days. Multivariate analysis showed that intrahospital mortality at 3 months was associated with low birth weight (OR 0.52, 95% CI [0.38-0.72], P < .001), associated cardiac abnormalities (OR 6.09 [1.96-18.89], P = .002), and prenatal diagnosis (OR 2.96 [1.08-8.08], P = .034). LoS was associated with low birth weight (-0.225 ± 0.035, P < .001), associated malformations (0.082 ± 0.118, P < .001), surgical difficulties (0.270 ± 0.107, P < .001), and complications (0.535 ± 0.099, P < .001) during the first year of life. Predictive factors for dependency on nutrition support at 1 year of age were complications before 1 year (OR 3.28 [1.23-8.76], P < .02) and initial hospital LoS (OR 1.96 [1.15-3.33], P < .01). CONCLUSIONS: EA has a low rate of early mortality, but morbidity is high during the first year of life. Identifying factors associated with morbidity may help to improve neonatal care of this population.
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Atresia Esofágica/mortalidade , Tempo de Internação/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Fístula Traqueoesofágica/mortalidade , Atresia Esofágica/diagnóstico , Feminino , França/epidemiologia , Cardiopatias Congênitas/complicações , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Apoio Nutricional/estatística & dados numéricos , Sistema de Registros , Fatores de Risco , Inquéritos e Questionários , Fístula Traqueoesofágica/diagnósticoRESUMO
Phenolic compounds from olive oil (ArOH-EVOO) are recognized for their antioxidant and neuroprotective capacities, but are often studied individually or through a natural extract. As their reactivity towards reactive oxygen species (ROS) depends on their structure and could implicate different complementary mechanisms, we hypothesized that their effects could be enhanced by an innovative combination of some of the most abundant ArOH-EVOO. Using electrochemical methods, we have compared their reactivity towards hydrogen peroxide and the superoxide anion radical. The mixture containing oleuropein, p-coumaric acid and tyrosol (Mix1), was more efficient than the mixture containing hydroxytyrosol, the oleuropein catechol moiety, and the two monophenols (Mix2). On neuronal SK-N-SH cells challenged with H2O2 or Paraquat, low concentrations (0.1 and 1â µM) of the Mix1 improved neuronal survival. These neuroprotective effects were supported by a decrease in intracellular ROS, in the protein carbonyl levels and the prevention of the redox-sensitive factors Nrf2 and NF-κB activation. These intracellular effects were supported by the demonstration of the internalization of these ArOH-EVOO into neuronal cells, evidenced by LC-HRMS. Our results demonstrated that this combination of ArOH-EVOO could be more efficient than individual ArOH usually studied for their neuroprotective properties. These data suggest that the Mix1 could delay neuronal death in neurodegenerative diseases related to oxidative stress such as Alzheimer's (AD) and Parkinson's diseases (PD).
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Transporte de Elétrons/efeitos dos fármacos , Azeite de Oliva/química , Fenóis/química , Fenóis/farmacologia , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Sinergismo Farmacológico , Eletroquímica , Sequestradores de Radicais Livres , Peróxido de Hidrogênio/antagonistas & inibidores , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores , Fenóis/farmacocinética , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Soluções , Superóxidos/antagonistas & inibidoresRESUMO
Phages are viruses that specifically infect and eventually kill their bacterial hosts. Bacterial fermentation and biotechnology industries see them as enemies, however, they are also investigated as antibacterial agents for the treatment or prevention of bacterial infections in various sectors. They also play key ecological roles in all ecosystems. Despite decades of research some aspects of phage biology are still poorly understood. In this study, we used label-free quantitative proteomics to reveal the proteotypes of Lactococcus lactis MG1363 during infection by the virulent phage p2, a model for studying the biology of phages infecting Gram-positive bacteria. Our approach resulted in the high-confidence detection and quantification of 59% of the theoretical bacterial proteome, including 226 bacterial proteins detected only during phage infection and 6 proteins unique to uninfected bacteria. We also identified many bacterial proteins of differing abundance during the infection. Using this high-throughput proteomic datasets, we selected specific bacterial genes for inactivation using CRISPR-Cas9 to investigate their involvement in phage replication. One knockout mutant lacking gene llmg_0219 showed resistance to phage p2 because of a deficiency in phage adsorption. Furthermore, we detected and quantified 78% of the theoretical phage proteome and identified many proteins of phage p2 that had not been previously detected. Among others, we uncovered a conserved small phage protein (pORFN1) coded by an unannotated gene. We also applied a targeted approach to achieve greater sensitivity and identify undetected phage proteins that were expected to be present. This allowed us to follow the fate of pORF46, a small phage protein of low abundance. In summary, this work offers a unique view of the virulent phages' takeover of bacterial cells and provides novel information on phage-host interactions.
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Proteínas de Bactérias/metabolismo , Bacteriófago P2/fisiologia , Lactococcus lactis/virologia , Proteoma/metabolismo , Sistemas CRISPR-Cas/genética , Edição de Genes , Genes Bacterianos , Lactococcus lactis/genética , Lactococcus lactis/crescimento & desenvolvimento , Proteínas Virais/metabolismoRESUMO
BACKGROUND: Malignant and multicystic peritoneal mesotheliomas are extremely rare tumors in children, developing from mesothelial cells. No specific guidelines are available at this age. METHODS: We performed a retrospective analysis of all identified children (< 18-year-old) treated in France from 1987 to 2017 for a diffuse malignant peritoneal mesothelioma (DMPM) or a multicystic peritoneal mesothelioma (MCPM). RESULTS: Fourteen patients (5 males and nine females), aged 2.2 to 17.5 years, were included. The most frequent presenting symptoms were abdominal pain, ascitis, and alteration in the general condition. Eight patients had epithelioid mesothelioma, three had biphasic mesothelioma, and three had MCPM. Eight patients with DMPM diagnosis received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Among them, six patients had neoadjuvant systemic chemotherapy, one patient, post-operative chemotherapy, and one patient CRS and HIPEC only. Three patients received only systemic chemotherapy. All patients with MCPM had only surgery. After a median follow-up of seven years (2-15), six patients (6/11; one death) with DMPM and two patients (two/three) with MCPM had a local and distant recurrences. CONCLUSION: Peritoneal mesothelioma in children is a rare condition with difficult diagnosis and high risk of recurrence. Worldwide interdisciplinary collaboration and networking are mandatory to help diagnosis and provide harmonious treatment guidelines.
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Quimioterapia Adjuvante/mortalidade , Cistos/terapia , Procedimentos Cirúrgicos de Citorredução/mortalidade , Hipertermia Induzida/mortalidade , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Terapia Neoadjuvante/mortalidade , Neoplasias Peritoneais/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Cistos/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Neoplasias Peritoneais/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific posttranslational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates. However, their role in LASV entry is not entirely understood. Here, we examine LASV receptor candidates in primary human cells and found coexpression of Axl with differentially glycosylated DG. To study LASV receptor use in the context of productive arenavirus infection, we employed recombinant lymphocytic choriomeningitis virus expressing LASV glycoprotein (rLCMV-LASV GP) as a validated biosafety level 2 (BSL2) model. We confirm and extend previous work showing that Axl can contribute to LASV entry in the absence of functional DG using "apoptotic mimicry" in a way similar to that of other enveloped viruses. We further show that Axl-dependent LASV entry requires receptor activation and involves a pathway resembling macropinocytosis. Axl-mediated LASV entry is facilitated by heparan sulfate and critically depends on the late endosomal protein LAMP-1 as an intracellular entry factor. In endothelial cells expressing low levels of functional DG, both receptors are engaged by the virus and can contribute to productive entry. In sum, we characterize the role of Axl in LASV entry and provide a rationale for targeting Axl in antiviral therapy.IMPORTANCE The highly pathogenic arenavirus Lassa virus (LASV) represents a serious public health problem in Africa. Although the principal LASV receptor, dystroglycan (DG), is ubiquitously expressed, virus binding critically depends on DG's posttranslational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as an alternative LASV receptor candidate, but its role in LASV entry is unclear. Here, we investigate the exact role of Axl in LASV entry as a function of DG's posttranslational modification. We found that in the absence of functional DG, Axl can mediate LASV entry via apoptotic mimicry. Productive entry requires virus-induced receptor activation, involves macropinocytosis, and critically depends on LAMP-1. In endothelial cells that express low levels of glycosylated DG, both receptors can promote LASV entry. In sum, our study defines the roles of Axl in LASV entry and provides a rationale for targeting Axl in antiviral therapy.
Assuntos
Distroglicanas/metabolismo , Vírus Lassa/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Virais/metabolismo , Ligação Viral , Internalização do Vírus , Células A549 , Antivirais/farmacologia , Infecções por Arenaviridae/metabolismo , Linhagem Celular Tumoral , Distroglicanas/genética , Endossomos/metabolismo , Expressão Gênica , Glicosilação , Células HEK293 , Células HeLa , Heparitina Sulfato/farmacologia , Humanos , Vírus Lassa/efeitos dos fármacos , Vírus Lassa/patogenicidade , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Pinocitose/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Tropismo , Receptor Tirosina Quinase AxlRESUMO
OBJECTIVE: To identify predictors of and factors associated with the performance of antireflux surgery during the first year of life in children born with esophageal atresia. STUDY DESIGN: All patients were included in a French registry for esophageal atresia. All 38 multidisciplinary French centers completed questionnaires about perinatal characteristics and one-year outcome for children born with esophageal atresia. RESULTS: Of 835 infants with esophageal atresia born in France from 2010 to 2014, 682 patients, excluding those with long-gap esophageal atresia, were included. Three patients had type I, 669 had type III, and 10 had type IV esophageal atresia. Fifty-three children (7.8%) received fundoplication during the first year of life. The median age at the time of the end-to-end esophageal anastomosis was 1.1 day (range 0-15). Multivariate analysis identified three perioperative factors that predicted the need for early antireflux surgery: anastomotic tension (P = .004), associated malformations (P = .019), and low birth weight (P = .018). Six other factors, measured during the first year of life, were associated with the need for antireflux surgery: gastroesophageal reflux (P < .001), anastomotic stricture (P < .001), gastrostomy (P < .001), acute life-threatening event (P = .002), respiratory complications (P = .045), and poor nutritional status (P < .001). CONCLUSIONS: Gastroesophageal reflux disease, low birth weight, poor nutrition, and surgical anastomosis difficulties predicted the performance of antireflux surgery in the first year of life in infants with esophageal atresia.
Assuntos
Atresia Esofágica/cirurgia , Fundoplicatura , Anastomose Cirúrgica/efeitos adversos , Constrição Patológica , Atresia Esofágica/classificação , Feminino , França , Refluxo Gastroesofágico/cirurgia , Gastrostomia , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Análise Multivariada , Estado Nutricional , Sistema de RegistrosRESUMO
Human pegivirus (HPgV, formerly GBV-C) is a member of the genus Pegivirus, family Flaviviridae. Despite its identification more than 20 years ago, both natural history and distribution of this viral group in human hosts remain under exploration. Analysis of HPgV genomes characterized up to now points out the scarcity of French pegivirus sequences in databases. To bring new data regarding HPgV genomic diversity, we investigated 16 French isolates obtained from hepatitis C virus-RNA and human immunodeficiency virus-RNA-positive blood donations following deep sequencing and coupled molecular protocols. Initial phylogenetic analysis of 5'-untranslated region (5'-UTR)/E2 partial sequences permitted to assign HPgV isolates to genotypes 2 (n = 15) and 1 (n = 1), with up to 16% genetic diversity observed for both regions considered. Seven nearly full-length representative genomes were characterized subsequently, with complete polyprotein coding sequences exhibiting up to 13% genetic diversity; closest nucleotide (nt) divergence with available HPgV sequences was in the range 7% to 11%. A 36 nts deletion located on the NS4B coding region (N-terminal part, 12 amino acids) of the genotype 1 HPgV genome characterized was identified, along with single nucleotide deletions in two genotype 2, 5'-UTR sequences.
Assuntos
Doadores de Sangue , Infecções por Flaviviridae/virologia , Flavivirus/genética , Infecções por HIV/complicações , Hepatite C/complicações , Sequenciamento de Nucleotídeos em Larga Escala , Flavivirus/classificação , Flavivirus/isolamento & purificação , França , Variação Genética , Genótipo , Humanos , RNA Viral/genéticaRESUMO
BACKGROUND: Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. METHODS: Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. RESULTS: Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. CONCLUSIONS: Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. CLINICAL TRIALS REGISTRATION: NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Junção Esofagogástrica/metabolismo , Polimorfismo Genético , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Ado-Trastuzumab Emtansina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Docetaxel/administração & dosagem , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Adulto JovemRESUMO
Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.