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BACKGROUND: Neoadjuvant immunotherapy emerges as a promising strategy for patients with localized colon cancer (CC) harboring microsatellite instability/mismatch repair deficiency (MSI/dMMR). The aim of this study is to evaluate the concordance between clinical cTN stage assessed by preoperative computed tomography (CT) scan and pTN stage of MSI/dMMR CC. PATIENTS AND METHODS: Consecutive patients diagnosed for localized MSI/dMMR CC and treated with upfront surgery between 2013 and 2022 in two French centers were eligible. Two independent radiologists, blinded to pathological findings, reviewed all preoperative CT scans and assessed cTN stage, with a third radiologist reviewing discordant cases. Radiological predictive diagnostic accuracy for pT4 and pN+ (N+ = N1 or N2) were calculated. RESULTS: One hundred and thirteen patients were included (right CCs = 79%). CT scan diagnostic performances for pT4 were sensitivity (Se) = 33.3%; specificity (Sp) = 94.0%; positive predictive value (PPV) = 66.7%; and negative predictive value (NPV) = 79.6% and for pN+ were Se = 70.3%; Sp = 59.2%; PPV = 45.6%; and NPV = 80.4%. When pT-pN were combined, 37.5% of tumors identified as cT4 and/or cN+ were actually pT1-3 and pN0, and 23.1% of the pT4 and pN+ population was not identified as such radiologically. CONCLUSION: The ability of preoperative CT scan to predict pT and pN stages is limited for localized MSI/dMMR CCs. Reassessing neoadjuvant strategies' benefit-risk balance in this population is needed.
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OBJECTIVES: The objectives were to assess trends over the past 10 years in vaccination coverage rates (VCR) among adolescents in France aged 14-15 years, factors influencing decisions to vaccinate, and mothers' opinions on adolescent vaccination. PATIENTS AND METHODS: The 'Vaccinoscopie' internet survey is completed each year by mothers of adolescents, with questions about vaccinations received by their children, and their attitudes and barriers to vaccination. The 2012 to 2021 surveys were analyzed in this study, including data from 1500 adolescents in 2012 and 1000 adolescents each year from 2013 to 2021. RESULTS: None of the adolescent VCR targets were met, despite significant increases since 2012 for vaccines with the lowest coverage rates and vaccines with high but insufficient coverage i.e., meningococcal C (28.7% to 60.8%), HPV in girls (14.2% to 40.8%), hepatitis B (31.6% to 47.3%) and pertussis (76.3% to 91.0%). Physicians remained the primary source of vaccination information for 90.4% of mothers, and their advice had a real impact on improving VCRs. Adolescents were increasingly involved (40.1%) in decisions about vaccination. Depending on the vaccine, over 80% of mothers currently consider adolescent vaccination as useful or essential. Since 2017, they also feel better informed. CONCLUSIONS: Low and under-target VCRs put adolescents at risk of severe disease, and do not enable herd immunity or reduced transmission to other vulnerable age groups to be accomplished. Healthcare professionals must take every opportunity to check adolescents' vaccination status and recommend catch-up vaccines where applicable. Vaccination in schools should be considered.
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BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
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Neoplasias Colorretais , DNA Polimerase III , DNA Polimerase II , Inibidores de Checkpoint Imunológico , Mutação , Proteínas de Ligação a Poli-ADP-Ribose , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Masculino , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Idoso , DNA Polimerase II/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , DNA Polimerase III/genética , Adulto , Instabilidade de Microssatélites , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNARESUMO
Boron substitution represents a promising approach to stabilize carbon clathrate structures, but no thermodynamically stable substitution schemes have been identified for frameworks other than the type-VII (sodalite) structure type. To investigate the possibility for additional tetrahedral carbon-based clathrate networks, more than 5000 unique boron decoration schemes were investigated computationally for type-I and type-II carbon clathrates with a range of guest elements including Li, Na, K, Rb, Cs, Mg, Ca, Sr, and Ba. Density functional theory calculations were performed at 10 and 50 GPa, and the stability and impact of boron substitution were evaluated. The results indicate that the boron-substituted carbon clathrates are stabilized under high-pressure conditions. Full cage occupancies of intermediate-sized guest atoms (e.g., Na, Ca, and Sr) are the most favorable energetically. Clathrate stability is maximized when the boron atoms are substituted within the hexagonal rings of the large [51262]/[51264] cages. Several structures with favorable formation enthalpies <-200 meV/atom were predicted, and type-I Ca8B16C30 is on the convex hull at 50 GPa. This structure represents the first thermodynamically stable type-I clathrate identified and suggests that boron-substituted carbon clathrates may represent a large family of diamond-like framework materials with a range of structure types and guest/framework substitutions.
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OBJECTIVES: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains. MATERIALS AND METHODS: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system. RESULTS: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine. CONCLUSION: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients.
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Ear, nose and throat (ENT) or upper respiratory tract infections (URTI) are the most common infections in children and the leading causes of antibiotic prescriptions. In most cases, these infections are due to (or are triggered by) viruses and even when bacterial species are implicated, recovery is usually spontaneous. The first imperative is to refrain from prescribing antibiotics in a large number of URTIs: common cold, most cases of sore throat, laryngitis, congestive otitis, and otitis media with effusion. On the contrary, a decision to treat sore throats with antibiotics is based primarily on the positivity of the Group A Streptococcus (GAS) rapid antigen diagnostic tests. For ear infections, only (a) purulent acute otitis media in children under 2 years of age and (b) complicated or symptomatic forms of purulent acute otitis media (PAOM) in older children should be treated with antibiotics. Amoxicillin is the first-line treatment in the most cases of ambulatory ENT justifying antibiotics. Severe ENT infections (mastoiditis, epiglottitis, retro- and parapharyngeal abscesses, ethmoiditis) are therapeutic emergencies necessitating hospitalization and initial intravenous antibiotic therapy.
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Anti-Infecciosos , Otite Média , Faringite , Infecções Respiratórias , Criança , Humanos , Lactente , Anti-Infecciosos/uso terapêutico , Faringite/diagnóstico , Faringite/tratamento farmacológico , Faringite/complicações , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/tratamento farmacológico , Antibacterianos/uso terapêutico , Otite Média/diagnóstico , Otite Média/tratamento farmacológico , Otite Média/complicaçõesRESUMO
OBJECTIVES: Following various changes in the vaccine strategy in 2013 and the mandatory vaccination in 2018, we aimed to analyze the vaccination status, age, and source of contamination of pertussis and parapertussis cases in outpatient surveillance. PATIENTS AND METHODS: Confirmed pertussis and parapertussis cases were enrolled by 35 pediatricians. RESULTS: From 2014 to 2022, 73 confirmed cases of pertussis (n = 65) and parapertussis (n = 8) were reported. For children below 6 years of age, the number of cases with a 2 + 1 schedule (n = 22) was higher than that of those with a 3 + 1 schedule (n = 7). The age of cases with a 3 + 1 or a 2 + 1 schedule was not significantly different (3.8y ± 1.4 vs 4.2y ± 1.5). The main source of contamination was either adults or adolescents. CONCLUSION: Vaccination status and source of contamination are crucial to study the impact of vaccination recommendations.
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Coqueluche , Adulto , Adolescente , Criança , Humanos , Coqueluche/epidemiologia , Coqueluche/prevenção & controle , Vacina contra Coqueluche , Incidência , Vacinação , França/epidemiologiaRESUMO
BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Instabilidade de Microssatélites , Estudos Prospectivos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/genéticaRESUMO
BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Reparo de Erro de Pareamento de DNA , Estudos Retrospectivos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , ImunoterapiaRESUMO
OBJECTIVE: Female carriers of BRCA1/2 gene mutations are at an increased lifetime risk for breast and ovarian cancers. They are recommended to undergo risk-reducing surgery, including bilateral salpingo-oophorectomy (RR-BSO), upon completion of childbearing. RR-BSO surgery decreases morbidity and mortality but results in early menopause. Menopausal hormone therapy (MHT) is under-utilized despite being shown as safe for carriers. We aim to evaluate the factors associated with decision-making regarding MHT use following RR-BSO in healthy BRCA mutation carriers. METHODS: Female carriers aged <50 years who underwent RR-BSO and were followed in a multidisciplinary clinic completed online multiple-choice and free-text questionnaires. RESULTS: A total of 142 women met the inclusion criteria and filled the questionnaire: 83 were MHT users and 59 were non-users. MHT users underwent RR-BSO earlier than non-users (40.82 ± 3.91 vs. 42.88 ± 4.34; p < 0.0001). MHT usage was positively associated with MHT explanation (odds ratio 4.318, 95% confidence interval [CI] [1.341-13.902], p = 0.014), and knowledge regarding the safety of MHT and its effects on general health (odds ratio 2.001, 95% CI [1.443-2.774], p < 0.0001). MHT users and non-users retrospectively evaluated their comprehension of RR-BSO consequences as significantly lower than before surgery (p < 0.001). CONCLUSION: Post-RR-BSO outcomes, including the effects on women's quality of life and its possible mitigation through MHT use, need to be addressed pre surgery by healthcare providers.
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Neoplasias da Mama , Neoplasias Ovarianas , Médicos , Feminino , Humanos , Menopausa , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Ovariectomia , Qualidade de Vida , Estudos Retrospectivos , Salpingo-Ooforectomia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Nucleares/metabolismoRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with adverse maternal and neonatal outcomes. Early studies suggested that COVID-19 was associated with a higher incidence of hypotension following neuraxial anesthesia in parturients. We explored the hemodynamic response to spinal anesthesia for cesarean delivery in pregnant severe respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) positive patients, using a retrospective case-control design. METHODS: We searched our electronic medical records for patients who received spinal anesthesia for cesarean delivery, and were SARS-CoV-2 positive or recovered at delivery, and used historical and SARS-CoV-2 negative controls from two tertiary care hospitals. We compared the demographic, clinical, and hemodynamic variables between patients who were SARS-CoV-2 positive at delivery, those who were positive during pregnancy and recovered before delivery, and controls. Analyses were stratified by normotensive versus hypertensive status of the patients at delivery. RESULTS: We identified 22 SARS-CoV-2 positive, 73 SARS-CoV-2 recovered, and 1517 controls. The SARS-CoV-2 positive, and recovered pregnant patients, had on average 5.6 and 2.2â¯mmHg, respectively, higher post-spinal mean arterial pressures (MAPs) than control patients, adjusting for covariates. Additionally, the lowest post-spinal MAP was negatively correlated with the number of daysbetween the onset of COVID-19 symptoms and delivery in patients with hypertension (correlation -0.55, 95% CI -0.81 to -0.09). CONCLUSIONS: Patients with SARS-CoV-2 infection during pregnancy exhibit less spinal hypotension than non-infected patients. While the clinical significance of this finding is unknown, it points to important cardiovascular effects of the virus.
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Raquianestesia , COVID-19 , Hipotensão , Complicações Infecciosas na Gravidez , Gravidez , Recém-Nascido , Feminino , Humanos , Estudos Retrospectivos , Estudos de Casos e Controles , SARS-CoV-2 , Raquianestesia/efeitos adversos , Hipotensão/etiologia , Hemodinâmica , Complicações Infecciosas na Gravidez/diagnósticoRESUMO
Helping behaviour is thought to play a major role in the evolution of group-living animals. Yet, it is unclear to what extent human males and human females use the same strategies to secure support. Accordingly, we investigate help-seeking over a 5-year period in relation to gender using data from virtually all adults in two Tamil villages (N = 782). Simulations of network dynamics (i.e. stochastic actor-oriented models) calibrated to these data broadly indicate that women are more inclined than men to create and maintain supportive bonds via multiple mechanisms of cooperation (e.g. reciprocity, kin bias, friend bias, generalized exchange). However, gender-related differences in the simulated dynamics of help-seeking are modest, vary based on structural position (e.g. out-degree), and do not appear to translate to divergence in the observed structure of respondents' egocentric networks. Findings ultimately suggest that men and women in the two villages are similarly social but channel their sociality differently. This article is part of the theme issue 'Cooperation among women: evolutionary and cross-cultural perspectives'.
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Comportamento de Ajuda , Rede Social , Masculino , Adulto , Animais , Humanos , Feminino , Índia , Fatores SexuaisRESUMO
Objectives: Understanding if police malfeasance might be "contagious" is vital to identifying efficacious paths to police reform. Accordingly, we investigate whether an officer's propensity to engage in misconduct is associated with her direct, routine interaction with colleagues who have themselves engaged in misbehavior in the past. Methods: Recognizing the importance of analyzing the actual social networks spanning a police force, we use data on collaborative responses to 1,165,136 "911" calls for service by 3475 Dallas Police Department (DPD) officers across 2013 and 2014 to construct daily networks of front-line interaction. And we relate these cooperative networks to reported and formally sanctioned misconduct on the part of the DPD officers during the same time period using repeated-events survival models. Results: Estimates indicate that the risk of a DPD officer engaging in misconduct is not associated with the disciplined misbehavior of her ad hoc, on-the-scene partners. Rather, a greater risk of misconduct is associated with past misbehavior, officer-specific proneness, the neighborhood context of patrol, and, in some cases, officer race, while departmental tenure is a mitigating factor. Conclusions: Our observational findings-based on data from one large police department in the United States-ultimately suggest that actor-based and ecological explanations of police deviance should not be summarily dismissed in favor of accounts emphasizing negative socialization, where our study design also raises the possibility that results are partly driven by unobserved trait-based variation in the situations that officers find themselves in. All in all, interventions focused on individual officers, including the termination of deviant police, may be fruitful for curtailing police misconduct-where early interventions focused on new offenders may be key to avoiding the escalation of deviance.
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Evolutionary studies of cooperation in traditional human societies suggest that helping family and responding in kind when helped are the primary mechanisms for informally distributing resources vital to day-to-day survival (e.g., food, knowledge, money, childcare). However, these studies generally rely on forms of regression analysis that disregard complex interdependences between aid, resulting in the implicit assumption that kinship and reciprocity drive the emergence of entire networks of supportive social bonds. Here I evaluate this assumption using individual-oriented simulations of network formation (i.e., Stochastic Actor-Oriented Models). Specifically, I test standard predictions of cooperation derived from the evolutionary theories of kin selection and reciprocal altruism alongside well-established sociological predictions around the self-organisation of asymmetric relationships. Simulations are calibrated to exceptional public data on genetic relatedness and the provision of tangible aid amongst all 108 adult residents of a village of indigenous horticulturalists in Nicaragua (11,556 ordered dyads). Results indicate that relatedness and reciprocity are markedly less important to whom one helps compared to the supra-dyadic arrangement of the tangible aid network itself.
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Rede Social , Apoio Social , Adulto , Altruísmo , Evolução Biológica , HumanosRESUMO
Vaccinating children against Covid raised a debate, due to generally mild clinical presentation. The decision to vaccinate teenagers was motivated by the global public health need: to decrease transmission to other age groups. Among adolescents, the efficacy (better immunity than in young adults) and safety of vaccines was clearly demonstrated. Among 5-to-12-year-olds, due to lower contamination the collective benefit is less clear, and when the m-RNA vaccines were available for this age group, the Omicron variant was predominant and their effect on non-severe infections and transmission had yet to be determined. Individual benefit is based both on somatic criteria and on the child's schooling and mental health. Children under 5 years of age received a 3 µg dose of vaccine, which is one tenth of the adult dose, resulting in immunogenicity similar to that of 16-to-25-year-olds.
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COVID-19 , Vacinas , Criança , Adolescente , Adulto Jovem , Humanos , Pré-Escolar , Vacinação , SARS-CoV-2 , COVID-19/prevenção & controleRESUMO
OBJECTIVES: To determine the predictors of a positive SARS-CoV-2 test in a pediatric ambulatory setting. PATIENTS AND METHODS: We performed a cross-sectional prospective study (November 2020-February 2022) of 93 ambulatory settings in France. We included symptomatic children < 15 years old tested for SARS-CoV-2. For each period corresponding to the spread of the original strain and its variants (period 1: original strain; period 2: Alpha, period 3: Delta; period 4: Omicron), we used a multivariate analysis to estimate adjusted odds ratios (aORs) associated with COVID-19 among age, signs, symptoms or contact, and 95 % confidence intervals (95CIs). RESULTS: Of 5,336 children, 13.9 % (95CI 13.0-14.8) had a positive test. During the first three periods, the positivity rate ranged from 5.6 % (95CI 4.6-6.7) to 12.6 % (95CI 10.8-14.6). The main factors associated with a positive test were contact with an infected adult at home or outside the home (aOR 11.5 [95CI 4.9-26.9] to 38.9 [95CI 19.3-78.7]) or an infected household child (aOR 15.0 [95CI 4.8-47.1] to 28.4 [95CI 8.7-92.6]). By contrast, during period 4, aORs for these predictors were substantially lower (2.3 [95CI 1.1-4.5] to 5.5 [95CI 3.2-7.7]), but the positivity rate was 45.7 % (95CI 42.3-49.2). CONCLUSIONS: In pediatric ambulatory settings, before the Omicron period, the main predictor of a positive test was contact with an infected person. During the Omicron period, the odds of these predictors were substantially lower while the positivity rate was higher. An accurate diagnostic strategy should only rely on testing and not on age, signs, symptoms or contact.
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COVID-19 , SARS-CoV-2 , Adulto , Humanos , Criança , Adolescente , COVID-19/diagnóstico , COVID-19/epidemiologia , Estudos Transversais , Estudos ProspectivosRESUMO
OBJECTIVE: Opening of voltage-gated sodium channels is crucial for neuronal depolarization. Proper channel opening and influx of Na+ through the ion pore, is dependent upon binding of Na+ ion to a specific amino-acid motif (DEKA) within the pore. In this study we used molecular dynamic simulations, an advanced bioinformatic tool, to research the dysfunction caused by pathogenic variants in SCN1a, SCN2a and SCN8a genes. METHOD: Molecular dynamic simulations were performed in six patients: three patients with Dravet syndrome (p.Gly177Ala,p.Ser259Arg and p.Met1267Ile, SCN1a), two patients with early onset drug resistant epilepsy(p.Ala263Val, SCN2a and p.Ile251Arg, SCN8a), and a patient with autism (p.Thr155Ala, SCN2a). After predicting the 3D-structure of mutated proteins by homology modeling, time dependent molecular dynamic simulations were performed, using the Schrödinger algorithm. The opening of the sodium channel, including the detachment of the sodium ion to the DEKA motif and pore diameter were assessed. Results were compared to the existent patch clamp analysis in four patients, and consistency with clinical phenotype was noted. RESULTS: The Na+ ion remained attached to DEKA filter longer when compared to wild type in the p.Gly177Ala, p.Ser259Arg,SCN1a, and p.Thr155Ala, SCN2a variants, consistent with loss-of-function. In contrast, it detached quicker from DEKA than wild type in the p.Ala263Val,SCN2a variant, consistent with gain-of-function. In the p.Met1267Ile,SCN1a variant, detachment from DEKA was quicker, but pore diameter decreased, suggesting partial loss-of-function. In the p.Leu251Arg,SCN8a variant, the pore remained opened longer when compared to wild type, consistent with a gain-of-function. The molecular dynamic simulation results were consistent with the existing patch-clamp analysis studies, as well as the clinical phenotype. SIGNIFICANCE: Molecular dynamic simulation can be useful in predicting pathogenicity of variants and the disease phenotype, and selecting targeted treatment based on channel dysfunction. Further development of these bioinformatic tools may lead to "virtual patch-clamp analysis".
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Epilepsias Mioclônicas , Canal de Sódio Disparado por Voltagem NAV1.1 , Epilepsias Mioclônicas/genética , Humanos , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Fenótipo , Sódio/metabolismoRESUMO
Mg2GeO4 is important as an analog for the ultrahigh-pressure behavior of Mg2SiO4, a major component of planetary interiors. In this study, we have investigated magnesium germanate to 275 GPa and over 2,000 K using a laser-heated diamond anvil cell combined with in situ synchrotron X-ray diffraction and density functional theory (DFT) computations. The experimental results are consistent with the formation of a phase with disordered Mg and Ge, in which germanium adopts eightfold coordination with oxygen: the cubic, Th3P4-type structure. DFT computations suggest partial Mg-Ge order, resulting in a tetragonal [Formula: see text] structure indistinguishable from [Formula: see text] Th3P4 in our experiments. If applicable to silicates, the formation of this highly coordinated and intrinsically disordered phase may have important implications for the interior mineralogy of large, rocky extrasolar planets.