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Flows through pipes and channels are, in practice, almost always turbulent, and the multiscale eddying motion is responsible for a major part of the encountered friction losses and pumping costs1. Conversely, for pulsatile flows, in particular for aortic blood flow, turbulence levels remain low despite relatively large peak velocities. For aortic blood flow, high turbulence levels are intolerable as they would damage the shear-sensitive endothelial cell layer2-5. Here we show that turbulence in ordinary pipe flow is diminished if the flow is driven in a pulsatile mode that incorporates all the key features of the cardiac waveform. At Reynolds numbers comparable to those of aortic blood flow, turbulence is largely inhibited, whereas at much higher speeds, the turbulent drag is reduced by more than 25%. This specific operation mode is more efficient when compared with steady driving, which is the present situation for virtually all fluid transport processes ranging from heating circuits to water, gas and oil pipelines.
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BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Anticolesterolemiantes , Aterosclerose , Hipercolesterolemia , Lipoproteína(a) , RNA Interferente Pequeno , Humanos , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Método Duplo-Cego , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipoproteína(a)/análise , Lipoproteína(a)/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Inibidores de PCSK9/uso terapêutico , Ezetimiba/uso terapêuticoRESUMO
BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.
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Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , LDL-Colesterol , Homozigoto , Hiperlipoproteinemia Tipo II , Inibidores de PCSK9 , Adolescente , Criança , Feminino , Humanos , Masculino , Fatores Etários , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , LDL-Colesterol/sangue , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Ezetimiba/efeitos adversos , Predisposição Genética para Doença , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Fenótipo , Pró-Proteína Convertase 9/genética , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Estudos Clínicos como AssuntoRESUMO
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.
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Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Pró-Proteína Convertase 9 , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol , Inibidores de PCSK9 , Doenças Cardiovasculares/tratamento farmacológico , Resultado do Tratamento , Aterosclerose/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
We describe 5 children who had Rocky Mountain spotted fever (RMSF) and manifested clinical symptoms similar to multisystem inflammatory syndrome in Sonora, Mexico, where RMSF is hyperendemic. Physicians should consider RMSF in differential diagnoses of hospitalized patients with multisystem inflammatory syndrome to prevent illness and death caused by rickettsial disease.
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Febre Maculosa das Montanhas Rochosas , Síndrome de Resposta Inflamatória Sistêmica , Humanos , México , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Criança , Masculino , Febre Maculosa das Montanhas Rochosas/diagnóstico , Feminino , Diagnóstico Diferencial , Pré-Escolar , Adolescente , HospitalizaçãoRESUMO
BACKGROUND AND AIMS: The prevalence of inflammatory bowel disease (IBD) among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-TNF immunogenicity (HLA-DQA1*05) in a cohort of Hispanic patients of diverse ancestral backgrounds. METHODS: We performed a multicenter, retrospective cohort study comprised of 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1*05, their ancestral origin (European, African, or Amerindian), and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, respectively, in exposed patients. RESULTS: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15 which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15*4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1*05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1*05 in the European allele subset. CONCLUSION: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1*05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with IBD.
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PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly used to image prostate cancer in clinical practice. We sought to develop and test a humanised PSMA minibody IAB2M conjugated to the fluorophore IRDye 800CW-NHS ester in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) to image prostate cancer cells during surgery. METHODS: The minibody was evaluated pre-clinically using PSMA positive/negative xenograft models, following which 23 men undergoing RARP between 2018 and 2020 received between 2.5 mg and 20 mg of IR800-IAB2M intravenously, at intervals between 24 h and 17 days prior to surgery. At every step of the procedure, the prostate, pelvic lymph node chains and extra-prostatic surrounding tissue were imaged with a dual Near-infrared (NIR) and white light optical platform for fluorescence in vivo and ex vivo. Histopathological evaluation of intraoperative and postoperative microscopic fluorescence imaging was undertaken for verification. RESULTS: Twenty-three patients were evaluated to optimise both the dose of the reagent and the interval between injection and surgery and secure the best possible specificity of fluorescence images. Six cases are presented in detail as exemplars. Overall sensitivity and specificity in detecting non-lymph-node extra-prostatic cancer tissue were 100% and 65%, and 64% and 64% respectively for lymph node positivity. There were no side-effects associated with administration of the reagent. CONCLUSION: Intraoperative imaging of prostate cancer tissue is feasible and safe using IR800-IAB2M. Further evaluation is underway to assess the benefit of using the technique in improving completion of surgical excision during RARP. REGISTRATION: ISCRCTN10046036: https://www.isrctn.com/ISRCTN10046036 .
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Antígenos de Superfície , Glutamato Carboxipeptidase II , Imagem Óptica , Prostatectomia , Neoplasias da Próstata , Masculino , Humanos , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/diagnóstico por imagem , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Imagem Óptica/métodos , Período Intraoperatório , Pessoa de Meia-Idade , Animais , Idoso , Cirurgia Assistida por Computador/métodos , CamundongosRESUMO
Recent years have witnessed an increasing interest in the synthesis and study of BODIPY-glycoconjugates. Most of the described synthetic methods toward these derivatives involve postfunctional modifications of the BODIPY core followed by the covalent attachment of the fluorophore and the carbohydrate through a "connector". Conversely, few de novo synthetic approaches to linker-free carbohydrate-BODIPY hybrids have been described. We have developed a reliable modular, de novo, synthetic strategy to linker-free BODIPY-sugar derivatives using the condensation of pyrrole C-glycosides with a pyrrole-carbaldehyde derivative mediated by POCl3. This methodology allows labeling of carbohydrate biomolecules with fluorescent-enough BODIPYs within the biological window, stable in aqueous media, and able to display singlet oxygen generation.
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Compostos de Boro , Glicosídeos , PirróisRESUMO
Purse-seine fishers using drifting fish aggregating devices (dFADs), mainly built with bamboo, plastic buoys, and plastic netting, to aggregate and catch tropical tuna, deploy 46,000-65,000 dFADs per year in the Pacific Ocean. Some of the major concerns associated with this widespread fishing device are potential entanglement of sea turtles and other marine fauna in dFAD netting; marine debris and pollution; and potential ecological damage via stranding on coral reefs, beaches, and other essential habitats for marine fauna. To assess and quantify the potential connectivity (number of dFADs deployed in an area and arriving in another area) between dFAD deployment areas and important oceanic or coastal habitat of critically endangered leatherback (Dermochelys coriacea) and hawksbill (Eretmochelys imbricata) sea turtles in the Pacific Ocean, we conducted passive-drift Lagrangian experiments with simulated dFAD drift profiles and compared them with known important sea turtle areas. Up to 60% of dFADs from equatorial areas were arriving in essential sea turtle habitats. Connectivity was less when only areas where dFADs are currently deployed were used. Our simulations identified potential regions of dFAD interactions with migration and feeding habitats of the east Pacific leatherback turtle in the tropical southeastern Pacific Ocean; coastal habitats of leatherback and hawksbill in the western Pacific (e.g., archipelagic zones of Indonesia, Papua New Guinea, and Solomon Islands); and foraging habitat of leatherback in a large equatorial area south of Hawaii. Additional research is needed to estimate entanglements of sea turtles with dFADs at sea and to quantify the likely changes in connectivity and distribution of dFADs under new management measures, such as use of alternative nonentangling dFAD designs that biodegrade, or changes in deployment strategies, such as shifting locations.
Simulación de las trayectorias de dispositivos de concentración de peces a la deriva para identificar las interacciones potenciales con las tortugas marinas en peligro de extinción Resumen Los pescadores que usan redes de cerco con dispositivos de concentración de peces a la deriva (dFADs), hechos principalmente con bambú, boyas de plástico y redes de plástico, para concentrar y capturar atún, instalan entre 46,000 y 65,000 dFADs al año en el Océano Pacífico. Algunas de las problemáticas principales asociadas con este dispositivo de pesca de uso extenso son el enredamiento potencial de tortugas marinas y otras especies marinas en las redes de los dFADs; los desechos marinos y la contaminación; y el potencial daño ecológico por el varamiento en los arrecifes de coral, playas y otros hábitats esenciales para la fauna marina. Realizamos experimentos lagrangianos de deriva pasiva con la simulación de perfiles de deriva de los dFADs y los comparamos con áreas conocidas de importancia para las tortugas marinas. Esto fue con el objetivo de evaluar y cuantificar la conectividad potencial (número de dFADs instalados en un área que llegan a otra área) entre las áreas de instalación de dFADs y los hábitats oceánicos o costeros importantes para la tortuga laúd (Dermochelys coriacea) y la tortuga de carey (Eretmochelys imbricata), ambas en peligro crítico de extinción, en el Océano Pacífico. Hasta el 60% de los dFADs de las áreas ecuatoriales llegaron a los hábitats esenciales para las tortugas marinas. La conectividad fue menor sólo cuando se usaron áreas en donde actualmente hay dFADs instalados. Nuestras simulaciones identificaron regiones potenciales de interacción entre los dFADs y los hábitats de migración y alimentación de la tortuga laúd en el sureste tropical del Océano Pacífico; los hábitats costeros de ambas especies en el Pacífico occidental (p. ej.: zonas de archipiélagos en Indonesia, Papúa Nueva Guinea y en las Islas Salomón); y en el hábitat de forrajeo de la tortuga laúd en una gran área ecuatorial al sur de Hawái. Se requiere de mayor investigación para estimar el enredamiento de las tortugas marinas con los dFADs en el mar y para cuantificar los cambios probables en la conectividad y la distribución de los dFADs bajo nuevas medidas de manejo, como el uso alternativo de diseños que eviten el enredamiento y sean biodegradables, o cambios en las estrategias de instalación, como la reubicación.
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OBJECTIVE: Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non-invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. METHODS: This was a cross-sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6-38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end-tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7-8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence-weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel-wise PlVR values across the placenta. RESULTS: PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non-linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. CONCLUSIONS: We present, for the first time, a non-invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Placenta , Complicações na Gravidez , Gravidez , Feminino , Humanos , Lactente , Placenta/irrigação sanguínea , Estudos Transversais , Dióxido de Carbono , Imageamento por Ressonância Magnética/métodos , OxigênioRESUMO
BACKGROUND AND OBJECTIVE: Sensitization to Blomia tropicalis is associated with asthma in various tropical and subtropical countries; however, information about the specific molecular components associated with this disease is scarce. Using molecular diagnosis, we sought to identify B tropicalis allergens associated with asthma in Colombia. METHODS: Specific IgE (sIgE) to 8 B tropicalis recombinant allergens (Blo t 2, 5, 7, 8, 10, 12, 13, and 21) was determined using an in-house ELISA system in asthma patients (n=272) and controls (n=298) recruited in a national prevalence study performed in several Colombian cities (Barranquilla, Bogotá, Medellín, Cali, and San Andrés). The study sample included children and adults (mean [SD] age, 28 [17] years). Cross-reactivity between Blo t 5 and Blo t 21 was evaluated using ELISA-inhibition. RESULTS: Specific IgE (sIgE) to 8 B tropicalis recombinant allergens (Blo t 2, 5, 7, 8, 10, 12, 13, and 21) was determined using an in-house ELISA system in asthma patients (n=272) and controls (n=298) recruited in a national prevalence study performed in several Colombian cities (Barranquilla, Bogotá, Medellín, Cali, and San Andrés). The study sample included children and adults (mean [SD] age, 28 [17] years). Cross-reactivity between Blo t 5 and Blo t 21 was evaluated using ELISA-inhibition. CONCLUSION: Although Blo t 5 and Blo t 21 are considered common sensitizers, this is the first report of their association with asthma. Both components should be included in molecular panels for diagnosis of allergy in the tropics.
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Alérgenos , Asma , Imunoglobulina E , Humanos , Asma/imunologia , Asma/diagnóstico , Asma/epidemiologia , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Adulto , Masculino , Feminino , Estudos de Casos e Controles , Criança , Adolescente , Colômbia/epidemiologia , Alérgenos/imunologia , Adulto Jovem , Pessoa de Meia-Idade , Antígenos de Plantas/imunologia , Reações Cruzadas , Clima Tropical , Prevalência , Pré-EscolarRESUMO
Asthma is one of the most common chronic diseases and is estimated to be severe in 3%-10% of affected patients. There is a need for additional biologic treatments that are highly efficacious across the spectrum of severe uncontrolled asthma. Currently available drugs inhibit 1 or 2 specific cytokines or IgE antibodies and thus only partially suppress the complex type 2 (T2) inflammatory cascade. Biologics targeting more upstream molecules in the pathophysiological pathway of asthma could treat asthma more effectively. Tezepelumab is a human monoclonal immunoglobulin G2λ antibody that targets the cytokine thymic stromal lymphopoietin (TSLP). It is the first marketed biologic against an epithelial cell-derived cytokine, preventing binding of TSLP to its receptor and reducing the immune stimuli that TSLP can trigger in different asthma endotypes. Tezepelumab reduces downstream biomarkers of inflammation, such as blood and airway eosinophils, FeNO, IgE, IL-5, and IL-13. Tezepelumab provides a clinical benefit in severe asthma, reducing the annualized asthma exacerbation rate in patients with either high or low levels of biomarkers of T2 inflammation, although the effect is greater among those with high levels. The drug has been shown to improve asthma control, quality of life, and lung function and reduce airway hyperresponsiveness. Therefore, tezepelumab can be used across the spectrum of patients with severe uncontrolled asthma, especially in T2-high patients. This review includes a positioning statement by the authors, all of whom are members of the SEAIC Asthma Committee.
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Anticorpos Monoclonais Humanizados , Asma , Qualidade de Vida , Humanos , Citocinas/metabolismo , Linfopoietina do Estroma do Timo , Inflamação , Biomarcadores , Imunoglobulina ERESUMO
Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3ß/ß-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3ß. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.
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Proteínas de Ciclo Celular/metabolismo , Neocórtex/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose/fisiologia , Carcinogênese/metabolismo , Células Cultivadas , Citocinese/fisiologia , Homozigoto , Humanos , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , FenótipoRESUMO
BACKGROUND: Precise preoperative localization of liver tumors facilitates successful surgical procedures, Intraoperative ultrasonography is a sensitive imaging modality. However, the presence of small non-palpable isoechoic intraparenchymal lesions may be challenging intraoperatively. METHODOLOGY AND MATERIAL DESCRIPTION: Onyx® is a non-adhesive liquid agent comprised of ethylene-vinyl alcohol usually used dissolved in dimethyl-sulfoxide and suspended micronized tantalum powder to provide contrast for visualization under fluoroscopy and ultrasonography and a macroscopic black shape. This embolization material has been increasingly used for the embolization of intracranial arteriovenous malformations. We present the novel application of Onyx® on liver surgery. CURRENT STATUS: We present the case of a female, 55 years-old, whose medical history revealed an elective sigmoidectomy (pT3N1a). After 17 months of follow up, by PET-CT scan, the patient was diagnosed of a small intraparenchymal hypo-attenuated 13 mm tumor located at segment V consistent with metachronous colorectal liver metastasis. Open metastasectomy was performed, ultrasonography-guided Onyx® infusion was delivered the day after, intraoperative ultrasonography showed a palpable hyperechoic material with a posterior acoustic shadowing artifact around the lesion. Onyx® is a promising new tool, without any previous application on liver surgery, feasible with advantages in small not palpable intraparenchymal liver lesions.
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Embolização Terapêutica , Neoplasias Hepáticas , Feminino , Humanos , Pessoa de Meia-Idade , Embolização Terapêutica/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Polivinil/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Resultado do TratamentoRESUMO
The global demand for valuable metals and minerals necessitates the exploration of alternative, sustainable approaches to mineral recovery. Seawater mining has emerged as a promising option, offering a vast reserve of minerals and an environmentally friendly alternative to land-based mining. Among the various techniques, Nanofiltration (NF) has gained significant attention as a preliminary treatment step in Minimum Liquid Discharge (MLD) and Zero Liquid Discharge (ZLD) schemes. This study focused on the potential of two underexplored commercial polyamide based NF membranes, Synder NFX and Vontron VNF1, with enhanced divalent over monovalent separation factors, in optimizing the extraction of magnesium hydroxide (Mg(OH)2) from seawater and seawater reverse osmosis (SWRO) brines. The research encompassed a thorough characterization of the membranes utilizing advanced physic-chemical analytical techniques, followed by rigorous experimental assessments using synthetic seawater and SWRO brine in concentration configuration. The findings highlighted the superior selectivity of NFX for magnesium recovery from SWRO brine and the promising concentration factors of VNF1 for seawater treatment. Cross-validation of experimental data with a mathematical model demonstrated the model's reliability as a process design tool in predicting membrane performance. A comprehensive techno-economic evaluation demonstrates the potential of NFX, operating optimally at 23 bar pressure and 70% permeate recovery rate, to yield an estimated annual revenue of 5.683 M/yr through Mg(OH)2 production from SWRO brine for a plant with a nominal capacity of 0.8 Mm3/y. This research shed light on the promising role of NF membranes in enhancing mineral recovery taking benefit of their separation factors and emphasizes the economic viability of leveraging NF technology for maximizing magnesium recovery from seawater and SWRO brines.
Assuntos
Filtração , Magnésio , Água do Mar , Água do Mar/química , Magnésio/química , Filtração/métodos , Membranas Artificiais , Osmose , SaisRESUMO
The aim of the study was to compare the relative gene expression of Haemonchus contortus P-glycoprotein genes (Hco-pgp) between fourth (L4), infective (L3), and transitory infective (xL3) larval stages as laboratory models to study ivermectin (IVM) resistance. The H. contortus resistant to IVM (IVMr) and susceptible to IVM (IVMs) strains were used to develop xL3in vitro culture and to infect Meriones unguiculatus (gerbils) to collect L4 stages. Morphometric differences were evaluated from 25 individuals of H. contortus from each strain. Relative gene expression from xL3 and L4 was determined between comparison of IVMr stages and from IVMr vs IVMs stages. Seven Hco-pgp genes (1, 2, 3, 4, 9, 10, and 16) were analysed by RT-qPCR using L3 stage as control group, per strain, and GAPDH and ß-tubulin as constitutive genes. Morphological changes were confirmed between xL3 and L4 developing oral shape, oesophagus, and intestinal tube. In addition, the body length and width showed statistical differences (p < 0.05). The Hco-pgp1, 2, 3, and 4 genes (p < 0.05) were upregulated from 7.1- to 463.82-fold changes between IVMr stages, and Hco-pgp9 (13.12-fold) and Hco-pgp10 (13.56-fold) genes showed differences between L4 and xL3, respectively. The comparative study between IVMr vs IVMs strains associated to xL3 and L4 displayed significant upregulation for most of the Hco-pgp genes among 4.89-188.71 fold-change. In conclusion, these results suggest the use of H. contortus xL3 and L4 as suitable laboratory models to study IVMr associated with Hco-pgp genes to contribute to the understanding of anthelmintic resistance.
Assuntos
Anti-Helmínticos , Hemoncose , Haemonchus , Humanos , Animais , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Gerbillinae , Haemonchus/genética , Larva/genética , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Resistência a Medicamentos/genética , Hemoncose/veterinária , Hemoncose/tratamento farmacológicoRESUMO
BACKGROUND: Traditional protocols for implant surgery suggest a healing period of 2-3 months from dental extraction to implant placement. Based on all the volumetric modifications produced by that approach, there are authors who advocate for immediate implantology. The aim of the present study was to determine the prevalence of different sockets, and the dimensions of the bone around the upper anterior incisors and canines, to determine the predictability of immediate implants in our population. MATERIAL AND METHODS: This is an observational, cross-sectional study based on cone-beam computed tomography images of the anterior maxila of patients attending the Odontological Hospital of the University of Barcelona (OHUB) and requesting for implant treatment. Different measurements were performed on every analyzed tooth, and also they were categorized by using the main dental sockets classifications. RESULTS: Bone attachment levels and cortical thickness are lower in women compared to men in all three types of teeth (the difference in the bone attachment levels ranges from 4.68%-8.63% and in the bone thickness goes from 0.02-0.58mm). Bone attachment level gradually reduces with age. The reductions observed in all the measurements are higher in the case of canines, compared with the other teeth. The differences from patients <45 years old and patients between 55-64 years old are 13.58±14.55mm in the case of central incisors, 10.04±5.52 in the case of lateral incisors and 22.39±13.65mm in the case of canines. CONCLUSIONS: According to our results, the canines are the teeth with the greatest complexity when it comes to immediate implantology treatments. Furthermore, that kind of treatment is more complex as age increases, since we observed a gradual percentage of unfavourable sockets in older patients.
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Alvéolo Dental , Humanos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Alvéolo Dental/cirurgia , Adulto , Idoso , Adulto Jovem , Carga Imediata em Implante Dentário , Tomografia Computadorizada de Feixe CônicoRESUMO
BACKGROUND: Oral lichen planus (OLP) is an inmuno-mediated mucocutaneous chronical inflammatory disease. Multiple predisposing factors are considered, such as autoimmune response, microorganisms, medications, dental materials, psychological stress, genetic predisposition or nutritional deficiencies. The deficiency of vitamin D has been related to various autoimmune diseases like OLP. MATERIAL AND METHODS: The electronic search was conducted in the MEDLINE (Pubmed), Scopus, Cochrane Library and Web of Science databases. To assess any potential risk of bias, the authors critically appraised each study by the Newcastle-Ottawa Scale for cohort and case-control studies. Pooled analyses were performed using a random-effects model. Heterogeneity of the studies was assessed by the I2 statistics. Forest Plots were performed to graphically represent the difference between vitamin D concentrations in the OLP compared to healthy group, with a 95% confidence interval. RESULTS: After applying our inclusion and exclusion criteria, 7 articles were included in our review. The median concentration vitamin D in ng/ml found in serum for patients with OLP was of 26,6311,75ng/ml and for healthy patients was of 31,438,7ng/ml. Regarding the quantitative analysis, 7 studies were included. The difference in the concentration of vitamin D in healthy patients and patients with OLP statistically significant (Weighted Mean Difference (WMD): -6.20, 95% CI: -11.24 to -1.15, p=0.02 and I2 heterogeneity: 94%, p<0.00001). CONCLUSIONS: The patients with OLP have statistically lower vitamin D levels than healthy patients.
Assuntos
Líquen Plano Bucal , Vitamina D , Humanos , Vitamina D/sangue , Líquen Plano Bucal/sangue , Deficiência de Vitamina D/complicaçõesRESUMO
BACKGROUND: Oral cancer is a common neoplasm worldwide, mostly corresponding to squamous cell carcinoma (OSCC). Unfortunately, its overall prognosis remains poor, with no improvement in recent decades. In this study, we have analysed the epidemiological, clinical, and prognostic characteristics of OSCC on patients of a specific Spanish region (Galicia), in order to improve its prognosis and apply effective preventive and early diagnosis measures. MATERIAL AND METHODS: We retrospectively analysed 243 cases of OSCC, diagnosed and treated in a single hospital centre in Galicia between 2010 and 2015 (minimum of 5 years of evolution). Overall and specific survival were calculated (Kaplan-Meier) and associated variables were identified (log rank test and Cox regression). RESULTS: The mean age of the patients was 67 years, with the majority being male (69.5%), smokers (45.9%) and alcohol consumers (58.6%), who lived in non-urban areas (79.4%). Cases diagnosed at advanced stages entailed the 48.1% of the sample, and 38.7% of cases relapsed. The 5-year overall and disease-specific survival rates were 39.9% and 46.1%, respectively. Patients who consumed tobacco and alcohol had a worse prognosis. OSCC cases referred to hospital by specialist dentists had a better prognosis, as those who were previously diagnosed with an oral potentially malignant oral disorder (OPMD) or received dental care during OSCC treatment. CONCLUSIONS: In view of these findings, we conclude that OSCC in Galicia (Spain) still has a very poor overall prognosis, which is mainly related to the advanced age of the patients and the late diagnosis. Our study highlights the better survival of OSCC in relation to the referring health professional, the presence of a previous OPMD and the dental care after diagnosis. This demonstrates the importance of dentistry as a health profession involved in the early diagnosis and multidisciplinary management of this malignant neoplasm.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Masculino , Idoso , Feminino , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/terapia , Estudos Retrospectivos , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/terapia , Seguimentos , Espanha/epidemiologiaRESUMO
Monocytes and neutrophils play key roles in the cytokine storm triggered by SARS-CoV-2 infection, which changes their conformation and function. These changes are detectable at the cellular and molecular level and may be different to what is observed in other respiratory infections. Here, we applied machine learning (ML) to develop and validate an algorithm to diagnose COVID-19 using blood parameters. In this retrospective single-center study, 49 hemogram parameters from 12,321 patients with clinical suspicion of COVID-19 and tested by RT-PCR (4239 positive and 8082 negative) were analysed. The dataset was randomly divided into training and validation sets. Blood cell parameters and patient age were used to construct the predictive model with the support vector machine (SVM) tool. The model constructed from the training set (5936 patients) achieved an accuracy for diagnosis of SARS-CoV-2 infection of 0.952 (95% CI: 0.875-0.892). Test sensitivity and specificity was 0.868 and 0.899, respectively, with a positive (PPV) and negative (NPV) predictive value of 0.896 and 0.872, respectively (prevalence 0.50). The validation set model (4964 patients) achieved an accuracy of 0.894 (95% CI: 0.883-0.903). Test sensitivity and specificity was 0.8922 and 0.8951, respectively, with a positive (PPV) and negative (NPV) predictive value of 0.817 and 0.94, respectively (prevalence 0.34). The area under the receiver operating characteristic curve was 0.952 for the algorithm performance. This algorithm may allow to rule out COVID-19 diagnosis with 94% of probability. This represents a great advance for early diagnostic orientation and guiding clinical decisions.