RESUMEN
Chemical transformation of 2-methyltetrol sulfates (2-MTS), key isoprene-derived secondary organic aerosol (SOA) constituents, through heterogeneous hydroxyl radical (â¢OH) oxidation can result in the formation of previously unidentified atmospheric organosulfates (OSs). However, detected OSs cannot fully account for the sulfur content released from reacted 2-MTS, indicating the existence of sulfur in forms other than OSs such as inorganic sulfates. This work investigated the formation of inorganic sulfates through heterogeneous â¢OH oxidation of 2-MTS aerosols. Remarkably, high yields of inorganic sulfates, defined as the moles of inorganic sulfates produced per mole of reacted 2-MTS, were observed in the range from 0.48 ± 0.07 to 0.68 ± 0.07. These could be explained by the production of sulfate (SO4 â¢-) and sulfite (SO3 â¢-) radicals through the cleavage of C-O(S) and (C)O-S bonds, followed by aerosol-phase reactions. Additionally, nonsulfated products resulting from bond cleavage were likely volatile and evaporated into the gas phase, as evidenced by the observed aerosol mass loss (≤25%) and concurrent size reduction upon oxidation. This investigation highlights the significant transformation of sulfur from its organic to inorganic forms during the heterogeneous oxidation of 2-MTS aerosols, potentially influencing the physicochemical properties and environmental impacts of isoprene-derived SOAs.
RESUMEN
Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR. Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis. Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups. Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325909.
Asunto(s)
Retardo del Crecimiento Fetal , Inhibidores de Fosfodiesterasa 5 , Humanos , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Retardo del Crecimiento Fetal/tratamiento farmacológico , Embarazo , Femenino , Recién Nacido , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Although health-promotion interventions that recommend changes across multiple behavioral domains are a newer alternative to single-behavior interventions, their general efficacy and their mechanisms of change have not been fully ascertained. This comprehensive meta-analysis (6,878 effect sizes from 803 independent samples from 364 research reports, N = 186,729 participants) examined the association between the number of behavioral recommendations in multiple-behavior interventions and behavioral and clinical change across eight domains (i.e., diet, smoking, exercise, HIV [Human Immunodeficiency Virus] prevention, HIV testing, HIV treatment, alcohol use, and substance use). Results showed a positive, linear effect of the number of behavioral recommendations associated with behavioral and clinical change across all domains, although approximately 87% of the samples included between 0 and 4 behavioral recommendations. This linear relation was mediated by improvements in the psychological well-being of intervention recipients and, in several domains (i.e., HIV, alcohol use, and drug use), suggested behavioral cuing. However, changes in information, motivation, and behavioral skills did not mediate the impact of the number of recommendations on behavioral and clinical change. The implications of these findings for theory and future intervention design are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Conductas Relacionadas con la Salud , Promoción de la Salud , Humanos , Promoción de la Salud/métodos , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Terapia Conductista/métodos , Trastornos Relacionados con Sustancias/psicología , Trastornos Relacionados con Sustancias/terapiaRESUMEN
PURPOSE OF REVIEW: This review aims to discuss recent advancements in the endoscopic management of early esophageal adenocarcinoma (T1 EAC). RECENT FINDINGS: Patients with high-risk EAC (defined by the presence of deep submucosal invasion, and/or lymphovascular invasion, and/or poor differentiation) have a higher risk of lymph node metastases than those with low-risk EAC. However, more recent, endoscopically-focused studies report a lower risk of lymph node metastases and distant metastases for high-risk EAC than previously assumed. Instead of referring all high-risk EAC patients for esophagectomy after a radical endoscopic resection, an alternative approach involving regular upper endoscopy with endoscopic ultrasound may allow for detection of intra-luminal recurrence and lymph node metastases at an early and potentially curable stage. SUMMARY: Endoscopic resection of mucosal and submucosal EAC might prove to be safe and curative for selected cases in the future, when followed by a strict follow-up protocol. Despite the promising results of preliminary studies, there is an ongoing need for personalized strategies and new risk stratification methods to decide on the best management for individual patients with high-risk T1 EAC.
Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Esofagoscopía , Medicina de Precisión , Humanos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/cirugía , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adenocarcinoma/cirugía , Medicina de Precisión/métodos , Esofagoscopía/métodos , Esofagectomía/métodos , Endosonografía , Metástasis Linfática , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.
Asunto(s)
Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Piridonas , Humanos , Adolescente , Infecciones por VIH/tratamiento farmacológico , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Piridonas/farmacocinética , Niño , Oxazinas/administración & dosificación , Oxazinas/uso terapéutico , Preescolar , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Piperazinas/administración & dosificación , Masculino , Femenino , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Carga Viral , Estudios de Equivalencia como Asunto , ARN Viral , Quimioterapia Combinada , Combinación de Medicamentos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/farmacocinéticaRESUMEN
Cluster of differentiation 36 (CD36) is a scavenger receptor (SR), recognizing diverse extracellular ligands in various types of mammalian cells. Long-chain fatty acids (FAs), which are important constituents of phospholipids and triglycerides, also utilize CD36 as a predominant membrane transporter, being incorporated from the circulation across the plasma membrane in several cell types, including cardiac and skeletal myocytes and adipocytes. CD36 is localized in intracellular vesicles as well as the plasma membrane, and its distribution is modulated by extracellular stimuli. Herein, we aimed to clarify the molecular basis of insulin-stimulated translocation of CD36, which leads to the enhanced uptake of long-chain FAs, in adipocytes. To this end, we developed a novel exofacial epitope-tagged reporter to specifically detect cell surface-localized CD36. By employing this reporter, we demonstrate that the small GTPase Rac1 plays a pivotal role in insulin-stimulated translocation of CD36 to the plasma membrane in 3T3-L1 adipocytes. Additionally, phosphoinositide 3-kinase and the protein kinase Akt2 are shown to be involved in the regulation of Rac1. Downstream of Rac1, another small GTPase RalA directs CD36 translocation. Collectively, these results suggest that CD36 is translocated to the plasma membrane by insulin through mechanisms similar to those for the glucose transporter GLUT4 in adipocytes.
Asunto(s)
Insulina , Proteínas de Unión al GTP Monoméricas , Animales , Adipocitos/metabolismo , Antígenos CD36/metabolismo , Membrana Celular/metabolismo , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/farmacología , Insulina/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transporte de Proteínas , Transducción de Señal , RatonesRESUMEN
We proposed a parameter-free volume element representation that satisfies the electron counting model and obtains accurate machine learning potential energy and direct force fitting of randomly perturbed hexagonal BN. Our method preserves permutational, translational, and rotational invariance and can be extended to three-dimensional systems, verified by a system of bulk Si. As a result, we obtained 0.57 meV/atom potential energy root mean squared error (RMSE) and 59 meV/Å force RMSE for perturbed bulk BN systems and 0.43 meV/atom potential energy RMSE and 36 meV/Å force RMSE for perturbed Si systems. In addition, an unbiased perturbation-based data set construction scheme is introduced and a continuous population distribution is obtained with a training data set of 4500, which is about 1 order of magnitude smaller than standard methods based on first-principles molecular dynamics simulations and saves a large amount of computing resources. General validity of our model is verified by structure optimization, molecular dynamics simulations, and extrapolations.
RESUMEN
The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is rising in the West, but little is known in Asia. This study elucidated changes in the incidence and HPV-positive portion of OPSCC in Hong Kong. Data from population-based cancer registry were used to analyze the incidence of OPSCC in association with other head and neck cancers. Archived tumor tissues were tested for HPV. From 1986 to 2020, there was a marked decrease in the incidence of nasopharyngeal and laryngeal cancers, but a persistent increase in OPSCC from 36 cases in 1986 to 116 cases in 2020. The average positive rate for high-risk HPV was 36.1% (112/310) among OPSCC diagnosed in 2010-2020. The HPV-positive rate in recent years was significantly higher than earlier cases (tonsil SCC: 64.7% (55/85) in 2016-2020 vs. 40.4% (19/47) in 2010-2015, p = 0.007). Patients with HPV-positive tonsil cancers were significantly younger than those negative (mean [SD]: 58.9 [9.9] vs. 64.3 [13.3] years, p = 0.006), but no significant difference was observed between genders. A persistent increase in the incidence of oropharyngeal cancer over the last few decades was observed in Hong Kong, which can be explained by the remarkable increase in HPV-positive tonsil cancers.
RESUMEN
Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de la Proteasa del VIH , Adulto , Niño , Humanos , Adolescente , Darunavir/farmacocinética , Ritonavir/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Sulfonamidas/farmacología , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéuticoRESUMEN
Rice is the primary staple food for half of the world's population but is low in lysine content. Previously, we developed transgenic rice with enhanced free lysine content in rice seeds (lysine-rich rice), which was shown safe for consumption and improved the growth in rats. However, the effects of lysine-rich rice on skeletal growth and development remained unknown. In this study, we hypothesized that lysine-rich rice improved skeletal growth and development in weaning rats. Male weaning Sprague-Dawley rats received lysine-rich rice (HFL) diet, wild-type rice (WT) diet, or wild-type rice with various contents of lysine supplementation diet for 70 days. Bone microarchitectures were examined by microcomputed tomography, bone strength was investigated by mechanical test, and dynamics of bone growth were examined by histomorphometric analysis. In addition, we explored the molecular mechanism of lysine and skeletal growth through biochemical testing of growth hormone, bone turnover marker, and amino acid content of rat serum analysis, as well as in a cell culture system. Results indicated that the HFL diet improved rats' bone growth, strength, and microarchitecture compared with the WT diet group. In addition, the HFL diet increased the serum essential amino acids, growth hormone (insulin-like growth factor-1), and bone formation marker concentrations. The cell culture model showed that lysine deficiency reduced insulin-like growth factor-1 and Osterix expression, Akt/mammalian target of rapamycin signaling, and matrix mineralization, and inhibited osteoblast differentiation associated with bone growth. Our findings showed that lysine-rich rice improved skeletal growth and development in weaning rats. A further increase of rice lysine content is highly desirable to fully optimize bone growth and development.
Asunto(s)
Lisina , Oryza , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Oryza/genética , Oryza/metabolismo , Plantas Modificadas Genéticamente/química , Plantas Modificadas Genéticamente/metabolismo , Microtomografía por Rayos X , Peso Corporal , Hormona del Crecimiento/metabolismo , Mamíferos/metabolismoRESUMEN
Organosulfates (OSs), characterized with a sulfate ester group (R-OSO3-), are abundant constituents in secondary organic aerosols. Recent laboratory-based investigations have revealed that OSs can undergo efficient chemical transformation through heterogeneous oxidation by hydroxyl radicals (ËOH, interchangeably termed as OH in this article), which freshly derives functionalized and fragmented OSs. The reaction not only contributes to the presence of structurally transformed OSs in the atmosphere of which sources were unidentified, but it also leads to the formation of inorganic sulfates (e.g., SO42-) with profound implication on the form of aerosol sulfur. In this article, we review the current state of knowledge regarding the heterogeneous OH oxidation of OSs based on state-of-the-art designs of experiments, computational approaches, and chemical analytical techniques. Here, we discuss the formation potential of new OSs and SO42-, in light of the influence of diverse OS structures on the relative importance of different reaction pathways. We propose future research directions to advance our mechanistic understanding of these reactions, taking into account aerosol matrix effects, interactions with other atmospheric pollutants, and the incorporation of experimental findings into atmospheric chemical transport models.
RESUMEN
Organosulfates comprise up to 30% of the organic fraction of aerosol. Organosulfate aerosol physical properties, such as water activity, density, refractive index, and surface tension, are key to predicting their impact on global climate. However, current understanding of these properties is limited. Here, we measure the physical properties of aqueous solutions containing sodium methyl or ethyl sulfate and parameterise the data as a function of solute concentration. The experimental data are compared to available literature data for organosulfates, as well as salts (sodium sulfate and sodium bisulfate) and organics (short alkyl chain length alcohols and carboxylic acids) to determine if the physical properties of organosulfates can be approximated by molecules of similar functionality. With the exception of water activity, we find that organosulfates have intermediate physical properties between those of the salts and short alkyl chain organics. This work highlights the importance of measuring and developing models for the physical properties of abundant atmospheric organosulfates in order to better describe aerosol's impact on climate.
RESUMEN
BACKGROUND: Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI. METHODS: In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated. RESULTS: Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4-0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1-1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT. CONCLUSIONS: In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017.
Asunto(s)
Lesión Renal Aguda , Enfermedad Crítica , Humanos , Lesión Renal Aguda/terapia , Enfermedad Crítica/terapia , Enfermedad Crítica/epidemiología , Hospitalización , Unidades de Cuidados Intensivos , Tiempo de Internación , Terapia de Reemplazo RenalRESUMEN
Diabetes Mellitus (DM) is a chronic disease characterized by abnormally uncontrolled high blood glucose level. The Risk Assessment and Management Program (RAMP) in Hong Kong has been providing long-term face-to-face follow-up to DM patients in the government out-patient clinics since 2009. However, under the current outbreak of COVID-19, these face-to-face consultations were ceased over and over again to lower the risk of disease transmission. With the advancement in technology, the recent emergence of telecare has provided an alternative to replace the conventional consultations in the clinics. Its clinical effectiveness on DM patients has also been supported by numerous studies. Yet, there is only a paucity of literatures discussing the practicality of such implementation design in the real-world settings. This study aims at studying both the effectiveness and implementation outcomes of telecare in Hong Kong DM patients. It adopts a type 2 hybrid effectiveness-implementation design. It will be conducted in seven government out-patient clinics in Hong Kong. The subjects will be randomly assigned to an intervention group or a control group when they 1) are aged 18 or above, 2) have a confirmed diagnosis of diabetes, and 3) are having regular follow-up appointment in the clinic. Subjects in the intervention group will receive a 84-week Risk Assessment and Management Program (RAMP) in an alternate telecare and face-to-face consultations mode, while the control group will receive the same program but in usual face-to-face consultation mode. RE-AIM is employed as the implementation and effectiveness outcome evaluation framework. The primary outcome measure will be HbA1c. Data will be collected pre-intervention (T1), 42-week (T2), and 84-week (T3). The study will provide effectiveness-implementation assessment of telecare mode for DM patients in Hong Kong, as an alternative or in addition to conventional face-to-face consultations. It also aimed to provide insights for the future adoption in a broader health care setting.
Asunto(s)
COVID-19 , Diabetes Mellitus , Humanos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Pacientes Ambulatorios , Atención Primaria de Salud , Medición de Riesgo , Adolescente , Adulto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: In a non-inferiority trial, the choice of margin depends on the expected control event risk. If the true risk differs from expected, power and interpretability of results can be affected. A non-inferiority frontier pre-specifies an appropriate non-inferiority margin for each value of control event risk. D3 is a non-inferiority trial comparing two treatment regimens in children living with HIV, designed assuming a control event risk of 12%, a non-inferiority margin of 10%, 80% power and a significance level (α) of 0.025. We consider approaches to choosing and implementing a frontier for this already funded trial, where changing the sample size substantially would be difficult. METHODS: In D3, we fix the non-inferiority margin at 10%, 8% and 5% for control event risks of ≥9%, 5% and 1%, respectively. We propose four frontiers which fit these fixed points, including a Smooth Away From Expected (SAFE) frontier. Analysis approaches considered are as follows: using the pre-specified significance level (α=0.025); always using a reduced significance level (to achieve α≤0.025 across control event risks); reducing significance levels only when the control event risk differs significantly from expected (control event risk <9%); and using a likelihood ratio test. We compare power and type 1 error for SAFE with other frontiers. RESULTS: Changing the significance level only when the control event risk is <9% achieves approximately nominal (<3%) type I error rate and maintains reasonable power for control event risks between 1 and 15%. The likelihood ratio test method performs similarly, but the results are more complex to present. Other analysis methods lead to either inflated type 1 error or badly reduced power. The SAFE frontier gives more interpretable results with low control event risks than other frontiers (i.e. it uses more reasonable non-inferiority margins). Other frontiers do not achieve power close (i.e. within 1%) to SAFE across the range of likely control event risks while controlling type I error. CONCLUSIONS: The SAFE non-inferiority frontier will be used in D3, and the non-inferiority margin and significance level will be modified if the control event risk is lower than expected. This ensures results will remain interpretable if design assumptions are incorrect, while achieving similar power. A similar approach could be considered for other non-inferiority trials where the control event risk is uncertain.
Asunto(s)
Conductas Relacionadas con la Salud , Insuflación , Niño , Humanos , Tamaño de la Muestra , IncertidumbreRESUMEN
BACKGROUND: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. METHODS: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). RESULTS: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. CONCLUSIONS: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.
RESUMEN
PURPOSE: Chronic diseases are notorious in the way that they interfere with many aspects of a child's development, and this holds true for children with Hirschsprung disease (HD). The present research aims to (1) determine whether the health-related quality of life (HRQoL) of HD children differs from healthy paediatric populations; and (2) explore the relationship between HD children's HRQoL and psychosocial outcomes of parents. METHODS: Using a cross-sectional survey study design, children's HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL), while parental psychosocial outcomes were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression short-forms, Family Management Measure (FaMM), and Parent Experience of Child Illness. Surveys were administered over telephone to parents of 48 Australian children treated for HD (87.5% male, median age 4.5 years) during the period May to November 2021. RESULTS: While postoperative HRQoL of HD children was comparable to that of healthy age-matched controls, psychosocial quality of life of HD children was significantly poorer (mean difference = 3.40, CI [0.05, 6.76]). All parental outcome measures were significantly correlated with the PedsQL (r = - 0.77-0.67, p < 0.05) in expected directions, with FaMM subscales (except parent mutuality) demonstrating the most variation (R2 = 0.41-0.59). Of note, 31.3% of parents reported moderate to severe symptoms of anxiety on the PROMIS. CONCLUSION: Despite overall positive results for children, parents reported elevated symptoms of anxiety. This study highlights the importance of long-term follow-up care for HD patients and their families.
Asunto(s)
Enfermedad de Hirschsprung , Calidad de Vida , Niño , Humanos , Masculino , Preescolar , Femenino , Calidad de Vida/psicología , Estudios Transversales , Australia , Encuestas y Cuestionarios , Padres/psicología , Melanoma Cutáneo MalignoRESUMEN
OBJECTIVE: Disadvantaged populations, including inhabitants of developing countries as well as racial/ethnic and sexual minorities in the United States, are disproportionally burdened by human immunodeficiency virus (HIV) infection, delayed HIV diagnosis, and unfavorable HIV-treatment outcomes. HIV interventions targeting single behaviors (e.g., testing) in these populations have shown to be efficacious at producing behavioral and clinical change but have been unable to eliminate the social health disparities associated with syndemics (i.e., a set of connected risks, interacting synergistically, and contributing to excess burden of disease in a population). METHOD: This meta-analysis of 331 reports (clusters; number of effect sizes [k] = 1,364) assessed whether multiple-behavior interventions that target clusters of syndemic risks are more efficacious for those in disadvantaged regions and social groups. RESULTS: Across the board, multiple-behavior interventions were more efficacious than single-behavior ones as well as passive control groups among samples from countries with lower log gross domestic product (GDP), lower Human Development Index (HDI), and lower Healthcare Access and Quality (HAQ) Index. CONCLUSIONS: Within the United States, the efficacy of multiple-behavior interventions was similar across different levels of representation of racial/ethnic and sexual minorities. The analyses used robust variance estimation with small-sample corrections to assess the differential effects of multiple-behavior interventions and Egger Sandwich test with the multilevel meta-analysis approach to detect selection biases. (PsycInfo Database Record (c) 2023 APA, all rights reserved).