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BACKGROUND: Following the initial acute phase of COVID-19, health care resource use has escalated among individuals with SARS-CoV-2 infection. OBJECTIVE: This study aimed to compare new diagnoses of long COVID and the demand for health services in the general population after the Omicron wave with those observed during the pre-Omicron waves, using similar assessment protocols for both periods and to analyze the influence of vaccination. METHODS: This matched retrospective case-control study included patients of both sexes diagnosed with acute SARS-CoV-2 infection using reverse transcription polymerase chain reaction or antigen tests in the hospital microbiology laboratory during the pandemic period regardless of whether the patients were hospitalized. We included patients of all ages from 2 health care departments that cover 604,000 subjects. The population was stratified into 2 groups, youths (<18 years) and adults (≥18 years). Patients were followed-up for 6 months after SARS-CoV-2 infection. Previous vaccination, new diagnoses, and the use of health care resources were recorded. Patients were compared with controls selected using a prospective score matched for age, sex, and the Charlson index. RESULTS: A total of 41,577 patients with a history of prior COVID-19 infection were included, alongside an equivalent number of controls. This cohort encompassed 33,249 (80%) adults aged ≥18 years and 8328 (20%) youths aged <18 years. Our analysis identified 40 new diagnoses during the observation period. The incidence rate per 100 patients over a 6-month period was 27.2 for vaccinated and 25.1 for unvaccinated adults (P=.09), while among youths, the corresponding rates were 25.7 for vaccinated and 36.7 for unvaccinated individuals (P<.001). Overall, the incidence of new diagnoses was notably higher in patients compared to matched controls. Additionally, vaccinated patients exhibited a reduced incidence of new diagnoses, particularly among women (P<.001) and younger patients (P<.001) irrespective of the number of vaccine doses administered and the duration since the last dose. Furthermore, an increase in the use of health care resources was observed in both adult and youth groups, albeit with lower figures noted in vaccinated individuals. In the comparative analysis between the pre-Omicron and Omicron waves, the incidence of new diagnoses was higher in the former; however, distinct patterns of diagnosis were evident. Specifically, depressed mood (P=.03), anosmia (P=.003), hair loss (P<.001), dyspnea (<0.001), chest pain (P=.04), dysmenorrhea (P<.001), myalgia (P=.011), weakness (P<.001), and tachycardia (P=.015) were more common in the pre-Omicron period. Similarly, health care resource use, encompassing primary care, specialist, and emergency services, was more pronounced in the pre-Omicron wave. CONCLUSIONS: The rise in new diagnoses following SARS-CoV-2 infection warrants attention due to its potential implications for health systems, which may necessitate the allocation of supplementary resources. The absence of vaccination protection presents a challenge to the health care system.
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COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Masculino , Estudos de Casos e Controles , Feminino , Adulto , Adolescente , Estudos Retrospectivos , Pessoa de Meia-Idade , Criança , Adulto Jovem , Idoso , SARS-CoV-2 , Pré-Escolar , Vacinas contra COVID-19/administração & dosagem , Pandemias , Efeitos Psicossociais da Doença , Lactente , Síndrome de COVID-19 Pós-AgudaRESUMO
Vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula or atresia, renal anomalies, and limb abnormalities (VACTERL) association is a complex congenital condition characterized by the presence of malformations that affect various organ systems. Most children born with VACTERL association require surgery shortly after birth, often undergoing multiple procedures during infancy, which can lead to a wide range of physical challenges. The unique combination of malformations in these children in addition to having complex care needs that need to be met can result in physical and social difficulties in their daily lives, affecting both their own and their caregivers' quality of life. In some cases, children with complex medical needs are placed in foster care. When children with complex health needs enter the foster care system, there is a risk of overwhelming the caretaker, leading to their needs continuing to be unmet. Pediatricians have a role not only in helping support families but also in knowing what resources are available to meet these needs, which can be dependent on what their communities offer. Pediatricians require current training to navigate their state's foster care system. This training allows pediatricians to effectively collaborate with foster families while also assisting and coordinating complex care to support these families. We present a case of a child with complex health needs placed in the foster care system, facing multiple healthcare challenges, with care delayed due to difficulty attending appointments. Highlighted is the importance of delivering supportive, personalized, and multidisciplinary care to families with children who have complex health needs, including when caretakers are within the foster care system.
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INTRODUCTION: Survival in paediatric patients with Hodgkin lymphoma (HL) has increased over the last decades. However, these patients are at increased risk of developing late thyroid sequelae due to the treatment with irradiation and alkylating agents. METHODS: We conducted an observational and retrospective study in patients with a diagnosis of HL between 2007 and 2022, in a hospital that is a paediatric oncology reference centre, through the review of electronic health records. We collected data on demographic (age, sex), clinical, radiological and histopathological variables, the dosage of alkylating agents and radiotherapy (RT) and on thyroid disorders using Microsoft Excel. The data analysis was conducted with SPSS version 17, using the Fisher exact test for qualitative data, a nonparametric test for quantitative data and Kaplan-Meier curves. RESULTS: Sixty patients received a diagnosis of HL from 2007 to 2022. The median duration of follow-up was 78.5 months. There were 4 detected cases of hypothyroidism, 5 of thyroid nodules and 1 of subclinical hyperthyroidism. Treatment with RT was significantly associated with the development of hypothyroidism (P= .026), thyroid nodules (P= .01) and thyroid disease overall (P= .003). We estimated that the risk of thyroid disease increased 8-fold with each additional Grey received (hazard ratio, 1.081; 95% CI, 1.014-1.152; P= .017). CONCLUSION: Hodgkin lymphoma patients treated with RT are at increased risk of late thyroid disorders, mainly hypothyroidism and malignancy. This risk is greater the higher the RT dosage and the longer the follow-up. We did not find evidence of an association between the use of alkylating agents and an increase in the risk of thyroid disease.
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Doença de Hodgkin , Humanos , Doença de Hodgkin/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Adolescente , Criança , Doenças da Glândula Tireoide/epidemiologia , Seguimentos , Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologia , Pré-EscolarRESUMO
In recent years, the growth of Internet of Things devices has increased the use of sustainable energy sources. An alternative technology is offered by triboelectric nanogenerators (TENGs) that can harvest green energy and convert it into electrical energy. Herein, we assessed three different nopal powder types that were used as triboelectric layers of eco-friendly and sustainable TENGs for renewable energy harvesting from environmental vibrations and powering electronic devices. These nanogenerators were fabricated using waste and recycled materials with a compact design for easy transportation and collocation on non-homogeneous surfaces of different vibration or motion sources. In addition, these TENGs have advantages such as high output performance, stable output voltage, lightweight, low-cost materials, and a simple fabrication process. These nanogenerators use the contact-separation mode between two triboelectric layers to convert the vibration energy into electrical energy. TENG with the best output performance is based on dehydrated nopal powder, generating an output power density of 2.145 mWm-2 with a load resistance of 39.97 MΩ under 3g acceleration and 25 Hz operating frequency. The proposed TENGs have stable output voltages during 22500 operating cycles. These nanogenerators can light 116 ultra-bright blue commercial LEDs and power a digital calculator. Also, the TENGs can be used as a chess clock connected to a mobile phone app for smart motion sensing. These nanogenerators can harvest renewable vibration energy and power electronic devices, sensors, and smart motion sensing.
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PURPOSE: Evaluate the structural damage and the changes in the photosynthesis and transpiration rates of aquatic lirium leaves caused by ultrasound (US) irradiation in search of environmentally friendly methodologies for the control of this weed. MATERIALS AND METHODS: Aquatic lirium plants were extracted from Xochimilco water canals in Mexico City. A part of the group of plants was selected for irradiation, and the rest formed the control group. The irradiation plants group was exposed to US irradiation of 17 kHz frequency and 30 W × 4 output power for 2 h, at noon and 25 °C room temperature. The structural analysis was done with a MOTICAM 1 digital camera, 800 × 600 pixels, incorporated into the MOTIC PSM-1000 optical microscope and edited with Motic Images Plus 2.0 ML software. The total stomata density and the damaged stomata density were determined by dividing the numbers of total and damaged stomata by the visual field area (67,917 mm2), respectively. The leaves' photosynthesis and transpiration rates were measured using an LI-6400XT Portable Photosynthesis System. RESULTS: Significant damage was observed in the stomata and epidermal cells, finding that the average ratio between the damaged and total stomata densities as a function of time (days) showed an exponential increase described by a Box-Lucas equation with a saturation value near unity and a maximum rate of change of the density of damaged stomata on zero-day (immediately after irradiation), decreasing as the days go by. The transpiration rate showed a sudden increase during the first hour after irradiation, reaching a maximum of 36% of its value before irradiation. It then quickly fell during the next 6 days and more slowly until the 21st day, decreasing 79.9% of its value before irradiation. The photosynthetic rate showed similar behavior with a 37.7% maximum increment and a 73.6% minimum decrease of its value before irradiation. CONCLUSIONS: The results of structural stomata damage on the ultrasound-irradiated aquatic lirium leaves are consistent with an excessive ultrasound stimulation on stomata's mechanical operation by guard cells that produce the measured significant increase of the photosynthetic and transpiration rates during the first hour after irradiation. The initial high evaporation could alter the water potential gradient, with a possible generation of tensions in the xylem that could cause embolism in their conduits. The loss of xylem conductivity or hydraulic failure would be consistent with the observed significant fall in the photosynthesis and transpiration rates of the aquatic lirium leaves after its sudden rise in the first hour after irradiation.
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Estômatos de Plantas , Transpiração Vegetal , Estômatos de Plantas/fisiologia , Transpiração Vegetal/fisiologia , Fotossíntese , Folhas de Planta , ÁguaRESUMO
Kelp communities are experiencing exacerbated heat-related impacts from more intense, frequent, and deeper marine heatwaves (MHWs), imperiling the long-term survival of kelp forests in the climate change scenario. The occurrence of deep thermal anomalies is of critical importance, as elevated temperatures can impact kelp populations across their entire bathymetric range. This study evaluates the impact of MHWs on mature sporophytes of Pterygophora californica (walking kelp) from the bathymetric extremes (8-10 vs. 25-27 m) of a population situated in Baja California (Mexico). The location is near the southernmost point of the species's broad distribution (from Alaska to Mexico). The study investigated the ecophysiological responses (e.g., photobiology, nitrate uptake, oxidative stress) and growth of adult sporophytes through a two-phase experiment: warming simulating a MHW and a post-MHW phase without warming. Generally, the effects of warming differed depending on the bathymetric origin of the sporophytes. The MHW facilitated essential metabolic functions of deep-water sporophytes, including photosynthesis, and promoted their growth. In contrast, shallow-water sporophytes displayed metabolic stress, reduced growth, and oxidative damage. Upon the cessation of warming, certain responses, such as a decline in nitrate uptake and net productivity, became evident in shallow-water sporophytes, implying a delay in heat-stress response. This indicates that variation in temperatures can result in more prominent effects than warming alone. The greater heat tolerance of sporophytes in deeper waters shows convincing evidence that deep portions of P. californica populations have the potential to serve as refuges from the harmful impacts of MHWs on shallow reefs.
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Kelp , Nitratos , México , Temperatura Alta , Água , EcossistemaRESUMO
Insertions in the epidermal growth factor receptor (EGFR) exon 20 (Ex20Ins) are the third most incident mutations in non-small cell lung cancer (NSCLC). The hypervariable nature of these driver mutations hinders their identification by traditional polymerase chain reaction (PCR)-based methods, requiring a comprehensive sequencing approach to detect all possible insertions. The prognosis of patients with EGFR Ex20Ins is similar to those with wild-type NSCLC, since no targeted drugs are approved in the first-line setting, and platinum-based chemotherapy is currently the front-line treatment. However, the new generation of drugs currently being tested in first and post-platinum settings will likely change the management of this entity. Here, we summarize the latest data on EGFR Ex20Ins molecular characteristics, patient profile, identification challenges, and emerging therapies to help lung clinicians face a growing treatment landscape.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Mutação , Éxons/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
AIMS: Assess the impact of glucagon-like peptide receptor agonists (GLP-1RA) compared to other glucose-lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and obesity in a Spanish metropolitan area. METHODS: A retrospective population-based type 2 diabetes cohort was identified from the Valencia Clinic-Malvarrosa Department electronic databases (2014-2019). Study groups included GLP-1RA, sodium-glucose co-transporter-2 inhibitors (SGLT2i), Insulin, and Miscellany (other glucose-lowering agents). 1:1:1:1 propensity score matching was conducted. The primary outcome was a composite of major adverse cardiovascular events (4-point MACE) comprising myocardial infarction, stroke, all-cause mortality, and heart failure. Secondary outcomes included individual 4-point MACE components. Hazard ratios were estimated using Cox regression analyses against the Miscellany group. RESULTS: From 26,944 subjects, 1,848 adults were selected per group. GLP-1RA did not show a significant reduction in 4-point MACE risk (HR 1.05 [95%CI 0.82-1.34]). SGLT2i significantly reduced the risk of heart failure (HR 0.16 [95%CI 0.05-0.54]) and atrial fibrillation (HR 0.58, [95%CI 0.35-0.95]). The Insulin group exhibited a higher risk for 4-point MACE and most individual outcomes compared to GLP-1RA and SGLT2i. CONCLUSIONS: Our findings do not provide evidence of a reduced cardiovascular risk, as assessed by 4-point MACE, with GLP-1RA. In contrast, SGLT2i demonstrated protective effects against heart failure and atrial fibrillation.
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Fibrilação Atrial , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/induzido quimicamente , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Glucose , Insuficiência Cardíaca/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
Many studies have shown that air quality in cities is affected due to emissions of carbon from vehicles. As a result, policymakers (e.g., municipalities) intensely search for new ways to reduce air pollution due to its relation to health diseases. With this concern, connected vehicle technologies can leverage alternative on-road emissions control policies. The present investigation studies the impact on air pollution by (i) updating vehicles' routes to avoid pollution exposure (route choice policy), (ii) updating vehicles' speed limits (speed control policy), and (iii) considering electric vehicles (EVs). Vehicles are informed in advance about route conditions (i.e., on-road emissions) using the vehicular network. We found that by updating vehicle routes, 7.43% less CO emissions are produced within the evaluated region. Also, we find no evidence of significant emissions reductions in the case of limiting vehicles' speed. Lastly, with 30% of EV penetration, safe CO emissions levels are reached.
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Frailty, characterized by reduced resistance to stressors, is associated with adverse outcomes in patients with myocardial infarction. The Fried score is commonly used to assess frailty but has several limitations. This study aimed to evaluate the relation between frailty and blood biomarkers and their predictive value for long-term mortality using a biochemical model. A total of 2 cohorts of elderly patients (>65 years old) hospitalized for acute coronary syndrome were included. Geriatric assessments and several blood biomarkers were measured. The predictive models for frailty were developed using logistic regression. The survival models were also developed using Cox regression. Among 466 patients, 9 biomarkers were significantly associated with frailty. Between these biomarkers, white blood cells count, hemoglobin, and fibrinogen showed the highest predictive power. Model 1, without growth differentiation factor 15 (GDF-15), showed a better accuracy in predicting the mortality than the Fried score. Model 2, with GDF-15, had a stronger correlation with frailty but had a lower predictive power for survival. Frailty is associated with dysregulation in the physiological systems and several biomarkers were linked to this fact in our study. However, the inclusion of GDF-15 did not significantly improve the model's predictive ability. Frailty assessment using blood biomarkers can provide valuable prognostic information in elderly patients with acute coronary syndrome.
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Síndrome Coronariana Aguda , Fragilidade , Infarto do Miocárdio , Idoso , Humanos , Fator 15 de Diferenciação de Crescimento , FibrinogênioRESUMO
Pseudomonas aeruginosa is a ubiquitous nosocomial opportunistic pathogen that harbors many virulence determinants. Part of P. aeruginosa success colonizing a variety of habitats resides in its metabolic robustness and plasticity, which are the basis of its capability of adaptation to different nutrient sources and ecological conditions, including the infected host. Given this situation, it is conceivable that P. aeruginosa virulence might be, at least in part, under metabolic control, in such a way that virulence determinants are produced just when needed. Indeed, it has been shown that the catabolite repression control protein Crc, which together with the RNA chaperon Hfq regulates the P. aeruginosa utilization of carbon sources at the post-transcriptional level, also regulates, directly or indirectly, virulence-related processes in P. aeruginosa. Among them, Crc regulates P. aeruginosa cytotoxicity, likely by modulating the activity of the Type III Secretion System (T3SS), which directly injects toxins into eukaryotic host cells. The present work shows that the lack of Crc produces a Type III Secretion-defective phenotype in P. aeruginosa. The observed impairment is a consequence of a reduced expression of the genes encoding the T3SS, together with an impaired secretion of the proteins involved. Our results support that the impaired T3SS activity of the crc defective mutant is, at least partly, a consequence of a defective protein export, probably due to a reduced proton motive force. This work provides new information about the complex regulation of the expression and the activity of the T3SS in P. aeruginosa. Our results highlight the need of a robust bacterial metabolism, which is defective in the ∆crc mutant, to elicit complex and energetically costly virulence strategies, as that provided by the T3SS.
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Pseudomonas aeruginosa , Sistemas de Secreção Tipo III , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo III/metabolismo , Virulência/genética , Pseudomonas aeruginosa/metabolismo , Fatores de Virulência/metabolismo , Fenômenos Fisiológicos Celulares , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão GênicaRESUMO
The consumption of antioxidants can prevent chronic non-communicable diseases and the exotic Colombian fruits, goldenberry (Physalis peruviana L.) and purple passion fruit (Passiflora edulis f. Edulis Sims), are rich in bioactive compounds. The aim of this work was to characterize and optimize the antioxidant activity of these fruits blend. The fruits were classified according to their maturity stages, the freeze-dried extracts were physiochemically characterized, and polyphenols, carotenoids and antioxidant activity were quantified, and an experimental mixture design was applied to optimize the antioxidant activity of the bend. For the goldenberry the maturity stage 3 had higher iron-reducing capacity and higher content of polyphenols. Meanwhile, for the purple passion fruit, this maturity stage had higher antioxidant activity by all methodologies and a higher concentration of polyphenols; the ultrasound-assisted extraction showed statistical differences for polyphenols, ABTS and FRAP. Antioxidant activity showed significant differences (p < 0.05) between samples (TBARS (3.98 ± 0.14 and 7.03 ± 0.85 µM-MDA/g), ABTS (36.53 ± 2.66 and 29.4 ± 4.88 µMTrolox/g), DPPH (36.53 ± 2.66 and 23.90 ± 0.96µMTrolox/g), ORAC (23.02 ± 0.36 and 32.44 ± 0.94 µM Trolox/g) and total polyphenols (5, 29 ± 0.34 and 9.12 ± 0.37mgGA/g). Some of the carotenoids identified by HPLC-MS in both fruits were lutein, α and ß-carotene, phytoene and lycopene. The optimum bend was goldenberry 0.83 and purple passion fruit 0.17.
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OBJECTIVE: Surgical intervention in pediatric patients can cause variable degrees of psychological stress with potential consequences in the perioperative period and even in the long term, after hospital discharge in the form of behavioral changes days and months later. The aim of our study was to determine which preoperative preparation strategy reduces postoperative maladaptive behavioral changes in children undergoing ambulatory pediatric surgery. MATERIALS AND METHODS: This prospective observational study included 638 pediatric American Society of Anesthesiologists physical status I or II patients who underwent ambulatory pediatric surgery. They were grouped into four preoperative preparation groups: not premedicated (NADA), premedicated with midazolam (MDZ), parental presence during induction of anesthesia (PPIA), and parental presence during induction of anesthesia and premedicated with midazolam (PPIA + MDZ). All patients included in the study were contacted by telephone during 1 year posthospital discharge to assess the postoperative maladaptive behavioral changes using the Posthospitalization Behavior Questionnaire (PHBQ). We performed a multivariate analysis to evaluate the influence of type of preparation and behavioral changes. RESULTS: Patients in the PPIA and PPIA + MDZ preparation groups presented less postoperative maladaptive behavioral changes compared to patients in the NADA and MDZ groups (odds ratio [OR]: 1.8 [1.1-2.8] and OR 2.2 [1.03-4.49]) during the first week and first month. The intensity of emergence delirium measured by the Pediatric Anesthesia Emergence Delirium (PAED) scale increases the probability of postoperative maladaptive behavioral changes (OR: 1.05 [1.006-1.103]). CONCLUSION: The presence of parents during induction of anesthesia (PPIA and PPIA + MDZ) is a very effective strategy in reducing postoperative behavioral changes. These benefits are more significant in children under 5 years of age.
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Juvenile ossifying fibroma (JOF) is a rare benign neoplastic fibro-osseous tumor commonly found in the maxilla and mandible of children usually between the ages of five and 15. Patients often present with aggressive, painless growth which is well demarcated from surrounding bone resulting in severe facial asymmetry. JOFs have high recurrence rates if not completely resected and should therefore be treated by a multidisciplinary team of physicians including a neurosurgeon to assess cranial nerve function. This case describes a child who presented to the ED after being referred by his primary care provider for facial swelling. The patient was diagnosed with JOF and had a delay in care due to a lack of access to multidisciplinary specialties to provide care due to payer difficulties which placed the patient at high risk of complications.
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One of the main causes of food spoilage is the lipid oxidation of its components, which generates the loss of nutrients and color, together with the invasion of pathogenic microorganisms. In order to minimize these effects, active packaging has played an important role in preservation in recent years. Therefore, in the present study, an active packaging film was developed using polylactic acid (PLA) and silicon dioxide (SiO2) nanoparticles (NPs) (0.1% w/w) chemically modified with cinnamon essential oil (CEO). For the modification of the NPs, two methods (M1 and M2) were tested, and their effects on the chemical, mechanical, and physical properties of the polymer matrix were evaluated. The results showed that CEO conferred to SiO2 NPs had a high percentage of 2,2-diphenyl-l-picrylhydrazyl (DPPH) free radical inhibition (>70%), cell viability (>80%), and strong inhibition to E. coli, at 45 and 11 µg/mL for M1 and M2, respectively, and thermal stability. Films were prepared with these NPs, and characterizations and evaluations on apple storage were performed for 21 days. The results show that the films with pristine SiO2 improved tensile strength (28.06 MPa), as well as Young's modulus (0.368 MPa) since PLA films only presented values of 27.06 MPa and 0.324 MPa, respectively; however, films with modified NPs decreased tensile strength values (26.22 and 25.13 MPa), but increased elongation at break (from 5.05% to 10.32-8.32%). The water solubility decreased from 15% to 6-8% for the films with NPs, as well as the contact angle, from 90.21° to 73° for the M2 film. The water vapor permeability increased for the M2 film, presenting a value of 9.50 × 10-8 g Pa-1 h-1 m-2. FTIR analysis indicated that the addition of NPs with and without CEO did not modify the molecular structure of pure PLA; however, DSC analysis indicated that the crystallinity of the films was improved. The packaging prepared with M1 (without Tween 80) showed good results at the end of storage: lower values in color difference (5.59), organic acid degradation (0.042), weight loss (24.24%), and pH (4.02), making CEO-SiO2 a good component to produce active packaging.
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GATA4 and GATA6 are transcription factors involved in the differentiation and development of PDAC. GATA6 expression is related to the classic molecular subtype, while its absence is related to the basal-like molecular subtype. The aim was to determine the clinical utility of IHC determination of GATA4 and GATA6 in a series of patients with resected PDAC. GATA4 and GATA6 expression was studied by IHC in TMA samples of normal tissue, PanIN, tumor tissue and lymph node metastases from a series of 89 patients with resected PDAC. Its relationship with clinicopathologic variables and the outcome was investigated. Seventy-two (81%) tumors were GATA6+ and 37 (42%) were GATA4+. While GATA4 expression was reduced during tumor progression, GATA6 expression remained highly conserved, except in lymph node metastases. All patients with early stages and well-differentiated tumors were GATA6+. The absence of GATA4 expression was related to smoking. Patients with GATA4+ or GATA6+ tumors had significantly lower Ca 19.9 levels. The expression of GATA4 and GATA6 was related to DFS, being more favorable in the GATA4+/GATA6+ group. The determination of the expression of GATA4 and GATA6 by IHC is feasible and provides complementary clinical and prognostic information that can help improve the stratification of patients with PDAC.
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INTRODUCTION: In type 2 diabetes (T2D), key barriers to optimal glycaemic control include lack of persistence with treatment, reduced medication adherence and therapeutic inertia. This study aimed to assess the impact of these barriers in obese adults with type 2 diabetes treated with a GLP-1 receptor agonist (GLP-1RA) and compare them against other glucose-lowering agents in a real-world setting. METHODS: A retrospective study was conducted using electronic medical records from 2014 to 2019 for adults with T2D at the Valencia Clínico-Malvarrosa Department of Health (Valencia, Spain). Four study groups were established: all GLP-1RA users, SGLT2i users, insulin users and other glucose-lowering agent users (miscellany group). To account for imbalance between groups, propensity score matching (PSM) including age, gender and pre-existing cardiovascular disease was performed. Chi-square tests were used for comparisons between groups. Time to first intensification was calculated using competing risk analysis. RESULTS: Among the 26,944 adults with T2D, 7392 individuals were selected following PSM, with 1848 patients in each group. At 2 years, GLP-1RA users were less persistent than non-users (48.4% versus 72.7%, p < 0.0001) but more adherent (73.8% versus 68.9%, respectively, p < 0.0001). A greater proportion of persistent GLP-1RA users than non-persistent users exhibited reduced HbA1c (40.5% versus 18.6%, respectively, p < 0.0001), but no differences in cardiovascular outcomes and death were found. Overall, therapeutic inertia was observed in 38.0% of the study population. The large majority of GLP-1RA users received treatment intensification, whereas only 50.0% of GLP-1RA non-users were intensified. CONCLUSION: Under real-life conditions, obese adults with T2D persistently treated with GLP-1RA showed improved glycaemic control. Despite benefits, persistence with GLP-1RA was limited after 2 years. Additionally, therapeutic inertia occurred in two out of three study participants. Strategies to facilitate medication adherence, persistence and treatment intensification in people with T2D should be made a priority in order to achieve and maintain glycaemic targets and improve outcomes in this population. TRAIL REGISTRATION: Study registered in clinicaltrials.org with the identifier NCT05535322.
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Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Linfócitos T , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Modelos Animais de DoençasRESUMO
Ambulatory BP monitoring is increasingly used in children and adolescents, and the persistence of discrepant phenotypes, such as white coat or masked hypertension, is a relevant issue. The objective of this study was to assess the persistence of BP phenotypes over time and the factors related to their persistence. The study included 582 children and adolescents (9.4 ± 2.8 years of age) of both sexes (51% females) referred for routine health maintenance. Anthropometric parameters and office and 24-h ABPM measurements were obtained twice (interval 19.5 ± 6.9 months). BP classification and phenotypes were qualified using the 2016 ESH Guidelines. The correlation coefficient and kappa statistics were used to assess the persistence of phenotypes, and the related factors were evaluated using logistic regression. Based on both systolic and diastolic BP measurements, 91.6%, 16%, 17.2% and 13.7% of the subjects with true normotension, sustained HTN, white coat HTN and masked HTN, respectively, remained in the same category (overall agreement 74.2%, kappa 0.20). The multivariate model predicted the lack of persistence and correctly classified 90.3% of the subjects, with the pathological baseline BP phenotype (mainly masked HTN) being the independent variable that contributed most to the model. Excluding the phenotypes, the rest of the model explained 14% of the lack of persistence, and a high office SBP and high waist circumference were related to the lack of persistence. Furthermore, subjects who experienced an increase in their BMI z score and change in their BMI category were at risk of a lack of persistence. In conclusion, children, especially those with BP phenotypes different from true normotension, should be re-evaluated because a large percentage are likely to become normotensive.