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The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity.
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Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Ingestão de Alimentos , Secretina/metabolismo , Termogênese , Adipócitos Marrons/citologia , Tecido Adiposo Marrom/citologia , Animais , Células HEK293 , Humanos , Lipólise , Camundongos , Camundongos Knockout , Camundongos Obesos , Secretina/genéticaRESUMO
Adoptive cell therapy using chimeric antigen receptor (CAR) T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has been limited in solid tumors. One key factor for this are cancer-associated fibroblasts (CAFs), that modulate the tumor microenvironment (TME) to inhibit T cell infiltration and induce "T cell dysfunction". Additionally, the sparsity of tumor-specific antigens (TSA) and expression of CAR-directed tumor-associated antigens (TAA) on normal tissues often results in "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR-T cell engineering strategy to overcome these challenges. Our allogeneic "Smart CAR T-cells" are designed to express a constitutive CAR, targeting FAP+ CAFs in solid tumors. Additionally, a second CAR targeting a Tumor Associated Antigen (TAA) such as mesothelin is specifically integrated at a TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF targeting induces expression of the mesothelin-CAR, establishing an IF/THEN-gated circuit sensitive to dual antigen sensing. Using this approach, we observe enhanced anti-tumor cytotoxicity, while limiting "on-target off-tumor" toxicity. Our study thus demonstrates TALEN-mediated gene editing capabilities for design of allogeneic IF/THEN-gated Dual CAR T-cells which efficiently target immunotherapy-recalcitrant solid tumors while mitigating potential safety risks, encouraging clinical development of this strategy.
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Antigen-specific immunotherapy involves the delivery of self-antigens as proteins or peptides (or using nucleic acids encoding them) to reestablish tolerance. The Endotope platform supports the optimal presentation of endogenously expressed epitopes on appropriate major histocompatibility complex (MHC) class I and II molecules. Using specific epitopes that are disease-relevant (including neoepitopes and mimotopes) and restricted to the subject's MHC haplotypes provides a more focused and tailored way of targeting autoreactive T cells. We evaluated the efficacy of an Endotope DNA vaccine tailored to the nonobese diabetic (NOD) mouse in parallel to one expressing the Proinsulin protein, a central autoantigen in NOD mice, and assessed the influence of several parameters (e.g., route, dosing frequency, disease stage) on diabetes prevention. Secretion of encoded peptides and intradermal delivery of DNA offered more effective disease prevention. Long-term weekly treatments were needed to achieve protection that can persist after discontinuation, likely mediated by regulatory T cells induced by at least one epitope. Although epitopes were presented for at least 2 wk, weekly treatments were needed, at least initially, to achieve significant protection. While Endotope and Proinsulin DNA vaccines were effective at both the prediabetic normoglycemic and dysglycemic stages of disease, Proinsulin provided better protection in the latter stage, particularly in animals with slower progression of disease, and Endotope limited insulitis the most in the earlier stage. Thus, our data support the possibility of applying a precision medicine approach based on tailored epitopes for the treatment of tissue-specific autoimmune diseases with DNA vaccines.
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Diabetes Mellitus Tipo 1 , Proinsulina , Vacinas de DNA , Animais , Diabetes Mellitus Tipo 1/prevenção & controle , Epitopos de Linfócito T/imunologia , Camundongos , Camundongos Endogâmicos NOD , Medicina de Precisão , Proinsulina/genética , Proinsulina/imunologia , Vacinação , Vacinas de DNA/imunologiaRESUMO
SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.
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Diabetes Mellitus Tipo 2 , Receptores dos Hormônios Gastrointestinais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Polipeptídeo Inibidor Gástrico/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Incretinas/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores dos Hormônios Gastrointestinais/uso terapêuticoRESUMO
OBJECTIVE: To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. BACKGROUND: Several studies have found an association between migraine and IBD. METHODS: In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). RESULTS: Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn's disease (54.9 ± 27.5 pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p = 0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p = 0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p = 0.028). CONCLUSION: Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.
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Peptídeo Relacionado com Gene de Calcitonina , Comorbidade , Doenças Inflamatórias Intestinais , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/epidemiologia , Estudos Transversais , Feminino , Masculino , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/complicações , Adulto , Pessoa de Meia-Idade , Ensaio de Imunoadsorção EnzimáticaRESUMO
INTRODUCTION: There is uncertainty about the optimal videolaryngoscope for awake tracheal intubation in patients with anticipated difficult airway. The use of channelled and unchannelled videolaryngoscopy has been reported, but there is a lack of evidence on which is the best option. METHODS: We conducted a randomised clinical trial to compare the efficacy of the C-MAC D-Blade® vs. Airtraq® in adult patients (aged ≥ 18 y) scheduled for elective or emergency surgery under general anaesthesia with anticipated difficult airway who required awake tracheal intubation under local anaesthesia and conscious sedation. The primary endpoint was the first-attempt tracheal intubation success rate. Secondary outcomes included the overall success rate; number of tracheal intubation attempts; Cormack and Lehane glottic view; level of difficulty (visual analogue score); patient discomfort (visual analogue score); and incidence of complications. RESULTS: Ninety patients (70/90 male (78%); mean (SD) age 65 (12) y) with anticipated difficult airways were randomly allocated to C-MAC D-Blade or Airtraq videolaryngoscopy. First-attempt successful tracheal intubation rate was higher in patients allocated to the C-MAC D-Blade group compared with those allocated to the Airtraq group (38/45 (84%) vs. 28/45 (62%), respectively; p = 0.006). The proportion of patients' tracheas that were intubated at the second and third attempt was 4/45 (9%) and 3/45 (7%) in those allocated to the C-MAC D-Blade group compared with 14/45 (31%) and 1/45 (2%) in those allocated to the Airtraq group (p = 0.006). There was no significant difference in overall tracheal intubation success rate (C-MAC D-Blade group 45/45 (100%) vs. Airtraq group 43/45 (96%), p = 0.494). DISCUSSION: In patients with anticipated difficult airway, first-attempt awake tracheal intubation success rate was higher with the C-MAC D-Blade compared with Airtraq laryngoscopy. No difference was found between the two videolaryngoscopes in overall tracheal intubation success rate.
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OBJECTIVE: Tracheal intubation in cardiac surgery patients has a higher incidence of difficult laryngoscopic views compared with patients undergoing other types of surgery. The authors hypothesized that using the McGrath Mac videolaryngoscope as the first intubation option for cardiac surgery patients improves the percentage of patients with "easy intubation" compared with using a direct Macintosh laryngoscope. DESIGN: A prospective, observational, before-after study. SETTING: At a tertiary-care hospital. PARTICIPANTS: One thousand one hundred nine patients undergoing cardiac surgery. INTERVENTION: Consecutive patients undergoing cardiac surgery were intubated using, as the first option, a Macintosh laryngoscope (preinterventional phase) or a McGrath Mac videolaryngoscope (interventional phase). MEASUREMENTS AND MAIN RESULTS: The main objective was to assess whether the use of the McGrath videolaryngoscope, as the first intubation option, improves the percentage of patients with "easy intubation," defined as successful intubation on the first attempt, modified Cormack-Lehane grades of I or IIa, and the absence of the need for adjuvant airway devices. A total of 1,109 patients were included, 801 in the noninterventional phase and 308 in the interventional phase. The incidence of "easy intubation" was 93% in the interventional phase versus 78% in the noninterventional phase (p < 0.001). First-success-rate intubation was higher in the interventional phase (304/308; 98.7%) compared with the noninterventional phase (754/801, 94.1%; p = 0.005). Intubation in the interventional phase showed decreases in the incidence of difficult laryngoscopy (12/308 [3.9%] v 157/801 [19.6%]; p < 0.001), as well as moderate or difficult intubation (5/308 [1.6%] v 57/801 [7.1%]; p < 0.001). CONCLUSIONS: The use of the McGrath videolaryngoscope as the first intubation option for tracheal intubation in cardiac surgery improves the percentage of patients with "easy" intubation," increasing glottic view and first-success-rate intubation and decreasing the incidence of moderate or difficult intubation.
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Procedimentos Cirúrgicos Cardíacos , Intubação Intratraqueal , Laringoscópios , Laringoscopia , Gravação em Vídeo , Humanos , Intubação Intratraqueal/instrumentação , Intubação Intratraqueal/métodos , Estudos Prospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Laringoscopia/métodos , Laringoscopia/instrumentação , Procedimentos Cirúrgicos Cardíacos/métodos , Procedimentos Cirúrgicos Cardíacos/instrumentação , Gravação em Vídeo/métodos , Salas CirúrgicasRESUMO
Hazelnut is among the most important nut crops in Chile, currently covering 46,000 ha. In 2023, the country exported 30,000-ton. In recent years the incidence of plants with internal discoloration, cankers and dieback has been increasing. In some cases, the trees died and had to be removed and, after a year, purple resupinate fruiting bodies were observed growing from the stumps. To determine the etiology of the symptoms and signs, wood samples (n=318) were collected since 2020, from 38 symptomatic orchards from Maule to La Araucanía Regions, primarily from the cvs. Tonda di Giffoni and Lewis. Wood sections 0.5 cm diameter were cut from the symptomatic tissues, disinfected using a sodium hypochlorite (10%) solution, and plated on a quarter-strength acidified potato dextrose agar (aPDA1/4). The plates were incubated and purified on PDA. Subsequently, isolates were identified by morphological and molecular means. Almost half of the isolates (47%) were preliminarily identified as basidiomycetes, based on mycelial features such as the presence of clamp connections, with 45% of them exhibiting abundant whitish cottony fast-growth mycelia, resembling Chondrostereum purpureum (Grinbergs et al., 2020). DNA was extracted and the 500-bp fragment, located between 5S and 18S ribosomal regions, was amplified using APN1 specific primers (Becker et al. 1999), identifying the isolates as C. purpureum. In addition, 5.8S gene of RGM1 (35°13'40.9"S 71°25'14.1"W), RGM2 (36°31'27.95"S 71°46'58.31"W), RGM3 (37°10'54.8"S 72°03'39.6"W), RGM4 (35°19'25.2"S 71°19'54.7"W) and RGM5 (36°35'30.8"S 72°05'18.8"W) isolates, representing different locations within the hazelnut growing area, was amplified using ITS1/ITS4 primers (White et al., 1990). The PCR product was sequenced, and the analysis showed 100% homology among isolates (Genebank codes: PP839283, PP839284, PP839285, PP839286 and PP839287, respectively). To determine the pathogenicity of the isolates, 30-cm healthy cuttings cv. Lewis were inoculated with mycelial plugs, while control shoots were inoculated with sterile agar plugs. Cuttings were vertically arranged in pots with 3-cm water and incubated for 60-d at 22°C. In addition, fresh cuts of 3-y potted plants cv. Lewis were inoculated with mycelial plugs and incubated for 137-d in a shadehouse. After incubation, bark was removed from inoculated cuttings and the length of necrotic lesions was measured. Although discoloration was reproduced by all the isolates in both pathogenicity tests, RGM1 isolate was the most aggressive, causing the complete discoloration of the cuttings and the death of the inoculated plants. To our knowledge this is the first report of C. purpureum causing wood disease in hazelnut. These findings are significant because the disease may not only reduce orchard longevity but also decrease fruit yield and quality, as observed in other fruit crops (Grinbergs et al., 2021).
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Beach handball is a fully developed sporting discipline on all five continents which has attracted the attention of researchers in the last decade, resulting in a proliferation of different studies focusing on players but not on referees. The main objective of this cross-sectional research was to determine the physical demands on elite male beach handball referees in four different competitions: U18 male; U18 female; senior male; and senior female. Twelve elite federated male referees (age: 30.86 ± 8 years; body height: 175.72 ± 4.51 cm; body weight: 80.18 ± 17.99 kg; fat percentage: 20.1 ± 4.41%; national or international experience) belonging to the Technical Committee of the Royal Spanish Handball Federation were recruited for this the study. The physical demands required of referees in official matches were measured by installing a GPS device. The sampling frequency used to record their speed and distance was 15 Hz. A triaxial accelerometer (100 Hz) was used to determine their acceleration. An analysis of variance (ANOVA) between competitions with post hoc comparisons using the Bonferroni adjustment was used to compare among categories. A higher distance covered in zone 1 and speeds of 0 to 6 km-h-1 were recorded. Most accelerations and decelerations occurred in zones 0 and 1 (zone 0: 0 to 1 m·s-2; zone 1: 1 to 2 m·s-2). The lack of differences (p > 0.05) between most analysed variables suggest quite similar physical demands of the four analysed competitions. These results provide relevant information to design optimal training plans oriented to the real physical demands on referees in an official competition.
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Desempenho Atlético , Corrida , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Sistemas de Informação Geográfica , Estudos Transversais , Aceleração , Desempenho Físico FuncionalRESUMO
OBJECTIVES: Medical tourism is expanding globally, with patients seeking cosmetic procedures abroad. To date, little information is known regarding the risks and outcomes of cosmetic tourism, especially potential stroke complications. Here, we present a case of fungal meningitis in the setting of medical tourism leading to ischemic strokes and vasospasm. MATERIAL AND METHODS: We describe an immunocompetent 29-year-old female patient who initially presented with intractable headaches and an abnormal cerebrospinal fluid (CSF) profile who was eventually diagnosed with Fusarium solani meningitis as a part of a common source outbreak in Matamoros, Mexico. These patients were part of a cohort who underwent cosmetic procedures requiring spinal anesthesia. This report also highlights the unusual clinical course leading to poor outcomes in such conditions. RESULTS: The patient initially presented with headaches, papilledema, elevated opening pressure on the spinal tap, abnormal CSF studies, and eventually developed ischemic strokes and hydrocephalus. CSF showed positive beta D-Glucan with repeated negative CSF fungal cultures. A cerebral angiogram revealed extensive basilar artery vasospasm that led to ischemic strokes. Continued clinical worsening and lack of response to antifungal treatment prompted further imaging that revealed significant non-obstructive hydrocephalus subsequently complicated by spontaneous intracranial hemorrhage. CSF PCR for Fusarium solani species was positive days after her passing. CONCLUSION: This novel case highlights fungal meningitis caused by Fusarium solani complicated by bilateral ischemic strokes stemming from basilar artery vasospasm. Complications from medical tourism impact not only individual patients but also the health systems of both countries. Professional and regulatory entities for cosmetic surgeries must highlight and educate patients on the risks and complications of cosmetic surgeries happening abroad. Physicians should be aware of ongoing outbreaks and possible complications of these procedures.
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Hidrocefalia , AVC Isquêmico , Turismo Médico , Meningite Fúngica , Meningite , Vasoespasmo Intracraniano , Humanos , Feminino , Adulto , Vasoespasmo Intracraniano/complicações , Vasoespasmo Intracraniano/diagnóstico por imagem , Meningite Fúngica/complicações , Meningite Fúngica/diagnóstico , Meningite Fúngica/tratamento farmacológico , Hidrocefalia/cirurgiaRESUMO
Telemedicine provided older adults the ability to safely seek care during the coronavirus disease (COVID-19) pandemic. This study aimed to evaluate the potential impact of acculturation factors in telemedicine uptake between ethnic groups. As part of the National Health and Aging Trends Study 2018 survey, 303 participants (≥65 years) were interviewed. We assessed the impact of acculturation on telemedicine readiness by race and ethnicity. Compared to the white non-Hispanic immigrant population, Hispanic and Asian/Pacific Islander (API) populations had significantly lower telemedicine readiness and uptake. Limited English proficiency or older age at the time of migration was associated with telemedicine unreadiness and uptake in the Hispanic and API populations. Our findings suggested that acculturation factors play a substantial role in telemedicine uptake among older adult immigrants in the United States. Therefore, acculturation factors should be considered when promoting and adopting telemedicine technologies in older adults.
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Aculturação , COVID-19 , Telemedicina , Humanos , Telemedicina/estatística & dados numéricos , Idoso , Feminino , Masculino , COVID-19/etnologia , Estados Unidos , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Idoso de 80 Anos ou mais , Emigrantes e Imigrantes/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , SARS-CoV-2 , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricosRESUMO
We present the case of a 52-year-old woman diagnosed with stage IV clear cell renal cell carcinoma who received combination of surgery and systemic therapy with nivolumab (anti-PD1) and ipilimumab (anti-CTLA-4). During treatment, patient presented oral intolerance, vomiting and abdominal pain. Computed tomography (CT) and gastroscopy (EGD) were performed, identifying findings suggestive of severe gastro-duodenitis with friability and diffuse oedema of the mucosa and deep ulcers. A gastrointestinal immunotherapy-induced toxicity was suspected so patient was managed with proton pump inhibitors (PPIs) and intravenous corticosteroids 1mg/Kg. Three weeks later, corticosteroid treatment failed. EGD was repeated and gastric biopsies were taken for histological and microbiological tests. Gastric biopsies revealed the presence of cytomegalovirus (CMV) inclusion bodies by immunohistochemistry (IHC). CMV viral load by quantitative PCR in plasma was 2,000 IU/mL so intravenous ganciclovir was prescribed. Then, the patient presented poor clinical course with persistent vomiting due to a failure of first-line corticosteroid and antiviral treatment. Another EGD was performed. Last IHC reveals a low CMV viral load. Second-line treatment with Anti-TNF was performed using a single-dose regimen of intravenous infliximab 5 mg/Kg. Finally, the patient presented a clinical and endoscopic response and a negative CMV DNA test in the blood after completing the antiviral treatment.
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Caring for female victims of violence presents health professionals with situations that require careful consideration due to the conflicts raised between the fundamental principles of bioethics. During this process, intermediate courses of action should be adopted in which none of the affected principles is totally compromised, yet always take into account due compliance with legal and deontological regulations. Within these conflicts, the possible impact on the autonomy of the victim must be taken into consideration, conditioned by the relationship of dominance with respect to their aggressor, a fundamental characteristic of gender violence. However, the fact that there is a legal obligation to issue an injury report or to communicate a well-founded suspicion of abuse is not enough to ignore the fact that the person, in this case the victim, must be a participant in the process. As such, the doctor has the obligation to inform his or her patient about this legal requirement, dedicating all the time and attention necessary to ensure that the victim understands the purpose and benefits of complying with this. In any case, and beyond the appropriate adaptation of the professional's conduct to current precepts, the ethical principle of care must be adhered to, by which the best thing the professional can do is to provide the victim with the means to avoid the repetition of new attacks, implementing prevention measures that have their origin in the accurate diagnosis of the situation of violence and in the communication of this to the authorities.
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BACKGROUND: Accidental dural puncture (ADP) is the most frequent major complication when performing an epidural procedure in obstetrics. Consequently, loss of pressure in the cerebrospinal fluid (CSF) leads to the development of post-dural puncture headache (PDPH), which occurs in 16%-86% of cases. To date, the efficacy of epidural fibrin patches (EFP) has not been evaluated in a controlled clinical trial, nor in comparative studies with epidural blood patches (EBP). METHODS: The objective of the present study was to compare the efficacy of EFP with respect to EBP for the treatment of refractory accidental PDPH. This prospective, randomized, open-label, parallel, comparative study included 70 puerperal women who received an EBP or EFP (35 in each group) after failure of the conventional analgesic treatment for accidental PDPH in a hospital. RESULTS: A higher percentage of women with EFP than EBP achieved complete PDPH relief after 2 (97.1% vs. 54.3%) and 12 h (100.0% vs. 65.7%) of the patch injection. The percentage of patients who needed rescue analgesia was significantly lower with EFP after 2 (2.9% vs. 48.6%) and 12 h (0.0% vs. 37.1%). After 24 h, PDPH was resolved in all women who received EFP. The recurrence of PDPH was reported in one woman from the EBP group (2.9%), who subsequently required a second patch. The mean length of hospital stay was significantly lower with EFP (3.9 days) than EBP (5.9 days). Regarding satisfaction, the mean value (Likert scale) was significantly higher with EFP (4.7 vs. 3.0). CONCLUSIONS: EFP provided better outcomes than EBP for the treatment of obstetric PDPH in terms of efficacy, safety, and patient satisfaction.
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Cefaleia Pós-Punção Dural , Gravidez , Humanos , Feminino , Cefaleia Pós-Punção Dural/terapia , Estudos Prospectivos , Fibrina , Placa de Sangue Epidural/métodos , Manejo da DorRESUMO
Binge drinking (BD) is the most common alcohol consumption model for adolescents, and has recently been related to the generation of high oxidation and insulin resistance (IR). White adipose tissue (WAT) is a target organ for insulin action that regulates whole-body metabolism by secreting adipokines. The present study aimed to analyse the oxidative, inflammatory, energetic and endocrine profile in the WAT of BD-exposed adolescent rats, to obtain an integrative view of insulin secretion and WAT in IR progression. Two groups of male adolescent rats were used: control (n = 8) and BD (n = 8). An intermittent i.p. BD model (20% v/v) was used during 3 consecutive weeks. BD exposure led to a pancreatic oxidative imbalance, which was joint to high insulin secretion by augmenting deacetylase sirtuin-1 (SIRT-1) pancreatic expression and serum adipsin levels. However, BD rats had hyperglycaemia and high homeostasis model assessment of insulin resistance value (HOMA-IR). BD exposure in WAT increased lipid oxidation, as well as decreased insulin receptor substrate 1 (IRS-1) and AKT expression, sterol regulatory element-binding protein 1 (SREBP1), forkhead box O3A (FOXO3a) and peroxisome proliferator-activated receptor γ (PPARγ), and adipocyte size. BD also affected the expression of proteins related to energy balance, such as SIRT-1 and AMP activated protein kinase (AMPK), affecting the adipokine secretion profile (increasing resistin/adiponectin ratio). BD altered the entire serum lipid profile, increasing the concentration of free fatty acids. In conclusion, BD led to an oxidative imbalance and IR process in WAT, which modified the energy balance in this tissue, decreasing the WAT lipogenic/lipolytic ratio, affecting adipokine secretion and the systemic lipid profile, and contributing to the progression of IR. Therefore, WAT is key in the generation of metabolic and endocrine disruption after BD exposure during adolescence in rats. KEY POINTS: Adolescent rat binge drinking (BD) exposure leads to hepatic and systemic oxidative stress (OS) via reactive oxygen species generation, causing hepatic insulin resistance (IR) and altered energy metabolism. In the present study, BD exposure in adolescent rats induces OS in the pancreas, with increased insulin secretion despite hyperglycaemia, indicating a role for IR in white adipose tissue (WAT) homeostasis. In WAT, BD produces IR and an oxidative and energetic imbalance, triggering an intense lipolysis where the serum lipid profile is altered and free fatty acids are increased, consistent with liver lipid accumulation and steatosis. BD exposure heightens inflammation in WAT, elevating pro-inflammatory and reducing anti-inflammatory adipokines, favouring cardiovascular damage. This research provides a comprehensive view of how adolescent BD in rats impacts liver, WAT and pancreas homeostasis, posing a risk for future cardiometabolic complications in adulthood.
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Consumo Excessivo de Bebidas Alcoólicas , Fígado Gorduroso , Hiperglicemia , Resistência à Insulina , Ratos , Masculino , Animais , Ácidos Graxos não Esterificados/metabolismo , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Tecido Adiposo/metabolismo , Adipocinas/metabolismo , Fígado Gorduroso/metabolismo , Tecido Adiposo Branco/metabolismo , Etanol/metabolismo , Hiperglicemia/metabolismo , Homeostase , Estresse OxidativoRESUMO
BACKGROUND: Coronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). However, its prognostic significance and its management remains controversial. AIMS: This study sought to determine whether the presence of CAD, its complexity, and angiography-guided percutaneous coronary intervention (PCI) are associated with outcomes after TAVI. METHODS: All patients undergoing TAVI at a tertiary referral center between 2008 and 2018 were included in a prospective observational study. Baseline SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) and a residual SS after PCI were calculated. The endpoints on the 5 year follow-up were all-cause mortality and a composite of mayor cardiovascular adverse events (MACE). RESULTS: In 379 patients, the presence of CAD and its complexity were not significantly associated with worse 5-year survival after TAVI, with a mortality for SS0 of 45%; for SS 1-22 of 36.5% (HR 0.77; 95% CI 0.53-1.11, p = 0.15) and for SS > 22 of 42.1% (HR 1.24; 95% CI 0.59-2.63, p = 0.57). Regarding the combined event of MACE, there were also no statistically significant differences between patients with CAD and without CAD (56.8% in patients without CAD and 54.9% in patients with CAD; HR 1.06; 95% CI 0.79-1.43, p = 0.7). Angiography-guided PCI or completeness of revascularization was not associated with different outcomes. CONCLUSIONS: In the present analysis, neither the presence nor the extent of CAD, nor the degree of revascularization, was associated with a prognostic impact in patients undergoing TAVI at 5-year follow-up.
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Estenose da Valva Aórtica , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Substituição da Valva Aórtica Transcateter , Humanos , Prognóstico , Seguimentos , Resultado do Tratamento , Fatores de Risco , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Angiografia CoronáriaRESUMO
The understanding of the host immune response to SARS-CoV-2 variants of concern is critical for improving diagnostics, therapy development, and vaccines. Here, we analyzed the level of neutralizing antibodies against SARS-CoV-2 D614G, Delta, Gamma, Mu, and Omicron variants in D614G infected healthcare workers during a follow-up up to 6 months after recovery. We followed up 76 patients: 60.5% were women and 39.5% men. The 96.1% and 3.9% were symptomatic and asymptomatic, respectively. The most frequent symptoms were headache, myalgia, and cough. The 65.8%, 65.8%, and 92.1% of the infected individuals were positive for neutralizing antibodies against D614G variant at 2, 4, and 6 months of follow-up, respectively. The 26.3%, 48.7% and 65.8% of patients neutralized Delta variant, 19.7%, 32.9% and 52.6% of patients neutralized Gamma, 7.9%, 19.7% and 44.7% of patients neutralized Mu, and 4.0%, 9.2% and 15.8% of patients neutralized Omicron. Low neutralization against Gamma and Mu variants was observed during the follow-up, and very low against the Omicron variant was detected during the same period. The median of neutralizing antibody titers against D614G and Delta variants increased significantly during the follow-up. An association was observed between the levels of neutralizing antibodies against D614G and Delta variants and the severity of the disease. Our results suggest an immune escape from neutralizing antibodies with the Omicron variant because of the many mutations localized in the S protein.
Assuntos
COVID-19 , SARS-CoV-2 , Masculino , Humanos , Feminino , SARS-CoV-2/genética , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
This study aimed to determine the relationship of body mass index (BMI), muscle-to-fat ratio (MFR), and handgrip strength-to-BMI ratio to physical fitness parameters in an active young population according to sex across four different time points. A total of 2256 Spanish children and adolescents (aged 5-18) from rural areas participating in an extracurricular sport in different municipal sports schools participated in this study. Participants were divided into children (5-10 years) and adolescents (11-18 years), boys and girls, and across four different time points (2018, 2019, 2020, 2021). Data on anthropometric measures (BMI, MFR, appendicular skeletal muscle mass) and physical fitness (handgrip strength, cardiorespiratory fitness, and vertical jump) were collected. Boys who were overweight, but especially boys with obesity, had higher absolute handgrip strength in children and adolescents than their normal weight counterparts in 2020 and 2021. Boys and girls with normal weight presented higher cardiorespiratory fitness and vertical jump than their overweight and obese peers over the years. The MFR was directly correlated with the cardiorespiratory fitness and vertical jump variables, but not with handgrip strength, in boys and girls. The handgrip strength-to-BMI ratio in both sexes was positively correlated to the different physical fitness parameters. Conclusion: BMI, MFR, and handgrip strength-to-BMI can be used as health and physical fitness indicators in this population. What is Known: ⢠BMI is the main indicator commonly used as a proxy for obesity for many years. Nevertheless, it cannot differentiate between fat mass and fat-free mass. ⢠There are other indicators such as MFR and handgrip strength-to-BMI that might be more accurate and can serve to monitor the health and fitness of children and adolescents. What is New: ⢠MFR showed a positive and significant correlation with cardiorespiratory fitness and vertical jump in both sexes. On the other hand, the handgrip strength-to-BMI presented a positive correlation with cardiorespiratory fitness, vertical jump, and handgrip strength. ⢠The use of these indicators obtained through different parameters of body composition and physical fitness can serve as a tool to identify the relationships of the paediatric population with physical fitness.
Assuntos
Força da Mão , Sobrepeso , Masculino , Feminino , Humanos , Adolescente , Criança , Índice de Massa Corporal , Sobrepeso/epidemiologia , Aptidão Física/fisiologia , Obesidade , MúsculosRESUMO
BACKGROUND: The U.S. Medical Licensing Examination (USMLE) Step 1 has been used as a screening tool for residency selection. In February 2020, Step 1 numerical scoring changed to pass/fail. OBJECTIVE: Our aim was to survey emergency medicine (EM) residency program attitudes towards the new Step 1 scoring change and to identify important applicant screening factors. METHODS: A 16-question survey was distributed through the Council of Residency Directors in Emergency Medicine listserv from November 11 through December 31, 2020. Given the Step 1 scoring change, the survey questioned the importance of EM rotation grades, composite standardized letters of evaluation (cSLOEs), and individual standardized letters of evaluation, using a Likert scale. Descriptive statistics of demographic characteristics and selection factors were performed along with a regression analysis. RESULTS: Of the 107 respondents, 48% were program directors, 28% were assistant or associate program directors, 14% were clerkship directors, and 10% were in other roles. Sixty (55.6%) disagreed with pass/fail Step 1 scoring change and, of those, 82% believed that numerical scoring was a good screening tool. The cSLOEs, EM rotation grades, and interview were the most important selection factors. Residencies with 50 or more residents had 5.25 odds (95% CI 1.25-22.1; p = 0.0018) of agreeing with pass/fail scoring and those who ranked cSLOEs as the most important selection factor had 4.90 odds (95% CI 1.125-21.37; p = 0.0343) of agreeing with pass/fail scoring. CONCLUSIONS: Most EM programs disagree with pass/fail scoring of Step 1 and will most likely use Step 2 score as a screening tool. The cSLOEs, EM rotation grades, and interview are considered the most important selection factors.