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A dysprosium (Dy3+ )-activated potassium calcium silicate (K4 CaSi3 O9 ) phosphor was prepared using a solid-state synthesis route. The phosphor had a cubic structure with the space group Pa 3 ¯ as confirmed using X-ray diffraction (XRD) measurements. Details of surface morphology and elemental composition of the as-synthesized undoped KCS phosphor was obtained using scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) spectroscopy. The chemical structure as well as the vibrational modes present in the as-prepared KCS phosphor was analyzed using Fourier transform infrared (FT-IR) spectroscopy. Diffuse reflectance spectra (DRS) were used to determine the optical bandgap of the phosphors and were found to be in the optical range 3.52-3.71 eV. Photoluminescence (PL) spectra showed intense yellow emission corresponding to the 4 F9/2 â6 H13/2 transition under 350 nm excitation. Commission International de l'Eclairage colour chromaticity coordinates were evaluated using the PL spectral data lie within the white region. Dexter theory and the Inokuti-Hirayama (I-H) model were applied to study the nature of the energy transfer mechanism in the as-prepared phosphors. The relatively high activation energy of the phosphors was evaluated using temperature-dependent PL (TDPL) data and confirmed the high thermal stability of the titled phosphor. The abovementioned results indicated that the as-prepared KCS:Dy3+ phosphor was a promising candidate for n-UV-based white light-emitting diodes.
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Luminescência , Substâncias Luminescentes , Substâncias Luminescentes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de CálcioRESUMO
BACKGROUND: The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder-dnfp (PTAH)-formerly AR101-has been established in clinical trials, but limited data past the first year of treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy-related quality of life. METHODS: We present a subset analysis of PALISADE-ARC004 participants (aged 4-17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n = 110) or ~2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double-blind, placebo-controlled food challenge (DBPCFC); skin prick testing; peanut-specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores. RESULTS: Continued maintenance with PTAH increased participants' ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose-limiting symptoms. Immune biomarkers showed a pattern consistent with treatment-induced desensitization. Among PTAH-continuing participants, the overall and treatment-related exposure-adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life. CONCLUSIONS: These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.
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Hipersensibilidade Alimentar , Hipersensibilidade a Amendoim , Administração Oral , Adolescente , Alérgenos , Arachis/efeitos adversos , Criança , Pré-Escolar , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Hipersensibilidade Alimentar/etiologia , Humanos , Fatores Imunológicos , Hipersensibilidade a Amendoim/diagnóstico , Hipersensibilidade a Amendoim/etiologia , Hipersensibilidade a Amendoim/terapia , Qualidade de VidaRESUMO
BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
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Alérgenos/administração & dosagem , Arachis/efeitos adversos , Produtos Biológicos/administração & dosagem , Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/terapia , Proteínas de Plantas/administração & dosagem , Administração Oral , Adolescente , Adulto , Fatores Etários , Alérgenos/efeitos adversos , Produtos Biológicos/efeitos adversos , Produtos Biológicos/imunologia , Criança , Pré-Escolar , Dessensibilização Imunológica/efeitos adversos , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Gastroenteropatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Plantas/efeitos adversos , Proteínas de Plantas/imunologia , Adulto JovemRESUMO
The treatment and management of ocular allergy (OA) remain a major concern for different specialties, including allergists, ophthalmologists, primary care physicians, rhinologists, pediatricians, dermatologists, clinical immunologists, and pharmacists. We performed a systematic review of all relevant publications in MEDLINE, Scopus, and Web Science including systematic reviews and meta-analysis. Publications were considered relevant if they addressed treatments, or management strategies of OA. A further wider systematic literature search was performed if no evidence or good quality evidence was found. There are effective drugs for the treatment of OA; however, there is a lack an optimal treatment for the perennial and severe forms. Topical antihistamines, mast cell stabilizers, or double-action drugs are the first choice of treatment. All of them are effective in reducing signs and symptoms of OA. The safety and optimal dosing regimen of the most effective topical anti-inflammatory drugs, corticosteroids, are still a major concern. Topical calcineurin inhibitors may be used in steroid-dependent/resistant cases of severe allergic keratoconjunctivitis. Allergen-specific immunotherapy may be considered in cases of failure of first-line treatments or to modify the natural course of OA disease. Based on the current wealth of publications and on the collective experience, recommendations on management of OA have been proposed.
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Oftalmopatias/diagnóstico , Oftalmopatias/terapia , Hipersensibilidade/diagnóstico , Hipersensibilidade/terapia , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Oftalmopatias/etiologia , Humanos , Hipersensibilidade/etiologia , Fatores de Risco , Resultado do TratamentoRESUMO
AIMS: In amyotrophic lateral sclerosis (ALS), death wish is expressed in a varying proportion of patients in different countries. In this first study from India, influence of belief system of religion/spirituality and attitude towards death, widely prevalent in the country, in decision making, was evaluated. MATERIAL AND METHODS: Twenty ALS patients were assessed using 'Wish-to-Die Questionnaire' (WDQ) developed to reflect seven domains, namely religion/spirituality, belief in karma, meaning of life, hope, family support, financial support and death wish. Functional impairment, depression, hopelessness and suicidal ideation were assessed by ALS Functional Rating Scale, Beck's Depression Inventory, Beck Hopelessness Scale and The Scale of Suicidal Ideation, respectively. RESULTS: On WDQ, all the 20 patients had belief in religion/spirituality, had hope and family support. Nineteen patients (95%) believed in karma, 16 (80%) still found life meaningful and 15 (75%) had financial support. Six patients (30%) had mild to moderate depression; hopelessness was present in 6 (30%) and suicidal ideation was present in one (5%). The 5 (25%) patients who expressed death wish did not significantly differ from others in 6 domains (religion/spirituality, belief in karma, meaning of life, hope, family support, financial support) of WDQ. The main reason in 3 patients who expressed death wish was lack of financial support. The fourth patient could not find meaning of life after the onset of illness, and the fifth wished to end his life since he had satisfactorily fulfilled all his responsibilities. CONCLUSION: Smaller proportion of patients of ALS expressed death wish in India compared to the Western countries. This may be attributed to belief in religion/spirituality and karma, having meaning of life and family support. As this is the first report from India, useful information may be obtained if similar studies are done on a larger sample.
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Esclerose Lateral Amiotrófica/psicologia , Atitude Frente a Morte , Transtorno Depressivo/psicologia , Status Econômico , Família , Religião e Psicologia , Apoio Social , Ideação Suicida , Adulto , Idoso , Atitude Frente a Morte/etnologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
The Schiff base 4-hydroxy-benzoic acid (4-diethylamino-2-hydroxy-benzylidene) hydrazide (SL) was synthesized and characterized. Its antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging action. Being a potent antioxidant its binding ability to the transport protein bovine serum albumin (BSA) was studied using fluorescence quenching and circular dichroism (CD) studies. The binding distance has been calculated by fluorescence resonance energy transfer (FRET) to be 1.85 Å and the Stern-Volmer quenching constant has been calculated to be (3.23 ± 0.45) × 10(5) M(-1). Quantum chemical analysis was carried out for the Schiff base using DFT with B3LYP and 6-311G** and related to the experimentally obtained results. For a deeper understanding of the mechanism of the interaction, the experimental data were complemented by protein-Schiff base docking calculations using Argus Lab.
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Antioxidantes/química , Etilaminas/química , Transferência Ressonante de Energia de Fluorescência , Hidrazinas/química , Simulação de Acoplamento Molecular , Teoria Quântica , Soroalbumina Bovina/química , Animais , Antioxidantes/síntese química , Bovinos , Dicroísmo Circular , Etilaminas/síntese química , Fluorescência , Hidrazinas/síntese químicaRESUMO
BACKGROUND: The incidence of anaphylaxis might be increasing. Data for fatal anaphylaxis are limited because of the rarity of this outcome. OBJECTIVE: We sought to document trends in anaphylaxis admissions and fatalities by age, sex, and cause in England and Wales over a 20-year period. METHODS: We extracted data from national databases that record hospital admissions and fatalities caused by anaphylaxis in England and Wales (1992-2012) and crosschecked fatalities against a prospective fatal anaphylaxis registry. We examined time trends and age distribution for fatal anaphylaxis caused by food, drugs, and insect stings. RESULTS: Hospital admissions from all-cause anaphylaxis increased by 615% over the time period studied, but annual fatality rates remained stable at 0.047 cases (95% CI, 0.042-0.052 cases) per 100,000 population. Admission and fatality rates for drug- and insect sting-induced anaphylaxis were highest in the group aged 60 years and older. In contrast, admissions because of food-triggered anaphylaxis were most common in young people, with a marked peak in the incidence of fatal food reactions during the second and third decades of life. These findings are not explained by age-related differences in rates of hospitalization. CONCLUSIONS: Hospitalizations for anaphylaxis increased between 1992 and 2012, but the incidence of fatal anaphylaxis did not. This might be due to increasing awareness of the diagnosis, shifting patterns of behavior in patients and health care providers, or both. The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent, which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades.
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Anafilaxia/epidemiologia , Hospitalização , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Anafilaxia/etiologia , Anafilaxia/história , Anafilaxia/mortalidade , Criança , Pré-Escolar , Epinefrina/administração & dosagem , Feminino , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , História do Século XX , História do Século XXI , Mortalidade Hospitalar , Humanos , Doença Iatrogênica , Lactente , Recém-Nascido , Mordeduras e Picadas de Insetos , Masculino , Pessoa de Meia-Idade , Mortalidade , Admissão do Paciente , Fatores de Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells. METHODS: Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo. RESULTS: Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model. CONCLUSIONS: Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.
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Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Genes Supressores de Tumor/fisiologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução GenéticaAssuntos
Hipersensibilidade a Amendoim , Alérgenos , Arachis/imunologia , Basófilos , Criança , Humanos , Imunoglobulina E , Testes CutâneosRESUMO
Across the globe, snake envenomation causes significant morbidity and mortality. Although many clinical presentations and complications are observed in different types of snake bites, the incidence of leukoencephalopathy is rare. Although most cases of leukoencephalopathy are seen in viper bites, they are rarely seen in neurotoxic snake bites. In this report, we present a unique case of snake bite-induced leukoencephalopathy following a neurotoxic snake bite. The case highlights the importance of considering this rare complication in cases of snake bites presenting with neurological symptoms, particularly in those affecting higher mental functions.
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Alérgenos/administração & dosagem , Arachis/imunologia , Dessensibilização Imunológica/métodos , Tolerância Imunológica , Hipersensibilidade a Amendoim/prevenção & controle , Administração Oral , Adolescente , Arachis/química , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Monitorização Fisiológica , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/fisiopatologia , AutoadministraçãoRESUMO
Background: Investigating the core component of social cognition, known as the theory of mind (ToM), becomes imperative in patients with moderate-to-severe traumatic brain injury (TBI) as they may present with social cognitive deficit-related disability interfering with patients' functional and behavioral status. Aims: This study aimed to investigate the neurocognitive and behavioral predictors of the ToM in patients with traumatic brain injury (PtTBI). Settings and Design: Thirty PtTBI and 30 healthy controls (HCs) were assessed on a set of tasks. Methods and Material: The assessment included ToM tasks (cognitive and affective, verbal and nonverbal, and first-order and second-order) along with various neuropsychological (NP) assessments to explore their memory, executive functioning, and intelligence. Further, TBI participants also underwent behavioral and functional outcome measures using the Functional Status Examination (FSE) and the Neurobehavioral Rating Scale (NBRS). Statistical Analysis: The obtained data were analyzed using descriptive statistics and regression analyses. Results: Findings confirmed ToM deficit across all modes of ToM tasks in PtTBI and implicated the role of executive function and working memory in the expression of ToM in this group. While cognitive faux pas (FPC) and first-order false belief together could explain poor performance on NBRS, the nonverbal ToM task predicts functional outcome in PtTBI. Conclusions: These findings have practical implications as they promote cognitive remediation intervention focused on restoring ToM, which may improve functional limitations and resulting disability in PtTBI.
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Background: The worldwide spread of COVID-19 infection and its preventive measures has resulted in global disruption of overall functioning of the individuals. In the post-COVID period, several stressors associated with the pandemic have exacerbated adjustment problems in students and impacted their mental health. Purpose: The study aims to assess the Academic Stress and Emotional Adjustment of male and female secondary school students in Uttar Pradesh, post-COVID-19 pandemic lockdown. Methods: A sample of 500 students from various schools in Uttar Pradesh pursuing high school were included in the study. A purposive sampling technique was employed for data collection based on inclusion and exclusion criteria. The Scale for Assessing Academic Stress and the Adolescents Emotional Adjustment Inventory were used to assess the academic stress and emotional adjustment of secondary school students post-COVID-19 pandemic lockdown. Results: The results of the study revealed that there was a significant difference in academic stress and emotional adjustment between male and female secondary school students. A significant positive relationship between academic stress and emotional adjustment was found, which indicates a high level of academic stress perpetuates emotional maladjustment. Furthermore, it was found that the level of academic stress and emotional adjustment were higher among females as compared to males. Conclusion: It can be concluded that the extended impact of COVID-19 has led to a surfeited level of distress propounding that females are more predisposed to academic stress and tend to have poor emotional adjustment than their male counterparts.
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Anaplastic thyroid cancer (ATC) is a rare and aggressive disease with 90% of patients succumbing to this disease 1 year after diagnosis. The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients. However, resistance to therapy remains a major problem. We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response. Herein, we determined that AKT is not a major mediator of sensitivity and instead PIK3CA-mutants that are resistant to combined dasatinib and trametinib have sustained activation of PDK1 signaling. Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.
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Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-akt , Dasatinibe/farmacologia , Proteínas Proto-Oncogênicas B-raf , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
Background: The existing structural framework of defining gender and sexuality based on heteronormative ideology led to the succession of the notions of stigma, prejudice, and hate towards the sexual and gender minority population. The presence of strong scientific evidence for the negative consequences of discriminatory and violent events has directed the association with mental and emotional distress. This study aims to comprehend the role of minority stress in emotional regulation and suppression among the sexual minority population globally using systematic review of literature through elaborate Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Summary: The analyses of the sorted literature premised on the PRISMA guidelines revealed that minority stress mediates the emotion regulation processes among the individuals who witness continuous episodes of discrimination and violence leading to emotional dysregulation and emotion suppression. Studies also reported the dominance of various health-risk behaviors such as alcohol addiction, drug abuse, and other forms of intoxication among sexual minority individuals. Increased instances of anxiety, stress, depression, and suicidal ideations were prominent in the findings of the empirical research suggesting an intricate role of minority stress in advancing the faulty emotion suppression and mental health concerns among the sexual and gender minority population. Key message: Minority stressors among sexual and gender minority individuals mediate emotion suppression and mental distress.
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Vernal keratoconjunctivitis (VKC) is a form of ocular allergy primarily affecting children. Considered a rare disease in Europe, its prevalence varies by geographic region and is poorly studied in the United Kingdom. There is considerable national variation in the management of VKC within the United Kingdom, risking misdiagnosis and delays to treatment for some children. This can significantly impact their quality of life, with the potential for lasting negative consequences. Based on discussions between experienced clinicians from six large centers across the United Kingdom, this article describes best practice recommendations for United Kingdom settings, including principles for diagnosis, referral, initial and long-term management, and supportive care. Recommendations include guidance on referral timing, which should depend on VKC severity, and a stepwise approach to treatment. Joint management by primary care and secondary care is recommended and the importance of supportive care, including emotional support and outreach to schools, is highlighted. Because frequent flareups are common in VKC, it is essential that families have access to the information they need to manage the disease and routes to access rapid care if needed. A thorough understanding of the nature of VKC, its triggers, and how best to manage it, by both patients and their families, is critical to ensuring appropriate management and to improving patient outcomes. [J Pediatr Ophthalmol Strabismus. 2023;60(1):6-17.].
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Conjuntivite Alérgica , Humanos , Criança , Conjuntivite Alérgica/diagnóstico , Conjuntivite Alérgica/epidemiologia , Conjuntivite Alérgica/terapia , Qualidade de Vida , Olho , Reino Unido/epidemiologia , PrevalênciaRESUMO
Patients with advanced thyroid cancer, including advanced papillary thyroid cancer and anaplastic thyroid cancer (ATC), have low survival rates because of the lack of efficient therapies available that can combat their aggressiveness. A total of 90% of thyroid cancers have identifiable driver mutations, which often are components of the MAPK pathway, including BRAF, RAS, and RET-fusions. In addition, Src is a non-receptor tyrosine kinase that is overexpressed and activated in thyroid cancer, which we and others have shown is a clinically relevant target. We have previously demonstrated that combined inhibition of Src with dasatinib and the MAPK pathway with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells. Herein, we identified the pro-apoptotic protein BCL2L11 (BIM) as being a key mediator of sensitivity in response to combined dasatinib and trametinib treatment. Specifically, cells that are sensitive to combined dasatinib and trametinib treatment have inhibition of FAK/Src, MEK/ERK, and AKT, resulting in the dramatic upregulation of BIM, while cells that are resistant lack inhibition of AKT and have a dampened induction of BIM. Inhibition of AKT directly sensitizes resistant cells to combined dasatinib and trametinib but will not be clinically feasible. Importantly, targeting BCL-XL with the BH3-mimeitc ABT-263 is sufficient to overcome lack of BIM induction and sensitize resistant cells to combined dasatinib and trametinib treatment. This study provides evidence that combined Src and MEK1/2 inhibition is a promising therapeutic option for patients with advanced thyroid cancer and identifies BIM induction as a potential biomarker of response.
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Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease characterized by chronic inflammation of the cornea and conjunctiva that may lead to loss of visual acuity and blindness. The disease occurs primarily in children and is more common in geographical regions characterized by warm temperatures and high humidity. The clinical manifestations of VKC, when inadequately treated, may lead to severe complications and corneal damage. The prevalence of allergen sensitization, specific serum immunoglobulin E (IgE), and specific tear IgE was reported in approximately 55%-60% of patients with VKC, confirming the involvement of IgE-mediated and non-IgE-mediated mechanisms in the pathophysiology of the condition. This article explores current knowledge on the immunological pathways of VKC and the role of the monoclonal anti-IgE antibody, omalizumab, in its management. The review evaluated the effects of omalizumab beyond the direct IgE-mediated reactions and discusses its potential as a therapeutic target for VKC. Multiple retrospective analyses, case series, and case reports have reported the effectiveness of omalizumab in the management of VKC. A summary of the clinical data from these studies revealed that in children with VKC omalizumab treatment was well tolerated with improvement or resolution of ocular symptoms, reduction in steroid use, and enhancement of quality of life. Omalizumab may serve as a promising treatment option for VKC due to its ability to target both IgE-mediated and non-IgE-mediated pathophysiological pathways. Larger, controlled clinical trials are needed to support these findings.
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Introduction: Conversion disorder is easily one of the least understood neuropsychiatric disorders. There is a great deal of ambiguity with respect to symptom presentation, assessment, etiology, diagnosis, and treatment. However, a common clinical practice associated with the assessment and management of the conversion disorder is the evaluation of a stressor. Recent studies in India have indicated that family stressors are the most frequent. Sociocultural aspects of the client's environment and the illness experience thus form an important part of the client's diagnostic formulation. These aspects also determine help-seeking, treatment adherence, and thus, the outcomes. Materials and Methods: Fifteen clients suffering from conversion disorder in a tertiary mental health setting in North India, recruited through purposive sampling, were interviewed in-depth. Data were elicited using the cultural formulation interview (CFI). Qualitative content analysis was carried out. Results: The content analyses summarized the cultural experiences of clients suffering from conversion disorder under structured domains of the CFI. The results are presented in tables along with content examples and represent individual client experiences and conceptualizations of diagnosis, treatment, and implications of suffering from conversion disorder. The findings of this study aim to describe and highlight the cultural experiences of clients with respect to their psychopathology. The most striking recurrent theme in the cultural formulations were the lack of understanding of the nature and cause of illness both in the client as well as the clinician, and therefore a lack of trust and hope in the treatment. Conclusion: The findings of the current study shed light on the cultural experiences of clients with conversion disorder. These findings emphasize the need for clinicians to incorporate the individual and collective cultural experiences of clients and cultural sensitivity in addition to the clinical diagnoses. The Cultural Formulation Interview of the DSM-5 was found to be very helpful in this regard and we encourage its use by clinicians, especially with clients suffering from conversion disorder, given the strong influences of socio-cultural experiences on psychopathology as well as the intervention.
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Although there is a general perception that the prevalence of food allergy is increasing, data supporting this are limited. Food is the least common cause of fatal anaphylaxis, and fortunately, it is a very rare event; however, it is also unpredictable. There is widespread consensus that severe reactions cannot be predicted in a clinically meaningful way. Certain food triggers are more frequently associated with fatal anaphylaxis than others. In observational studies, peanut and tree nuts account for at least 30% to 50% of fatalities, with seafood and cow's milk also associated with fatal reactions. Fatal food-induced anaphylaxis is most likely to occur during adolescence and young adulthood, although the reasons for this are unclear. International guidelines agree that intramuscular (IM) epinephrine is the treatment of choice for managing food-triggered anaphylaxis and has a good safety profile when given by the IM route. However, fatalities still occur despite the timely administration of epinephrine. Food-allergic individuals must navigate a world that requires daily vigilance for allergens and preparedness for allergic reactions. Although the actual risk of fatal reactions is minimal, it is not zero, and severe reactions are unpredictable. Clinicians need to help patients better understand the very low but real risk of fatal reaction and enable them to lead as normal a life as possible through appropriate education, safety netting, and risk reduction.