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The presence of pharmaceutical pollutants in water sources has become a growing concern due to its potential impacts on human health and other organisms. The physicochemical properties of pharmaceuticals based on their intended therapeutical application, which include antibiotics, hormones, analgesics, and antidepressants, is quite diverse. Their presence in wastewater, sewerage water, surface water, ground water and even in drinking water is reported by many researchers throughout the world. Human exposure to these pollutants through drinking water or consumption of aquatic and terrestrial organisms has raised concerns about potential adverse effects, such as endocrine disruption, antibiotic resistance, and developmental abnormalities. Once in the environment, they can persist, undergo transformation, or degrade, leading to a complex mixture of contaminants. Application of treated wastewater, compost, manures or biosolids in agricultural fields introduce pharmaceutical pollutants in the environment. As pharmaceuticals are diverse in nature, significant differences are observed during their uptake and accumulation in plants. While there have been extensive studies on aquatic ecosystems, the effect on agricultural land is more disparate. As of now, there are few reports available on the potential of plant uptake and transportation of pharmaceuticals within and between plant organs. This review summarizes the occurrence of pharmaceuticals in aquatic water bodies at a range of concentrations and their uptake, accumulation, and transport within plant tissues. Research gaps on pharmaceutical pollutants' specific effect on plant growth and future research scopes are highlighted. The factors affecting uptake of pharmaceuticals including hydrophobicity, ionization, physicochemical properties (pKa, logKow, pH, Henry's law constant) are discussed. Finally, metabolism of pharmaceuticals within plant cells through metabolism phase enzymes and plant responses to pharmaceuticals are reviewed.
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BACKGROUND: The role of children and staff in SARS-CoV-2 transmission outside and within households is still not fully understood when large numbers are in regular, frequent contact in schools. METHODS: We used the self-controlled case-series method during the alpha- and delta-dominant periods to explore the incidence of infection in periods around a household member infection, relative to periods without household infection, in a cohort of primary and secondary English schoolchildren and staff from November 2020 to July 2021. RESULTS: We found the relative incidence of infection in students and staff was highest in the 1-7 days following household infection, remaining high up to 14 days after, with risk also elevated in the 6--12 days before household infection. Younger students had a higher relative incidence following household infection, suggesting household transmission may play a more prominent role compared with older students. The relative incidence was also higher among students in the alpha variant dominant period. CONCLUSIONS: This analysis suggests SARS-CoV2 infection in children, young people and staff at English schools were more likely to be associated with within-household transmission than from outside the household, but that a small increased risk of seeding from outside is observed.
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COVID-19 , Composición Familiar , SARS-CoV-2 , Instituciones Académicas , Estudiantes , Humanos , COVID-19/epidemiología , COVID-19/transmisión , Niño , Inglaterra/epidemiología , Incidencia , Estudiantes/estadística & datos numéricos , Femenino , Masculino , Adolescente , Adulto , Adulto Joven , Persona de Mediana EdadRESUMEN
Most patients diagnosed with and dying from cancer in Canada are older adults, with aging contributing to the large projected growth in cancer incidence. Older adults with cancer have unique needs, and on a global scale increasing efforts have been made to address recognized gaps in their cancer care. However, in Canada, geriatric oncology remains a new and developing field. There is increasing recognition of the value of geriatric oncology and there is a growing number of healthcare providers interested in developing the field. While there is an increasing number of dedicated programs in geriatric oncology, they remain limited overall. Developing novel methods to delivery geriatric care in the oncology setting and improving visibility is important. Formal incorporation of a geriatric oncology curriculum into training is critical to both improve knowledge and demonstrate its value to healthcare providers. Although a robust group of dedicated researchers exist, increased collaboration is needed to capitalize on existing expertise. Dedicated funding is critical to promoting clinical programs, research, and training new clinicians and leaders in the field. By addressing challenges and capitalizing on opportunities for improvement, Canada can better meet the unique needs of its aging population with cancer and ultimately improve their outcomes.
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Neoplasias , Humanos , Canadá , Neoplasias/terapia , Anciano , Oncología Médica/métodos , Geriatría/métodos , Anciano de 80 o más Años , Mejoramiento de la CalidadRESUMEN
Background: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions). Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death). Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate. Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.
Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.
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BACKGROUND AND PURPOSE: Conclusions from prior literature regarding the impact of sex, age, and height on spinal cord (SC) MRI morphometrics are conflicting, while the effect of body weight on SC morphometrics has been found to be nonsignificant. The purpose of this case-control study is to assess the associations between cervical SC MRI morphometric parameters and age, sex, height, and weight to establish their potential role as confounding variables in a clinical study of people with multiple sclerosis (MS) compared to a cohort of healthy volunteers. METHODS: Sixty-nine healthy volunteers and 31 people with MS underwent cervical SC MRI at 3 Tesla field strength. Images were centered at the C3/C4 intervertebral disc and processed using Spinal Cord Toolbox v.4.0.2. Mixed-effects linear regression models were used to evaluate the effects of biological variables and disease status on morphometric parameters. RESULTS: Sex, age, and height had significant effects on cord and gray matter (GM) cross-sectional area (CSA) as well as the GM:cord CSA ratio. There were no significant effects of body weight on morphometric parameters. The effect of MS disease duration on cord CSA in the C4 level was significant when controlling for all other variables. CONCLUSIONS: Studies of disease-related changes in SC morphometry should control for sex, age, and height to account for physiological variation.
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Médula Cervical , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Adulto , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Médula Cervical/diagnóstico por imagen , Médula Cervical/patología , Persona de Mediana Edad , Vértebras Cervicales/diagnóstico por imagen , Adulto Joven , Estudios de Casos y Controles , Valores de ReferenciaRESUMEN
Russia has higher cardiovascular disease (CVD) mortality compared to other European countries. The major CVD risk factors are age, male sex, and three conditions, namely hypertension, hypercholesterolemia, and diabetes mellitus (DM). This study aimed to assess awareness of these three conditions among Russian adults (N = 3803) and the associated socio-demographic, lifestyle, and health characteristics. We used cross-sectional data from a randomly drawn population-based sample of Russians aged 35-69 years, who participated in the Know Your Heart (KYH) study conducted in Arkhangelsk and Novosibirsk between 2015-2018. Participants' self-reported awareness of hypertension, hypercholesterolemia, and DM was assessed against the measures at the KYH health check (blood pressure, cholesterol, HbA1c and/or use of medication for each condition). Prevalence estimates for the awareness were age- and sex-standardized to the Standard European Population. Socio-demographic, lifestyle, and health-related correlates of the awareness were investigated using logistic regression modelling. Among participants with hypertension (N = 2206), hypercholesterolemia (N = 3171), and DM (N = 329) recorded at a health check, 79%, 45%, and 61% self-reported these conditions, respectively. Higher awareness of hypercholesterolemia and hypertension was associated with older age, female sex, nonsmoking status, obesity, and history of CVD diagnoses. Low household income and history of CVD diagnoses were associated with being aware of DM. The awareness rates of hypertension were relatively high, whereas awareness rates of hypercholesterolemia and DM were relatively low. CVD prevention and early intervention could be improved in Russia through increasing the awareness of the risk factors.
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There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Antígeno B7-H1 , Biomarcadores , Factores Inmunológicos , Inmunoterapia , Biomarcadores de TumorRESUMEN
Background: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations. Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons. Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.
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The efficacy of explicit measures in assessing fire interest is often compromised by social desirability biases, presenting a challenge for early intervention programs aimed at preventing firesetting behaviour. The current study aimed to validate a novel fire interest Implicit Association Task (IAT), as a more reliable measure of implicit fire interest in adolescents. An Australian community adolescent sample of 85 participants, aged 10-17 (M = 13.65, SD = 1.81), completed a series of questionnaires, and the novel fire interest IAT. Based on self-reports, participants were classified as firelighters (n = 52) or non-firelighters (n = 33). IAT outcomes revealed an inclination towards associating "fire" with "interesting." Notably, firelighters, compared to non-firelighters, performed significantly quicker during hypothesis-consistent trials of the IAT where fire-images were paired with interesting-words. Moreover, a weak correlation emerged between the speed of responses in these hypothesis-consistent IAT trials and self-reported fire interest. This investigation is one of the few that examined the efficacy of implicit measures of fire interest and is the first to do so using a modified IAT. With continued refinement, the fire interest IAT could be successfully used to assist with early intervention programs aimed at preventing child firesetting behaviour. PsychINFO Code: 3230.
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Piromanía , Humanos , Adolescente , Femenino , Masculino , Niño , Encuestas y Cuestionarios , Tiempo de Reacción/fisiología , Australia , AsociaciónRESUMEN
PURPOSE OF REVIEW: This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. RECENT FINDINGS: ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Anciano , Envejecimiento/inmunología , Geriatría/métodos , Oncología Médica/métodos , Inmunoterapia/métodosRESUMEN
OBJECTIVE: The aim of this study was to assess the efficacy and safety of a third-generation lentivirus-based vector encoding the feline erythropoietin (EPO) (feEPO) gene in vitro and in rodent models in vivo. This vector incorporates a genetic mechanism to facilitate the termination of the therapeutic effect in the event of supraphysiologic polycythemia, the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene." ANIMALS: CFRK cells and replication-defective lentiviral vectors encoding feEPO were used for in vitro experiments. Eight Fischer rats were enrolled in the pilot in vivo study, 24 EPO-deficient mice were used in the initial mouse study, and 15 EPO-deficient mice were enrolled in the final mouse study. METHODS: Efficacy of a third-generation lentivirus encoding feEPO was determined in vitro using western blot assays. Subsequently, in a series of rodent experiments, animals were administered the viral vector in progressively increasing inoculation doses with serial measurements of blood packed cell volume (PCV) over time. RESULTS: We documented production of feEPO protein in transduced CRFK cells with subsequent cessation of production when treated with the HSV-TK substrate ganciclovir. In vivo, we demonstrated variably persistent elevated PCV values in treated rats and mice with eventual return to baseline values over time. CLINICAL RELEVANCE: These results provide justification for a lentiviral gene therapy approach to the treatment of nonregenerative anemia associated with chronic renal disease in cats.
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Anemia , Eritropoyetina , Terapia Genética , Vectores Genéticos , Lentivirus , Ratas Endogámicas F344 , Animales , Eritropoyetina/genética , Terapia Genética/veterinaria , Lentivirus/genética , Ratones , Anemia/veterinaria , Anemia/terapia , Gatos , Ratas , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/veterinaria , Masculino , Femenino , Línea CelularRESUMEN
The DREAMS partnership aims to deliver a comprehensive package to reduce HIV incidence among adolescent girls and young women (AGYW), including through shifting gender norms. We evaluate DREAMS' effect on attitudes towards gender norms in two Kenyan settings. AGYW aged 15-22 in Nairobi (n = 852) and Gem (n = 761) were randomly selected for cohort enrolment in 2017-18 and followed-up to 2019. We described the proportion of AGYW and their male peers with equitable attitudes towards gender norms, using an adapted version of the GEM scale. We estimated the association between self-reported invitation to DREAMS (in 2017-18) and AGYW's attitudes towards two dimensions of gender norms, and then applied a causal inference framework to estimate the difference in the proportion of AGYW with equitable attitudes under the counterfactual scenarios that all versus none were DREAMS beneficiaries. We estimated that overall, 90.2% versus 87.1% of AGYW would have equitable norms around sexual and reproductive health decision-making in Nairobi if all versus none were DREAMS beneficiaries (+3.1; 95%CI:-2.5, +9.0). In Gem, we estimated a risk difference of +1.0 (89.6% vs 88.6%, 95%CI: -3.6,+5.6). There was no evidence for an effect of DREAMS on attitudes towards violence-related norms (Nairobi: 82.7% vs 82.2%, +0.5; 95%CI: -5.3,+6.5; Gem: 44.3% vs 48.2%, -3.9; 95%CI: -11.7,+3.0). We found no evidence of an impact of DREAMS invitation on individual attitudes towards gender norms. In some cases, equitable attitudes at enrolment left limited scope for improvement, and additional effort may be required to shift inequitable violence attitudes among both AGYW and their male peers.
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In the original publication [...].
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The enzyme choline acetyltransferase (ChAT) synthesizes acetylcholine from acetyl-CoA and choline at the neuromuscular junction and at the nerve terminals of cholinergic neurons. Mutations in the ChAT gene (CHAT) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for Chat (Chat-/-) die at birth. To circumvent the lethality of this model, we crossed mutant mice possessing loxP sites flanking Chat exons 4 and 5 with mice that expressed Cre-ERT2. Injection of tamoxifen (Tx) at postnatal (P) day 11 in these mice induced downregulation of Chat, autonomic failure, weakness, and death. However, a proportion of Chatflox/flox-Cre-ERT2 mice receiving at birth an intracerebroventricular injection of 2 × 1013 vg/kg adeno-associated virus type 9 (AAV9) carrying human CHAT (AAV9-CHAT) survived a subsequent Tx injection and lived to adulthood without showing signs of weakness. Likewise, injection of AA9-CHAT by intracisternal injection at P28 after the onset of weakness also resulted in survival to adulthood. The expression of Chat in spinal motor neurons of Chatflox/flox-Cre-ERT2 mice injected with Tx was markedly reduced, but AAV-injected mice showed a robust recovery of ChAT expression, which was mainly translated by the human CHAT RNA. The biodistribution of the viral genome was widespread but maximal in the spinal cord and brain of AAV-injected mice. No significant histopathological changes were observed in the brain, liver, and heart of AAV-injected mice after 1 year follow-up. Thus, AAV9-mediated gene therapy may provide an effective and safe treatment for patients severely affected with CHAT-CMS.
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Colina O-Acetiltransferasa , Dependovirus , Ratones , Humanos , Animales , Colina O-Acetiltransferasa/genética , Colina O-Acetiltransferasa/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Distribución Tisular , Ratones Noqueados , Terapia GenéticaRESUMEN
Investigating the relationship between alcohol consumption and physical performance, we used data from the 2015-2018 Know Your Heart study on 4215 adults aged 35-69 from Arkhangelsk and Novosibirsk, Russia. We classified participants' drinking status into non-drinking, non-problem drinking, hazardous drinking, and harmful drinking based on their self-reported drinking behaviors. To evaluate physical performance, we developed a Composite Physical Performance Scale (CPPS), which combined the results of three functional tests: grip strength (GS), closed-eyes balance, and chair rises (CR). We applied multivariable linear regression to assess the relationship between alcohol consumption and CPPS score, and ordinal logistic regression to explore the associations between alcohol consumption and the three functional tests separately. The results showed that harmful drinking was associated with lower CPPS scores compared to non-problem drinking. Among harmful drinking men, the decrease in CPPS scores was explained by all three tests equally and exceptionally by GS among women. Non-drinking was also associated with decreased CPPS, linked to lower GS and CR scores in men, and only lower GS scores in women. The study revealed a reduced physical performance in the non-drinking and harmful drinking groups compared to non-problem drinking.
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Consumo de Bebidas Alcohólicas , Alcoholismo , Masculino , Adulto , Humanos , Femenino , Consumo de Bebidas Alcohólicas/epidemiología , Autoinforme , Rendimiento Físico Funcional , Federación de Rusia/epidemiologíaRESUMEN
Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.
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Ceramidas , Proteínas de Unión al GTP , Animales , Humanos , Longevidad/genética , Células Endoteliales/metabolismo , Mamíferos/metabolismoRESUMEN
Importance: Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined. Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs. Design, Setting, and Participants: This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line. Exposure: Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs). Main Outcomes and Measures: The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS. Results: Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001). Conclusions and Relevance: In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alberta/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Cohortes , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Pacientes Ambulatorios , Estudios Retrospectivos , Adolescente , AdultoRESUMEN
The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.
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Alucinógenos , Profármacos , Humanos , Psilocibina/farmacología , Psilocibina/uso terapéutico , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológicoRESUMEN
BACKGROUND: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system. METHODS: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes. RESULTS: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring. CONCLUSIONS: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC.