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OBJECTIVE: Pharmacy students must be able to locate and use legal resources to prepare for licensure and be practice-ready. We aimed to assess pharmacy students' ability and confidence in locating and using publicly available legal resources. METHODS: The "Locate the Law" activity was implemented in a pharmacy law course in the fall of 2021, 2022, and 2023 for third-year pharmacy students at 1 college of pharmacy in the Mid-South. The activity consisted of a 108-question (61 law questions) survey that evaluated the students' confidence before and after they were required to locate publicly available legal resources online and answer a set of guided questions about each resource. Descriptive and inferential statistics were conducted to evaluate student responses. The University of Tennessee Institutional Review Board approved this study. RESULTS: A total of 363 students participated in the study (response rate: 77%) over a 3-year period. Most students were female (67%), on average 25 years old, and reported having pharmacy work experience (95%). Before the activity, students reported being slight to somewhat confident in finding a statute (mean [M]: 2.5) or regulation (M: 2.5). Most graded question responses averaged ≥ 90%, and no question scored below a 75% average. After the activity, students' confidence increased significantly increased in finding a statute (M: 4.1) or regulation (M: 4.1). CONCLUSION: The "Locate the Law" activity significantly improved student pharmacists' self-reported confidence in locating publicly available legal resources, and most students correctly answered most activity questions. Pharmacy law educators should consider incorporating training on using legal resources in the pharmacy law course.
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OBJECTIVES: To summarise the rationale, workflow and recommendations for the conduct of exposure assessment critiques in key human studies evaluated for International Agency for Research on Cancer (IARC) Monographs on the Identification of Carcinogenic Hazards. METHODS: Approaches to evaluating exposure assessment quality in human cancer and mechanistic studies were reviewed according to the precepts outlined in the IARC Monographs Preamble, using two agents as case studies. Exposure assessment 'domains', that is, salient aspects of exposure assessment for the agent under evaluation, were selected for review across the key human studies. RESULTS: The case studies of night shift work (volume 124) and 1,1,1-trichloroethane (volume 130) used a common approach, tailored to the agents' specific exposure scenarios, to evaluate exposure assessment quality. Based on the experiences of IARC Working Groups to date, the implementation of exposure assessment critique requires the need for agent-specific knowledge, consideration of the validity of time-varying exposure metrics related to duration and intensity, and transparent, concise reviews that prioritise the most important strengths and limitations of exposure assessment methods used in human studies. CONCLUSIONS: Exposure assessment has not historically been a fully appreciated component for evaluating the quality of epidemiological studies in cancer hazard identification. Exposure assessment critique in key human cancer and mechanistic studies is now an integral part of IARC Monographs evaluations and its conduct will continue to evolve as new agents are evaluated. The approaches identified here should be considered as a potential framework by others when evaluating the exposure assessment component of epidemiological studies for systematic reviews.
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Carcinógenos , Exposición Profesional , Humanos , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Carcinógenos/toxicidad , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Medición de Riesgo/métodos , Horario de Trabajo por Turnos/efectos adversos , Agencias InternacionalesAsunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Adolescente , Estados Unidos , Femenino , Masculino , Fármacos Anti-VIH/uso terapéutico , Adulto Joven , Aceptación de la Atención de Salud/estadística & datos numéricos , Niño , Cumplimiento de la Medicación/estadística & datos numéricosRESUMEN
This retrospective study examined the predictive ability of cognitive and non-cognitive factors, including grit, on first attempt pass rate on the National Board for Certification in Occupational Therapy exam. A convenience sample of 226 graduates from six cohorts of one occupational therapy program was used. Binary logistic regression revealed that grit was not a significant predictor. Program grade point average and verbal and quantitative Graduate Record Examination scores were independent predictors of passing on the first attempt. These findings can be used to identify at-risk students who could benefit from support to increase student success on the licensure exam.
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BACKGROUND: Emerging adults (aged 18-29) are less likely to receive the COVID-19 vaccine than any other adult age group. Black Americans are less likely than non-Hispanic white Americans to be fully vaccinated against COVID-19. This study explored factors which affect vaccine intention and attitudes in Black American emerging adults with asthma. METHODS: Participants were recruited from an NHLBI-funded clinical trial to improve asthma control. Fifty-nine Black American emerging adults completed a Qualtrics survey that assessed asthma control, intention to vaccinate, and factors which may affect the decision to vaccinate. Twenty-five participants also completed a semi-structured interview via Zoom. Bivariate correlations and descriptive statistics, including Chi Square analyses, were run using SPSS. Interview thematic analyses were conducted via QDA Miner. RESULTS: Of the 59 Black American emerging adults with asthma who completed surveys, 32.2% responded that they were highly unlikely to receive the COVID-19 vaccine, while 50.8% responded that they were highly likely to receive it. Increased asthma control was significantly correlated with a higher likelihood to discuss the COVID-19 vaccine with their healthcare provider (ρ = 0.339, α = 0.011). Concerns about immediate (ρ= -0.261, α = 0.050) and long-term (ρ= -0.280, α = 0.035) side effects were inversely correlated with intention to vaccinate. Only 17% of the participants who were unemployed stated that they were highly likely to receive the vaccines compared to 65% of the participants who were employed; however, interview participants who were unemployed stated not needing the vaccine because they were protecting themselves by social distancing. When deciding whether to receive the vaccine, safety, efficacy, and immediate side effects were the top three factors for 91%, 54%, and 49% of the participants, respectively. Beliefs about the vaccines' safety and efficacy, information gathering, personal factors, and societal factors emerged as important themes from the interviews. CONCLUSION: Only half of the surveyed Black American emerging adults with asthma were highly likely to receive the COVID-19 vaccine. Safety and efficacy were important for the majority of the participants, regardless of vaccine intention. Greater asthma control, but not access to asthma-related healthcare, was correlated with intention to discuss the vaccine with their healthcare provider.
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Asma , Negro o Afroamericano , Vacunas contra la COVID-19 , COVID-19 , Intención , Humanos , Asma/etnología , Asma/psicología , Adulto , Masculino , Vacunas contra la COVID-19/administración & dosificación , Femenino , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Adulto Joven , COVID-19/prevención & control , COVID-19/etnología , Adolescente , Estados Unidos , Conocimientos, Actitudes y Práctica en Salud , Encuestas y CuestionariosRESUMEN
Preparing the next generation of pharmacists to succeed in practice and provide premier care starts with ensuring pharmacy education standards are met and align with innovative practices and that education incorporates topics that are important to promoting health. For example, recent reports link endocrine disrupting chemicals (EDCs) to numerous diseases such as reproductive disorders, metabolic diseases, and developmental abnormalities. Considering the suboptimal awareness and knowledge about EDCs, it is imperative to provide public health education through a pharmacy curriculum. The objective of this study was to evaluate student pharmacists' perceptions of the impact of a role play activity on their knowledge of EDCs and counseling skills. A secondary objective was to explore student pharmacists' perceptions of how role play might impact their future career as a pharmacist. A retrospective qualitative study consisting of a lecture, a pre-brief, a low-fidelity simulation centered on role-play, and debrief to develop knowledge of EDCs to practice counseling skills, and a post reflection was implemented to explore this aim. Third year student pharmacists who were enrolled on the public health elective course were eligible to participate in the study. All reflections were de-identified, imported into a qualitative software, Dedoose®, Version 9.2.6 and thematically analyzed using an inductive approach. Thematic analysis revealed three master themes, which tell the story of an initial lack of familiarity with EDCs that was rectified by the lecture and low-fidelity simulation. In the first theme, we can see that all of the participants noted their positive perceptions of the low-fidelity simulation, especially the role playing on a topic they lacked familiarity with. In the second theme, participants revealed the activity's impact on their performance or behaviors. Finally, the third theme explores the future implications of a pharmacist's impact on public health. This novel study contributes to a growing body of literature on the impact of pharmacy education practices and instruction on public health. The findings suggest that pharmacy educators might consider incorporating role playing instruction for public health topics, EDCs, or topics not traditionally taught in the pharmacy curriculum.
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BACKGROUND: Air pollution harms health across the life course. Children are at particular risk of adverse effects during development, which may impact on health in later life. Interventions that improve air quality are urgently needed both to improve public health now, and prevent longer-term increased vulnerability to chronic disease. Low Emission Zones are a public health policy intervention aimed at reducing traffic-derived contributions to urban air pollution, but evidence that they deliver health benefits is lacking. We describe a natural experiment study (CHILL: Children's Health in London and Luton) to evaluate the impacts of the introduction of London's Ultra Low Emission Zone (ULEZ) on children's health. METHODS: CHILL is a prospective two-arm parallel longitudinal cohort study recruiting children at age 6-9 years from primary schools in Central London (the focus of the first phase of the ULEZ) and Luton (a comparator site), with the primary outcome being the impact of changes in annual air pollutant exposures (nitrogen oxides [NOx], nitrogen dioxide [NO2], particulate matter with a diameter of less than 2.5micrograms [PM2.5], and less than 10 micrograms [PM10]) across the two sites on lung function growth, measured as post-bronchodilator forced expiratory volume in one second (FEV1) over five years. Secondary outcomes include physical activity, cognitive development, mental health, quality of life, health inequalities, and a range of respiratory and health economic data. DISCUSSION: CHILL's prospective parallel cohort design will enable robust conclusions to be drawn on the effectiveness of the ULEZ at improving air quality and delivering improvements in children's respiratory health. With increasing proportions of the world's population now living in large urban areas exceeding World Health Organisation air pollution limit guidelines, our study findings will have important implications for the design and implementation of Low Emission and Clean Air Zones in the UK, and worldwide. CLINICALTRIALS: GOV: NCT04695093 (05/01/2021).
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Contaminación del Aire , Salud Infantil , Niño , Humanos , Contaminación del Aire/efectos adversos , Contaminación del Aire/prevención & control , Estudios de Cohortes , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/prevención & control , Londres , Estudios Longitudinales , Material Particulado , Estudios Prospectivos , Calidad de VidaRESUMEN
Background: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Methods: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. Results: In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. Conclusion: MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.
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Células Supresoras de Origen Mieloide , Neoplasias de la Vejiga Urinaria , Humanos , Ratones , Animales , Gemcitabina , Células Supresoras de Origen Mieloide/metabolismo , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Inmunoterapia Adoptiva , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Citocinas/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. METHODS: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. RESULTS: We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL. CONCLUSIONS: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.
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Linfocitos Infiltrantes de Tumor , Melanoma , Humanos , Inmunoterapia Adoptiva/métodos , Estudios Prospectivos , Linfocitos T CD4-PositivosRESUMEN
Background: The role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) neutralizing antibody response from natural infection and vaccination, and the potential determinants of this response are poorly understood. Characterizing this antibody response and the factors associated with neutralization can help inform future prevention efforts and improve clinical outcomes in those infected. Objectives: The goals of this study were to prospectively evaluate SARS-CoV-2 antibody levels and the neutralizing antibody responses among naturally infected adults and to determine demographic and behavioral factors independently associated with these responses. Methods: Serum was collected from seropositive individuals at baseline, four-weeks, and three-months following their first study visit to be evaluated for antibody levels. Detection of neutralizing antibodies was performed at baseline. Participant demographic and behavioral information was collected via web questionnaire prior to their first visit. Results: At baseline, higher antibody levels were associated with better neutralization capacity, with 83% of participants having detectable neutralizing antibodies. We found an age-dependent effect on antibody level and neutralization capacity with participants over 65 years having significantly higher levels. Ethnicity, heart disease, autoimmune disease, and COVID symptoms were associated with higher antibody levels, but not with increased neutralization capacity. Work environment during the pandemic correlated with increased neutralization capacity, while kidney or liver disease and traveling out of state after February 2020 correlated with decreased neutralization capacity, however neither correlated with antibody levels. Conclusions: Our data show that natural infection by SARS-CoV-2 can induce a humoral response reflected by high antibody levels and neutralization capacity.
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Military personnel may be exposed to a range of hazards. The assessment, documentation and reporting of military exposure information are important steps to guide health protection, services, and research to support actively serving members and veterans. In 2021, a Working Group of researchers from veteran and defense administrations across the Five Eyes countries (Australia, Canada, New Zealand, the United Kingdom, and the United States) was established to examine large military exposure data sources available in each country, their applications, and opportunities to leverage information across administrations and internationally. We provide a brief summary of this work here to highlight some successful examples of data applications and to elicit interest in this evolving area of exposure science.
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Personal Militar , Veteranos , Humanos , Estados Unidos , Fuentes de Información , Reino Unido , InternacionalidadRESUMEN
Globally, bladder cancer has been identified as one of the most frequent occupational cancers, but our understanding of occupational bladder cancer risk in Iran is less advanced. This study aimed to assess the risk of bladder cancer in relation to occupation in Iran. We used the IROPICAN case-control study data including 717 incident cases and 3477 controls. We assessed the risk of bladder cancer in relation to ever working in major groups of the International Standard Classification of Occupations (ISCO-68) while controlling for cigarette smoking, opium consumption. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). In men, decreased ORs for bladder cancer were observed in administrative and managerial workers (OR 0.4; CI: 0.2, 0.9), and clerks (OR 0.6; CI: 0.4, 0.9). Elevated ORs were observed in metal processors (OR 5.4; CI: 1.3, 23.4), and workers in occupations with likely exposure to aromatic amines (OR 2.2; CI: 1.2, 4.0). There was no evidence of interactions between working in aromatic amines-exposed occupations and tobacco smoking or opium use. Elevated risk of bladder cancer in men in metal processors and workers likely exposed to aromatic amines aligns with associations observed outside Iran. Other previously confirmed associations between high-risk occupations and bladder cancer were not observed, possibly due to small numbers or lack of details on exposure. Future epidemiological studies in Iran would benefit from the development of exposure assessment tools such as job exposure matrices, generally applicable for retrospective exposure assessment in epidemiological studies.
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Enfermedades Profesionales , Exposición Profesional , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Estudios de Casos y Controles , Estudios Retrospectivos , Irán/epidemiología , Factores de Riesgo , Ocupaciones , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/etiología , Exposición Profesional/efectos adversos , Exposición Profesional/análisisRESUMEN
BACKGROUND: African American emerging adults tend to have low adherence to asthma controller medication, as well as a disproportionate burden of asthma morbidity and mortality. This study explored constructs from the Information-Motivation-Behavioral Skills model as predictors of controller medication adherence in urban African Americans ages 18-29 (N=152) with uncontrolled asthma using multiple measures of self-reported adherence. METHODS: Structural equation modeling (SEM) was employed to test the hypothesized mediation model that specified the relationship among psychological distress, substance use, asthma knowledge, motivation, self-efficacy, and adherence. RESULTS: Results suggested that motivation is an important predictor of adherence to medication; moreover, higher self-efficacy was associated with higher motivation. Results also highlighted psychological distress as an important intervention target to improve medication adherence in emerging adults. CONCLUSIONS: The model tested in this study may offer a feasible framework for beginning to understand adherence to controller medication in this population.
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Antiasmáticos , Asma , Humanos , Adulto , Asma/tratamiento farmacológico , Asma/epidemiología , Antiasmáticos/uso terapéutico , Negro o Afroamericano , Autoinforme , Cumplimiento de la Medicación/psicologíaRESUMEN
BACKGROUND: Anxiety and depression are mental health disorders that are often comorbid with asthma. Urban African American young adults with asthma often experience increased risk of anxiety and depression. OBJECTIVE: To explore relationships between symptoms of psychological distress and asthma-related anxiety with asthma outcomes among urban African American young adults with poorly controlled persistent asthma. METHODS: A secondary analysis of baseline data from a larger study of 141 African American young adults with uncontrolled persistent asthma was examined. Participants completed the Brief Symptom Inventory (BSI-18), Youth Asthma-related Anxiety Scale, Asthma Control Test (ACT), a daily diary to assess asthma symptoms; and number of asthma attacks. Spirometry assessed airway obstruction. Generalized linear models tested associations. RESULTS: In multivariable models testing, higher somatization scores were significantly associated with lower ACT scores (adjusted ß = -0.49; 95% CI = -0.69, -0.28; p < 0.01), and higher symptoms (adjusted ß = 0.39; 95% CI = 0.14, 0.65; p < 0.01). After adding asthma-related anxiety to the model, the somatization subscale and asthma-related anxiety were significantly associated with ACT scores (adjusted ß = -0.36; 95% CI = -0.57, -0.15; p < 0.01), (adjusted ß = -0.32; 95% CI = -0.50, -0.14; p < 0.01), respectively. Asthma-related anxiety was also significantly associated with asthma attacks (adjusted ß = 0.24; 95% CI = 0.05, 0.43; p < 0.05). CONCLUSION: This study suggests, asthma-related anxiety may differ from general anxiety and be related to poorly controlled asthma among African American young adults.
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Asma , Adolescente , Humanos , Adulto Joven , Asma/diagnóstico , Depresión/epidemiología , Negro o Afroamericano , Ansiedad/epidemiología , Trastornos de AnsiedadRESUMEN
INTRODUCTION: Military sexual trauma (MST) is an ongoing problem. We used a 2002 population-based sample, followed up in 2018, to examine: (1) the prevalence of MST and non-MST in male and female currently serving members and veterans of the Canadian Armed Forces, and (2) demographic and military correlates of MST and non-MST. METHODS: Data came from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (n = 2,941, ages 33 years + ). Individuals endorsing sexual trauma were stratified into MST and non-MST and compared to individuals with no sexual trauma. The prevalence of lifetime MST was computed, and correlates of sexual trauma were examined using multinomial regression analyses. RESULTS: The overall prevalence of MST was 44.6% in females and 4.8% in males. Estimates were comparable between currently serving members and veterans. In adjusted models in both sexes, MST was more likely among younger individuals (i.e., 33-49 years), and MST and non-MST were more likely in those reporting more non-sexual traumatic events. Among females, MST and non-MST were more likely in those reporting lower household income, non-MST was less likely among Officers, and MST was more likely among those with a deployment history and serving in an air environment. Unwanted sexual touching by a Canadian military member or employee was the most prevalent type and context of MST. INTERPRETATION: A high prevalence of MST was observed in a follow-up sample of Canadian Armed Forces members and veterans. Results may inform further research as well as MST prevention efforts.
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Personal Militar , Delitos Sexuales , Trastornos por Estrés Postraumático , Veteranos , Masculino , Femenino , Humanos , Salud Mental , Trauma Sexual Militar , Prevalencia , Estudios de Seguimiento , Canadá/epidemiología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicologíaRESUMEN
BACKGROUND: Globally, lung cancer is the most frequent occupational cancer, but the risk associated with the occupations or occupational environment in Iran is not clear. We aimed to assess occupations with the risk of lung cancer. METHODS: We used the IROPICAN nationwide case-control study data including 658 incident lung cancer cases and 3477 controls. We assessed the risk of lung cancer in relation to ever working in major groups of International Standard Classification of Occupations, high-risk occupations for lung cancer and duration of employment and lung cancer subtype among construction workers and farmers while controlling for cigarette smoking and opium consumption. We used unconditional regression logistic models to estimate ORs for the association between increased lung cancer risk and occupations. RESULTS: We observed elevated ORs for lung cancer in male construction workers (OR=1.4; 95% CI: 1.0 to 1.8), petroleum industry workers (OR=3.2; 95% CI: 1.1 to 9.8), female farmers (OR=2.6; 95% CI: 1.3 to 5.3) and female bakers (OR=5.5; 95% CI: 1.0 to 29.8). A positive trend by the duration of employment was observed for male construction workers (p< 0.001). Increased risk of squamous cell carcinoma was observed in male construction workers (OR=1.9; 95% CI: 1.2 to 3.0) and female farmers (OR=4.3; 95% CI: 1.1 to 17.2), who also experienced an increased risk of adenocarcinoma (OR=3.8; 95% CI: 1.4 to 9.9). DISCUSSION: Although we observed associations between some occupations and lung cancer consistent with the literature, further studies with larger samples focusing on exposures are needed to better understand the occupational lung cancer burden in Iran.
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Neoplasias Pulmonares , Enfermedades Profesionales , Exposición Profesional , Femenino , Humanos , Masculino , Estudios de Casos y Controles , Irán/epidemiología , Modelos Logísticos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Enfermedades Profesionales/etiología , Enfermedades Profesionales/complicaciones , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Ocupaciones , Factores de Riesgo , Oportunidad RelativaRESUMEN
PURPOSE: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs. PATIENTS AND METHODS: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production. RESULTS: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. CONCLUSIONS: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs.
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Melanoma , Neoplasias Primarias Secundarias , Humanos , Tratamiento Basado en Trasplante de Células y Tejidos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor , Melanoma/tratamiento farmacológico , Nivolumab , Melanoma Cutáneo MalignoRESUMEN
Miltefosine is a repurposed anticancer drug and currently the only orally administered drug approved to treat the neglected tropical disease leishmaniasis. Miltefosine is hygroscopic and must be stored at subzero temperatures. In this work, we report the X-ray structures of miltefosine monohydrate and methanol solvate, along with 12- and 14-carbon chain analogue hydrates and a solvate. The three hydrates are all isostructural and are conformational isomorphs with Z' = 2. Water bridges the gap between phosphocholine head groups caused by the interdigitated bilayer structure. The two methanol solvates are also mutually isostructural with the head groups adopting a more extended conformation. Again, the solvent bridges the gap between head groups in the bilayer. No anhydrous form of miltefosine or its analogues were isolated, with dehydration resulting in significantly reduced crystallinity. This arises as a result of the integral role that hydrogen-bond donors (in the form of water or solvent molecules) play in the stability of the zwitterionic structures.
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OBJECTIVE: To assess survival outcomes with the intervention of an interprofessional mobilization program for patients with COVID-19 who were receiving venovenous extracorporeal membrane oxygenation (VV-ECMO). DESIGN: Preintervention and postintervention retrospective cohort study. METHODS: Survival outcomes of nonmobilized, adult patients (n = 16) with COVID-19 who were receiving VV-ECMO (May 2020 through December 2020) were compared with those of 26 patients who received a mobility care plan (January 2021 through November 2021). In the preintervention group, full sedation and paralysis were used. In the postintervention group, an early mobilization strategy involving interprofessional collaboration was introduced. RESULTS: The postintervention group had improved survival (73.1% vs 43.8%; P < .04); fewer days of receiving paralytics, fentanyl, and midazolam (P < .01 for all); but more days of dexmedetomidine, morphine, and ketamine administration (P < .01 for all). Concomitantly, more patients in the postintervention cohort received oral or transdermal analgesics, oral anxiolytics, and oral antipsychotics (P < .01 for all), and also required more VV-ECMO cannula adjustments (P = .03). CONCLUSION: Early mobilization of patients with COVID-19 who were receiving VV-ECMO improved survival rates but led to more cannula adjustments.