RESUMO
BACKGROUND: Cervical cancer remains a significant but preventable threat to women's health throughout much of the developing world, including Uganda. Cervical cancer screening and timely treatment of pre-cancerous lesions is a cost-effective means of mitigating cervical cancer morbidity and mortality. However, only 5% of women in Uganda have ever been screened. Barriers to screening, such as social stigma and access to safe conditions, have been previously identified, but insights into the role of male spouses in encouraging or discouraging screening have been limited. To our knowledge, no studies have compared barriers and facilitators among women who had or had not yet been screened and male partners of screened and unscreened women. METHODS: To resolve this gap, we conducted 7 focus groups- 3 among women who had been screened, 3 among those who had not been screened, and 1 among men whose female partners had or had not been screened. We performed qualitative thematic analysis on the focus group data. RESULTS: We identified several important factors impacting screening and the decision to screen among women, ranging from stigma, availability of screening, false beliefs around the procedure and side effects, and the role of spousal support in screening promotion. Male spousal perspectives for screening ranged from full support to hesitancy around male-performed exams and possible prolonged periods without intercourse. CONCLUSION: This exploratory work demonstrates the importance of dialogue both among women and their male partners in enhancing screening uptake. Efforts to address screening uptake are necessary given that it is an important means of mitigating the burden of cervical cancer. Interventions along these lines need to take these barriers and facilitators into account in order to drive up demand for screening.
Assuntos
Detecção Precoce de Câncer , Grupos Focais , Conhecimentos, Atitudes e Prática em Saúde , Pesquisa Qualitativa , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/diagnóstico , Feminino , Masculino , Uganda/epidemiologia , Detecção Precoce de Câncer/psicologia , Adulto , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Estigma Social , Programas de Rastreamento/métodos , Cônjuges/psicologiaRESUMO
BACKGROUND: Food insecurity and HIV-related stigma negatively affect HIV outcomes. Few studies have examined how food security interventions affect HIV-related stigma and social support. SETTING: Two HIV clinics in the Dominican Republic. METHODS: A pilot cluster randomized controlled trial of an urban gardens and peer nutritional counseling intervention was conducted to examine outcomes of HIV-related stigmas and social support. Adult patients (≥18 years of age) with moderate or severe household food insecurity and evidence of suboptimal ART adherence and/or a detectable viral load were enrolled; standard measures of internalized and experienced stigmas and social support were collected at baseline and at 6 and 12 months. Intervention clinic participants received training and materials from agronomists for a home garden, 3-4 sessions of nutritional counseling from the clinic's peer counselor, and a garden produce cooking workshop facilitated by professional nutritionists. RESULTS: Of 109 study participants (46 intervention and 63 control), 103 (94%) completed 12-month follow-up. Difference-in-differences multivariate longitudinal linear regressions adjusting for sociodemographic factors found that intervention participants had reduced internalized stigma by 3.04 points (scale 0-32) at 12 months (P = 0.002); reduced probability of experiencing HIV-related stigma or discrimination in the past 6 months (20 percentage points at 6 months, P = 0.05 and 25 percentage points at 12 months, P = 0.02); and modestly improved social support at 12 months (1.85 points on 30-pt scale, P = 0.093). CONCLUSION: A fully powered, larger trial is needed to establish the efficacy of the intervention and assess pathways by which the intervention may improve HIV stigma and social support.
Assuntos
Aconselhamento , Insegurança Alimentar , Infecções por HIV , Estigma Social , Apoio Social , Humanos , Infecções por HIV/psicologia , Infecções por HIV/prevenção & controle , Masculino , Feminino , República Dominicana , Adulto , Pessoa de Meia-Idade , Jardins , Grupo Associado , População Urbana , Projetos PilotoRESUMO
BACKGROUND: Cerebral perfusion may change depending on arterial cannulation site and may affect the incidence of neurologic adverse events in post-cardiotomy extracorporeal life support (ECLS). The current study compares patients' neurologic outcomes with three commonly used arterial cannulation strategies (aortic vs. subclavian/axillary vs. femoral artery) to evaluate if each ECLS configuration is associated with different rates of neurologic complications. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring post-cardiotomy ECLS between January 2000 and December 2020 present in the Post-Cardiotomy Extracorporeal Life Support (PELS) Study database. Patients with Aortic, Subclavian/Axillary and Femoral cannulation were compared on the incidence of a composite neurological end-point (ischemic stroke, cerebral hemorrhage, brain edema). Secondary outcomes were overall in-hospital mortality, neurologic complications as cause of in-hospital death, and post-operative minor neurologic complications (seizures). Association between cannulation and neurological outcomes were investigated through linear mixed-effects models. RESULTS: This study included 1897 patients comprising 26.5% Aortic (n = 503), 20.9% Subclavian/Axillary (n = 397) and 52.6% Femoral (n = 997) cannulations. The Subclavian/Axillary group featured a more frequent history of hypertension, smoking, diabetes, previous myocardial infarction, dialysis, peripheral artery disease and previous stroke. Neuro-monitoring was used infrequently in all groups. Major neurologic complications were more frequent in Subclavian/Axillary (Aortic: n = 79, 15.8%; Subclavian/Axillary: n = 78, 19.6%; Femoral: n = 118, 11.9%; p < 0.001) also after mixed-effects model adjustment (OR 1.53 [95% CI 1.02-2.31], p = 0.041). Seizures were more common in Subclavian/Axillary (n = 13, 3.4%) than Aortic (n = 9, 1.8%) and Femoral cannulation (n = 12, 1.3%, p = 0.036). In-hospital mortality was higher after Aortic cannulation (Aortic: n = 344, 68.4%, Subclavian/Axillary: n = 223, 56.2%, Femoral: n = 587, 58.9%, p < 0.001), as shown by Kaplan-Meier curves. Anyhow, neurologic cause of death (Aortic: n = 12, 3.9%, Subclavian/Axillary: n = 14, 6.6%, Femoral: n = 28, 5.0%, p = 0.433) was similar. CONCLUSIONS: In this analysis of the PELS Study, Subclavian/Axillary cannulation was associated with higher rates of major neurologic complications and seizures. In-hospital mortality was higher after Aortic cannulation, despite no significant differences in incidence of neurological cause of death in these patients. These results encourage vigilance for neurologic complications and neuromonitoring use in patients on ECLS, especially with Subclavian/Axillary cannulation.
Assuntos
Aorta , Oxigenação por Membrana Extracorpórea , Artéria Femoral , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Oxigenação por Membrana Extracorpórea/métodos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Idoso , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/epidemiologia , Adulto , Artéria Subclávia , Cateterismo/métodos , Cateterismo/efeitos adversos , Cateterismo/estatística & dados numéricos , Cateterismo Periférico/métodos , Cateterismo Periférico/efeitos adversos , Cateterismo Periférico/estatística & dados numéricos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Mortalidade Hospitalar/tendênciasRESUMO
BACKGROUND: Although most survivors of breast cancer report substantial sexual concerns following treatment, few receive support for these concerns. Delivering sexual health care to survivors of breast cancer via the internet could overcome many of the barriers to in-person treatment. Even when delivered remotely, survivor time constraints remain a leading barrier to sexual health intervention uptake. OBJECTIVE: Guided by the multiphase optimization strategy methodological framework, the primary objective of this study is to identify the most efficient internet-delivered sexual health intervention package that is expected to provide survivors of breast cancer the greatest benefit with the fewest (and least-intensive) intervention components. This study aims to determine how intervention components work (mediators) and for whom they work best (moderators). METHODS: Partnered, posttreatment adult female survivors of breast cancer (N=320) experiencing at least 1 bothersome sexual symptom (ie, pain with sex, vaginal dryness, low sexual desire, and difficulty with orgasm) related to their breast cancer treatment will be enrolled. Clinic-based recruitment will be conducted via the Wake Forest National Cancer Institute Community Oncology Research Program (NCORP) Research Base. Participants will be randomly assigned to 1 of 16 combinations of four intervention components with two levels each in this factorial trial: (1) psychoeducation about cancer-related sexual morbidity (receive either enhanced vs standard versions); (2) communication skills training for discussing concerns with health care providers (received vs not received); (3) communication skills training for discussing concerns with a partner (received vs not received); and (4) intimacy promotion skills training (received vs not received). Cores will be fully automated and implemented using a robust internet intervention platform with highly engaging elements such as animation, video, and automated email prompts. Survivors will complete web-based assessments at baseline (prerandomization time point) and again at 12 and 24 weeks later. The primary study aim will be achieved through a decision-making process based on systematically evaluating the main and interaction effects of components on sexual distress (Female Sexual Distress Scale-Desire, Arousal, Orgasm) and sexual functioning (Female Sexual Function Index) using a generalized linear model approach to ANOVA with effect coding. Mediation analyses will be conducted through a structural equation modeling approach, and moderation analyses will be conducted by extending the generalized linear model to include interaction effects. RESULTS: This protocol has been reviewed and approved by the National Cancer Institute Central Institutional Review Board. Data collection is planned to begin in March 2024 and conclude in 2027. CONCLUSIONS: By identifying the combination of the fewest and least-intensive intervention components likely to provide survivors of breast cancer the greatest sexual health benefit, this study will result in the first internet intervention that is optimized for maximum impact on the undertreated, prevalent, and distressing problem of breast cancer-related sexual morbidity. TRIAL REGISTRATION: ClinicalTrials.gov NCT06216574; https://clinicaltrials.gov/study/NCT06216574. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/57781.
Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Intervenção Baseada em Internet , Saúde Sexual , Humanos , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Feminino , Sobreviventes de Câncer/psicologia , Adulto , Internet , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Testing for plasma tumor tissue modified viral (TTMV)-HPV DNA has emerged as a biomarker strategy for post-treatment surveillance to identify recurrent disease. We aimed to understand the prognostic and predictive potential of TTMV-HPV DNA when monitoring patients who had developed recurrent or metastatic (R/M) HPV+OPSCC. METHODS: This retrospective observational cohort study included 80 patients from 4 academic centers with R/M HPV+OPSCC if they had ≥ 1 plasma TTMV-HPV DNA test obtained at any point during their R/M disease course. Physician-reported clinical data and treatment history were captured in a centralized database, along with investigator-assessed response to therapy and survival. Descriptive statistics and non-parametric tests of association were employed along with survival analyses (Kaplan-Meier method). RESULTS: Sixteen (20 %) patients had ≥ 5 test results over time. Consecutive TTMV-HPV DNA tests were performed a median of 73 days apart. Median TTMV-HPV DNA scores were higher with an increasing per-patient number of metastatic sites (<2 vs. 2+; p < 0.01). Score changes over time were influenced by R/M treatment modality and became undetectable in 67 % (12/18) of patients who achieved a complete response to R/M therapy. Patients with detectable scores at last follow-up had significantly worse survival compared with those who were undetectable (log-rank test, p < 0.01). CONCLUSIONS: TTMV-HPV DNA appears useful as a prognostic tool for monitoring response to therapy in the R/M setting. In the future, TTMV-HPV DNA could be explored as an exploratory clinical trial endpoint in the metastatic setting.
RESUMO
Perinatal depression has been shown to have deleterious effects on maternal post-partum functioning, as well as early child development. However, few studies have documented whether depression care helps to mitigate these effects. We examined the effects of the M-DEPTH (Maternal Depression Treatment in HIV) depression care model (including antidepressants and individual Problem Solving Therapy) on maternal functioning and infant development in the first 6 months post-delivery in an ongoing cluster randomized controlled trial of 391 HIV-infected women with at least mild depressive symptoms enrolled across eight antenatal care clinics in Uganda. A subsample of 354 (177 in each of the intervention and control groups) had a live birth delivery and comprised the analytic sample, of whom 69% had clinical depression at enrollment; 70% of women in the intervention group (including 96% of those with clinical depression) received depression treatment. Repeated-measures multivariable regression models found that the intervention group reported better infant care, lower parental burden, and greater perceived adequacy of parental support, compared to the control group. These findings suggest that depression care for pregnant women living with HIV is important not only for maternal mental health, but it also helps women to better manage parenting and care for their infant.
RESUMO
OBJECTIVES: Black Americans have been disproportionally affected by the HIV epidemic, and experience significant disparities in sleep health, mental health, and physical health domains. Using longitudinal data from a sample of Black adults with HIV, the current study examined the associations between stigma and mental and physical health outcomes and how sleep disturbance may play a mediating role. METHODS: Data were drawn from a recent randomized controlled trial. Questionnaires were used to examine internalized and anticipated HIV stigma, perceived discrimination (enacted stigma) based on multiple social identities (i.e., HIV-serostatus, race, sexual orientation), sleep disturbance, mental health problems (depressive and posttraumatic stress disorder [PTSD] symptoms), and mental and physical health-related quality of life (HRQOL) at baseline, 7-month follow-up, and 13-month follow-up assessments. Linear mixed modeling was used to examine main effects of stigma on health outcomes; causal mediation analysis was used to estimate indirect paths through sleep disturbance. RESULTS: Internalized and anticipated HIV stigma and multiple discrimination were associated with more sleep disturbance, more depressive and PTSD symptoms, and poorer mental and physical HRQOL. Results also indicated significant indirect paths (i.e., mediation) through greater sleep disturbance between HIV-related stigma and discrimination and mental health and health-related quality of life. CONCLUSIONS: Results support that sleep disturbance is a mediating pathway through which different forms of stigmas impact health outcomes. Sleep may be an intervention target to help improve mental and physical well-being and reduce health disparities among racial and ethnic minority people with HIV.
RESUMO
Background: When arsenic trioxide (ATO) was combined with radiation for treatment of transplanted murine gliomas in the brain, tumor response improved with disrupted tumor blood flow and survival was significantly prolonged. Methods: Total of 31 patients with newly diagnosed glioblastoma were accrued to a multi-institutional, NCI-funded, phase I study to determine the maximum tolerated dose (MTD) of ATO administered with radiation. Secondary objectives were survival and pharmacodynamic changes in perfusion on magnetic resonance imaging (MRI). Patients (unknown MGMT and IDH status) received ATO either once or twice weekly during radiation without concurrent or adjuvant temozolomide. Results: Median age: 54.9 years, male: 68%, KPS ≥ 90: 77%, debulking surgery: 77%. Treatments were well-tolerated: 81% of patients received all the planned ATO doses. Dose-limiting toxicities included elevated liver function tests, hypokalemia, and edema. The MTD on the weekly schedule was 0.4 mg/kg and on the biweekly was 0.3 mg/kg. The median survival (mOS) for all patients was 17.7 months. Survival on the biweekly schedule (22.8 months) was longer than on the weekly schedule (12.1 months) (Pâ =â .039) as was progression-free survival (Pâ =â .004). Similarly, cerebral blood flow was significantly reduced in patients treated on the biweekly schedule (Pâ =â .007). Conclusions: ATO with standard radiation is well tolerated in patients with newly diagnosed glioblastoma. Even without temozolomide or adjuvant therapy, the overall survival of all patients (17.7 months) and especially patients who received biweekly ATO (22.8 months) is surprising and accompanied by pharmacodynamic changes on MRI. Further studies of this regimen are warranted.
RESUMO
KEY MESSAGE: De novo genotyping in potato using methylation-sensitive GBS discovers SNPs largely confined to genic or gene-associated regions and displays enhanced effectiveness in estimating LD decay rates, population structure and detecting GWAS associations over 'fixed' SNP genotyping platform. Study also reports the genetic architectures including robust sequence-tagged marker-trait associations for sixteen important potato traits potentially carrying higher transferability across a wider range of germplasm. This study deploys recent advancements in polyploid analytical approaches to perform complex trait analyses in cultivated tetraploid potato. The study employs a 'fixed' SNP Infinium array platform and a 'flexible and open' genome complexity reduction-based sequencing method (GBS, genotyping-by-sequencing) to perform genome-wide association studies (GWAS) for several key potato traits including the assessment of population structure and linkage disequilibrium (LD) in the studied population. GBS SNPs discovered here were largely confined (~ 90%) to genic or gene-associated regions of the genome demonstrating the utility of using a methylation-sensitive restriction enzyme (PstI) for library construction. As compared to Infinium array SNPs, GBS SNPs displayed enhanced effectiveness in estimating LD decay rates and discriminating population subgroups. GWAS using a combined set of 30,363 SNPs identified 189 unique QTL marker-trait associations (QTL-MTAs) covering all studied traits. The majority of the QTL-MTAs were from GBS SNPs potentially illustrating the effectiveness of marker-dense de novo genotyping platforms in overcoming ascertainment bias and providing a more accurate correction for different levels of relatedness in GWAS models. GWAS also detected QTL 'hotspots' for several traits at previously known as well as newly identified genomic locations. Due to the current study exploiting genome-wide genotyping and de novo SNP discovery simultaneously on a large tetraploid panel representing a greater diversity of the cultivated potato gene pool, the reported sequence-tagged MTAs are likely to have higher transferability across a wider range of potato germplasm and increased utility for expediting genomics-assisted breeding for the several complex traits studied.
Assuntos
Genótipo , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Solanum tuberosum , Tetraploidia , Solanum tuberosum/genética , Solanum tuberosum/crescimento & desenvolvimento , Técnicas de Genotipagem/métodos , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Fenótipo , Genoma de Planta , Estudos de Associação GenéticaRESUMO
Postcardiotomy shock in the cardiac surgical patient is a highly morbid condition characterized by profound myocardial impairment and decreased systemic perfusion inadequate to meet end-organ metabolic demand. Postcardiotomy shock is associated with significant morbidity and mortality. Poor outcomes motivate the increased use of mechanical circulatory support (MCS) to restore perfusion in an effort to prevent multiorgan injury and improve patient survival. Despite growing acceptance and adoption of MCS for postcardiotomy shock, criteria for initiation, clinical management, and future areas of clinical investigation remain a topic of ongoing debate. This article seeks to (1) define critical cardiac dysfunction in the patient after cardiotomy, (2) provide an overview of commonly used MCS devices, and (3) summarize the relevant clinical experience for various MCS devices available in the literature, with additional recognition for the role of MCS as a part of a modified approach to the cardiac arrest algorithm in the cardiac surgical patient.
RESUMO
PURPOSE: Skin pigmentation influences peripheral oxygen saturation (SpO2) compared to arterial saturation of oxygen (SaO2). Occult hypoxemia (SaO2 ≤ 88% with SpO2 ≥ 92%) is associated with increased in-hospital mortality in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO2-SaO2 discrepancy due to significant hemolysis. METHODS: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO2 and SaO2 measurements from over 500 centers in the Extracorporeal Life Support Organization Registry (1/2018-5/2023) were included. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO2-SaO2 calculations. RESULTS: Of 13,171 VV-ECMO patients, there were 7772 (59%) White, 2114 (16%) Hispanic, 1777 (14%) Black, and 1508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic patients versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively). In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18-2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95% CI = 1.16-2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95% CI = 1.15-2.55, P = 0.008) had higher risk versus White patients. Higher pump flow rates (aOR = 1.29, 95% CI = 1.08-1.55, P = 0.005) and on-ECMO 24-h lactate (aOR = 1.06, 95% CI = 1.03-1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia. CONCLUSION: SaO2 should be carefully monitored if using SpO2 during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.
Assuntos
Oxigenação por Membrana Extracorpórea , Hipóxia , Sistema de Registros , Humanos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hipóxia/terapia , Hipóxia/sangue , Hipóxia/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Saturação de Oxigênio , Hispânico ou Latino/estatística & dados numéricos , Mortalidade Hospitalar , População Branca , Idoso , Estados Unidos/epidemiologia , Negro ou Afro-Americano , HemóliseRESUMO
Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas-dominant, Staphylococcus-dominant, and mixed dominance cluster. Shannon's diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT.
Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Indóis , Microbiota , Quinolonas , Humanos , Fibrose Cística/microbiologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Quinolonas/uso terapêutico , Feminino , Adulto , Masculino , Indóis/uso terapêutico , Microbiota/efeitos dos fármacos , Sistema Respiratório/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/efeitos dos fármacos , Pirróis/uso terapêutico , Sinusite/microbiologia , Sinusite/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto Jovem , Piridinas/uso terapêutico , Pseudomonas/efeitos dos fármacos , Pseudomonas/isolamento & purificação , Pseudomonas/genética , Pessoa de Meia-Idade , PirrolidinasRESUMO
PURPOSE: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. EXPERIMENTAL DESIGN: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12-17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46-119.5; P = 0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.
Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Masculino , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Adulto , Idoso de 80 Anos ou mais , Medicina de Precisão/métodos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , PrognósticoRESUMO
PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Recidiva Local de Neoplasia , Temozolomida , Humanos , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Reparo do DNA/efeitos dos fármacos , Hidroxilaminas/uso terapêutico , Hidroxilaminas/administração & dosagem , Prognóstico , Reparo por ExcisãoRESUMO
Peer advocacy can promote HIV protective behaviors, but little is known about the concordance on prevention advocacy(PA) reports between people living with HIV(PLWH) and their social network members. We examined prevalence and correlates of such concordance, and its association with the targeted HIV protective behavior of the social network member. Data were analyzed from 193 PLWH(index participants) and their 599 social network members(alters). Kappa statistics measured concordance between index and alter reports of PA in the past 3 months. Logistic and multinomial regressions evaluated the relationship between advocacy concordance and alter condom use and HIV testing behavior and correlates of PA concordance. Advocacy concordance was observed in 0.3% of index-alter dyads for PrEP discussion, 9% for condom use, 18% for HIV testing, 26% for care engagement, and 49% for antiretroviral use discussions. Fewer indexes reported condom use(23.5% vs. 28.1%;[Formula: see text]=3.7, p=0.05) and HIV testing(30.5% vs. 50.5%; [Formula: see text]=25.3, p<0.001) PA occurring. Condom advocacy concordance was higher if the index and alter were romantic partners(OR=3.50; p=0.02), and lower if the index was 10 years younger than the alter(OR=0.23; p = 0.02). Alters had higher odds of using condoms with their main partner when both reported condom advocacy compared to dyads where neither reported advocacy(OR=3.90; p<0.001) and compared to dyads where only the index reported such advocacy(OR = 3.71; p=0.01). Age difference and relationship status impact advocacy agreement, and concordant perceptions of advocacy are linked to increased HIV protective behaviors. Alters' perceptions may be crucial for behavior change, informing strategies for improving advocacy.
RESUMO
Leachables in pharmaceutical products may react with biomolecule active pharmaceutical ingredients (APIs), for example, monoclonal antibodies (mAb), peptides, and ribonucleic acids (RNA), potentially compromising product safety and efficacy or impacting quality attributes. This investigation explored a series of in silico models to screen extractables and leachables to assess their possible reactivity with biomolecules. These in silico models were applied to collections of known leachables to identify functional and structural chemical classes likely to be flagged by these in silico approaches. Flagged leachable functional classes included antimicrobials, colorants, and film-forming agents, whereas specific chemical classes included epoxides, acrylates, and quinones. In addition, a dataset of 22 leachables with experimental data indicating their interaction with insulin glargine was used to evaluate whether one or more in silico methods are fit-for-purpose as a preliminary screen for assessing this biomolecule reactivity. Analysis of the data showed that the sensitivity of an in silico screen using multiple methodologies was 80%-90% and the specificity was 58%-92%. A workflow supporting the use of in silico methods in this field is proposed based on both the results from this assessment and best practices in the field of computational modeling and quality risk management.
Assuntos
Simulação por Computador , Contaminação de Medicamentos , Contaminação de Medicamentos/prevenção & controle , Preparações Farmacêuticas/química , Preparações Farmacêuticas/análise , Anticorpos Monoclonais/químicaRESUMO
This article describes the development of a representative dataset of extractables and leachables (E&L) from the combined Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the Product Quality Research Institute (PQRI) published datasets, representing a total of 783 chemicals. A chemical structure-based clustering of the combined dataset identified 142 distinct chemical classes with two or more chemicals across the combined dataset. The majority of these classes (105 chemical classes out of 142) contained chemicals from both datasets, whereas 8 classes contained only chemicals from the ELSIE dataset and 29 classes contain only chemicals from the PQRI dataset. This evaluation also identified classes containing chemicals that were flagged as potentially mutagenic as well as potent (strong or extreme) dermal sensitizers by in silico tools. The prevalence of alerting structures in the E&L datasets was approximately 9% (69 examples) for mutagens and 3% (25 examples) for potent sensitizers. This analysis showed that most (80%; 20 of 25) E&L predicted to be strong or extreme dermal sensitizers were also flagged as potential mutagens. Only two chemical classes, each containing three chemicals (alkyl bromides and isothiocyanates), were uniquely identified in the PQRI dataset and contained chemicals predicted to be potential mutagens and/or potent dermal sensitizers.