To explore the utility of brief financial screening items to facilitate the implementation of routine financial toxicity screening.
50 women with breast cancer completed a one-time survey that ...included the Comprehensive Score for Financial Toxicity (COST): A FACIT Measure of Financial Toxicity, a visual analog scale, and a brief sociodemographic questionnaire.
Survey responses were examined to assess the psychometric properties of individual COST items and the visual analog scale by calculating Cronbach's alpha and Pearson's correlation coefficients.
The mean COST was 21.4, and 27 respondents met criteria for financial toxicity (a COST lower than 22). As expected, all items correlated strongly to the overall COST, but four items (items 3, 6, 8, and 10) performed strongest (r > 0.8).
This study provides evidence for individual COST items to be used as brief screening items. Future research should test the utility of these items in larger sample sizes with a more diverse representation of patients by age, race, ethnicity, and tumor type and stage.
Abstract Background No guidelines exist for credentialing extracorporeal membrane oxygenation (ECMO) physicians despite variable training backgrounds. We aim to identify national patterns of ...institutional credentialing for ECMO physicians. Methods Program directors from 173 US ECMO centers were surveyed regarding credentialing, recertification, training elements, and barriers. Results Response rate was 42% (73/173). ECMO credentialing for physicians was required in 66% of responding ECMO centers. Only 57% reported an established institutional ECMO credentialing program. Yearly recertification was required in 16%. Common elements included didactic courses (90%), simulation (73%), and proctored cases (68%). Lack of standardization for credentialing (36%) and too little time (36%) were major barriers to program establishment. No differences were found between small- and large-volume centers with respect to credentialing or recertification. Conclusions Not all physicians managing ECMO are credentialed and only about half of US centers have established credentialing programs. Standardization of ECMO credentialing may increase training rates and improve variability in credentialing practices across the United States
Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities ...of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine “KL-50” is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA–MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA–MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.
ObjectiveTo examine (1) if tobacco retail outlets (TROs) closer to middle and high schools have more tobacco advertisements than TROs farther away and (2) the potential impact of two place-based ...tobacco control strategies on tobacco advertisements: a simulated ban of TROs (1) within 1000ft of schools and (2) within 500 ft of other TROs.MethodsTROs within half-mile of 53 middle and high schools in the four largest Metropolitan areas in Texas were audited for all tobacco marketing. ArcGIS was used for mapping and grouping TROs by distance from the schools and simulating the ban. Mean differences in the number of tobacco advertisements were examined with t-tests. Percentage reductions in tobacco advertisements were calculated after simulation of both bans, reported by school type and by location, product and flavour.ResultsTROs within 1000 ft of schools had significantly more tobacco advertisements as compared with TROs located within 1000-2000 ft (p=0.03) for all schools combined and middle schools. Simulation of the 1000 ft ban of TROs led to a slightly greater reduction in advertisements (19.4%) as compared with the 500 ft ban of TROs from other TROs (17.9%). The reduction in all advertisement types was greater around middle schools and greatest for e-cigarettes (23.6%).ConclusionStudents can be exposed to a great deal of tobacco advertising in TROs around their schools. The implementation of a 1000 ft ban of TROs, or at minimum a ban on tobacco advertising outside and within these outlets, is one way to prevent or reduce the use of tobacco among adolescents.
To examine the features of the tapetal-like reflex (TLR) in female carriers of RPGR-associated retinopathy by means of adaptive optics scanning light ophthalmoscopy (AOSLO) and spectral domain ...optical coherence tomography.
Nine molecularly confirmed RPGR carriers and three healthy controls underwent ocular examination and the following retinal imaging modalities: color photography, near-infrared reflectance, fundus autofluorescence, spectral domain optical coherence tomography, and AOSLO. After identifying TLR areas across all imaging modalities, normalized local contrast of outer retinal bands on spectral domain optical coherence tomography was calculated and AOSLO-acquired photoreceptor mosaic analysis was performed.
Seven carriers had TLR areas, which colocalized with increased rod photoreceptor reflectivity on confocal AOSLO and reduced cone photoreceptor densities. Parafoveal TLR areas also exhibited reduced local contrast (i.e., increased reflectivity) of the outer retinal bands on spectral domain optical coherence tomography (inner segment ellipsoid zone and outer segment interdigitation zone). Healthy controls did not show TLR.
The cellular resolution provided by AOSLO affords the characterization of the photoreceptor mosaic in RPGR carriers with a TLR. Features revealed include reduced cone density, increased cone inner segment diameter, and increased rod outer segment reflectivity.
Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of ...this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P), were protected from development of NASH. The aim of this study was to elucidate the role of hepatocyte-specific SphK1 in development of NASH and to compare its contribution to hepatosteatosis in male and female mice.
We assessed mouse livers in early-stage fibrosis induced by high fat feeding, using single harmonic generation microscopy, LC-MS/MS analysis of hydroxyproline levels, and expression of fibrosis markers. We identified an antifibrotic intercellular signaling mechanism by culturing primary mouse hepatocytes alongside, and in co-culture with, LX2 hepatic stellate cells.
We generated hepatocyte-specific SphK1 knockout mice (SphK1-hKO). Unlike the global knockout, SphK1-hKO male mice were not protected from diet-induced steatosis, inflammation, or fibrogenesis. In contrast, female SphK1-hKO mice were protected from inflammation. Surprisingly, however, in these female mice, there was a ∼10-fold increase in the fibrosis markers Col1α1 and 2–3 fold induction of alpha smooth muscle actin and the pro-fibrotic chemokine CCL5. Because increased fibrosis in female SphK1-hKO mice occurred despite an attenuated inflammatory response, we investigated the crosstalk between hepatocytes and hepatic stellate cells, central players in fibrosis. We found that estrogen stimulated release of S1P from female hepatocytes preventing TGFβ-induced expression of Col1α1 in HSCs via S1PR3.
The results revealed a novel pathway of estrogen-mediated cross-talk between hepatocytes and HSCs that may contribute to sex differences in NAFLD through an anti-fibrogenic function of the S1P/S1PR3 axis. This pathway is susceptible to pharmacologic manipulation, which may lead to novel therapeutic strategies.
•A sphingosine kinase 1 hepatocyte-specific knockout mouse was developed.•A high saturated fat feeding study revealed sexual dimorphism in NAFLD/NASH pathology.•Female knockout mice had reduced inflammation, but exacerbated fibrosis.•A novel S1P-mediated mechanism for direct hepatocyte-hepatic stellate cell communication.
The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and ...resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.
IMPORTANCE Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe ...and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00740714
High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) ...patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.
Communities with more people of color and economically disadvantaged residents are disproportionately exposed to tobacco marketing from tobacco companies. This study examined if banning tobacco ...retail outlets (TROs) within 1000 ft of schools would reduce these marketing disparities through a greater reduction in the amount of tobacco advertising around schools in these communities.
Data from objectively audited advertisement data from 106 convenience stores and gas stations around 42 middle and high schools located in the four major metropolitan areas of Texas were linked with schools' enrollment data. ArcGIS (Aeronautical Reconnaissance Coverage Geographic Information System) was used to simulate a 1000-ft ban of tobacco sales around the schools. Independent sample T-tests and Mann-Whitney U tests were used to test mean differences where appropriate.
Schools with a higher enrollment of Hispanic/Latino (mean = 171.6, SD = 96.9) and economically disadvantaged students (mean = 168.9, SD = 102.3) were surrounded with significantly greater advertising at TROs than schools with lower enrollment of these groups (mean = 82.8, SD = 49.1 and mean = 89.2, SD = 50.6, respectively). A simulated 1000 ft ban of TROs around schools led to greater advertising reduction around schools with a higher enrollment of Hispanic/Latino students (13.3%-29.4% reductions) in comparison to schools with lower Hispanic/Latino student enrollment. However, the more economically disadvantaged schools had a smaller reduction in the number of advertisements (5.9%-21.9% reductions) in comparison to schools with less economically disadvantaged students.
The implementation of a ban of tobacco sales at TROs within 1000 ft of schools is one policy approach to reduce youth exposure to tobacco marketing, particularly among students of color.
Tobacco retail outlets (TROs) around schools with a higher enrollment of Hispanic/Latino and economically disadvantaged students had significantly more tobacco advertisements in comparison to schools with lower enrollment of these student groups. A simulated ban of TROs within 1000 ft of schools led to greater advertising reduction around schools with a higher enrollment of Hispanic/Latino students. For schools with more economically disadvantaged students, the ban led to a smaller reduction in advertisements in comparison to schools with less economically disadvantaged students. This proposed place-based strategy could be a successful means to reduce tobacco advertising and marketing disparity among communities of color.
PDF
