Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential ...therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies.
Chemical proteomics and phenotypic profiling illustrate the aryl hydrocarbon receptor (AhR) is a target of ezutromid, the first‐in‐class utrophin modulator for the treatment of Duchenne muscular dystrophy. Ezutromid binds to AhR with an apparent KD of 50 nm and functions as an AhR antagonist. Other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications, could also be exploited in future DMD therapies.
The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at ...an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment.
We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk.
We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12–2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67–4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81–10.26; deep 1/3, HR 7.05, CI 2.99–16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25–17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI.
Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.
•Adenocarcinoma is a distinct cervical cancer subtype and treatment should be based on data specific to this subtype.•Risk factors for recurrence differ for squamous cell carcinoma and adenocarcinoma of the cervix.•For adenocarcinoma of the cervix, tumor size is the risk factor associated with the highest risk of recurrence.•For squamous cell carcinoma, depth of invasion is the risk factor associated with the highest risk of recurrence.•Histology-specific nomograms accurately and linearly represent risk of recurrence for squamous cell and adenocarcinoma.
•Adds high spatially-resolved exposure data compared to previous studies.•Mutually adjusted estimates for air and noise pollution in susceptible population.•Primary traffic pollutants were not more ...strongly associated with prognosis.•Traffic noise only moderately correlated with air pollution.•Modest association between traffic noise and mortality independent of air pollution.
There is relatively little evidence of health effects of long-term exposure to traffic-related pollution in susceptible populations. We investigated whether long-term exposure to traffic air and noise pollution was associated with all-cause mortality or hospital readmission for myocardial infarction (MI) among survivors of hospital admission for MI.
Patients from the Myocardial Ischaemia National Audit Project database resident in Greater London (n=18,138) were followed for death or readmission for MI. High spatially-resolved annual average air pollution (11 metrics of primary traffic, regional or urban background) derived from a dispersion model (resolution 20m×20m) and road traffic noise for the years 2003–2010 were used to assign exposure at residence. Hazard ratios (HR, 95% confidence interval (CI)) were estimated using Cox proportional hazards models.
Most air pollutants were positively associated with all-cause mortality alone and in combination with hospital readmission. The largest associations with mortality per interquartile range (IQR) increase of pollutant were observed for non-exhaust particulate matter (PM10) (HR=1.05 (95% CI 1.00, 1.10), IQR=1.1μg/m3); oxidant gases (HR=1.05 (95% CI 1.00, 1.09), IQR=3.2μg/m3); and the coarse fraction of PM (HR=1.05 (95% CI 1.00, 1.10), IQR=0.9μg/m3). Adjustment for traffic noise only slightly attenuated these associations. The association for a 5dB increase in road-traffic noise with mortality was HR=1.02 (95% CI 0.99, 1.06) independent of air pollution.
These data support a relationship of primary traffic and regional/urban background air pollution with poor prognosis among MI survivors. Although imprecise, traffic noise appeared to have a modest association with prognosis independent of air pollution.
Background
Medical mistrust has had devastating consequences during the COVID-19 pandemic, particularly in rural communities. Community Health Workers (CHWs) have been shown to build trust, but there ...is little research on trust-building by CHWs in rural communities.
Objective
This study aims to understand the strategies that CHWs use to build trust with participants of health screenings in frontier Idaho.
Design
This is a qualitative study based on in-person, semi-structured interviews.
Participants
We interviewed CHWs (
N
=6) and coordinators of food distribution sites (FDSs; e.g., food banks and pantries) where CHWs hosted a health screening (
N
=15).
Approach
Interviews were conducted with CHWs and FDS coordinators during FDS-based health screenings. Interview guides were initially designed to assess facilitators and barriers to health screenings. Trust and mistrust emerged as dominant themes that determined nearly every aspect of the FDS-CHW collaboration, and thus became the focus of interviews.
Key Results
CHWs encountered high levels of interpersonal trust, but low institutional and generalized trust, among the coordinators and clients of rural FDSs. When working to reach FDS clients, CHWs anticipated confronting mistrust due to their association with the healthcare system and government, especially if CHWs were perceived as “outsiders.” Hosting health screenings at FDSs, which were trusted community organizations, was important for CHWs to begin building trust with FDS clients. CHWs also volunteered at FDS locations to build interpersonal trust before hosting health screenings. Interviewees agreed that trust building was a time- and resource-intensive process.
Conclusions
CHWs build interpersonal trust with high-risk rural residents, and should be integral parts of trust building initiatives in rural areas. FDSs are vital partners in reaching low-trust populations, and may provide an especially promising environment to reach some rural community members. It is unclear whether trust in individual CHWs also extends to the broader healthcare system.
Diabetic retinopathy features inflammation as well as injury to glial cells and the microvasculature, which are influenced by hypertension and overactivity of the renin-angiotensin system. FT011 is ...an anti-inflammatory and anti-fibrotic agent that has been reported to attenuate organ damage in diabetic rats with cardiomyopathy and nephropathy. However, the potential therapeutic utility of FT011 for diabetic retinopathy has not been evaluated. We hypothesized that FT011 would attenuate retinopathy in diabetic Ren-2 rats, which exhibit hypertension due to an overactive extra-renal renin-angiotensin system. Diabetic rats were studied for 8 and 32 weeks and received intravitreal injections of FT011 (50 μM) or vehicle (0.9% NaCl). Comparisons were to age-matched controls. In the 8-week study, retinal inflammation was examined by quantitating vascular leukocyte adherence, microglial/macrophage density and the expression of inflammatory mediators. Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours. In the 32-week study, severe retinal vasculopathy was examined by quantitating acellular capillaries and extracellular matrix proteins. In diabetic rats, FT011 reduced retinal leukostasis, microglial density and mRNA levels of intercellular adhesion molecule-1 (ICAM-1). In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6. Late intervention with FT011 reduced acellular capillaries and the elevated mRNA levels of collagen IV and fibronectin in diabetic rats. In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.
An in silico screen of 41 of the 81 coding regions of the Nicotiana plastid genome generated a shortlist of 12 candidates as DNA barcoding loci for land plants. These loci were evaluated for ...amplification and sequence variation against a reference set of 98 land plant taxa. The deployment of multiple primers and a modified multiplexed tandem polymerase chain reaction yielded 85-94% amplification across taxa, and mean sequence differences between sister taxa of 6.1 from 156 bases of accD to 22 from 493 bases of matK. We conclude that loci should be combined for effective diagnosis, and recommend further investigation of the following six loci: matK, rpoB, rpoC1, ndhJ, ycf5 and accD.
Non-native fish have been shown to have deleterious impacts on freshwater ecosystems in New Zealand. Early detection is critical for their effective management. Traditional capture-based techniques ...may not detect newly introduced fish, especially if they are present in low abundance. Molecular techniques that target environmental DNA (eDNA) have been shown, in many instances, to be more sensitive, cost-effective and require lower sampling effort. However, appropriate sampling strategies are needed to ensure robust and interpretable data are obtained. In this study we used droplet digital PCR assays to investigate the presence of two non-native fish in New Zealand, the European perch (
) and rudd (
) in three small lakes. Samples were collected from water and surface sediment at near-shore and mid-lake sites. Probabilistic modelling was used to assess the occupancy of fish eDNA and develop guidance on sampling strategies. Based on the detection probability measures from the present study, at least six sites and five replicates per site are needed to reliably detect fish eDNA in sediment samples, and twelve sites with eight replicates per site for water samples. The results highlight the potential of developing monitoring and surveillance programs adapted to lakes, that include the use of assays targeting eDNA. This study focused on small shallow lakes, and it is likely that these recommendations may vary in larger, deeper, and more geomorphologically complex lakes, and this requires further research.
Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, ...effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels.
We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes.
Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm–based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone–binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy.
Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho ρ=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0–19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7–13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, −61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones.
Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post–risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.
Both angiotensin II and vascular endothelial growth factor are angiogenic agents that have recently been implicated in the pathogenesis of proliferative diabetic retinopathy. In this study, retinal ...neovascularization was examined in a model of retinopathy of prematurity with the use of neonatal transgenic (mRen-2)27 rats, which overexpress renin in tissues, and Sprague-Dawley rats. Blockers of the renin-angiotensin system were administered during the neovascularization period. The ACE inhibitor lisinopril and the angiotensin type 1 receptor antagonist losartan both increased retinal renin levels and prevented inner retinal blood vessel growth. Quantitative in situ hybridization revealed that the expression of vascular endothelial growth factor and its type 2 receptor in the inner retina and proliferating blood vessels were increased in rats with retinopathy of prematurity. Lisinopril reduced both retinal vascular endothelial growth factor and its type 2 receptor mRNA in retinopathy of prematurity rats, whereas losartan had no effect. It is predicted that agents that interrupt the renin-angiotensin system may play an important role as retinoprotective agents in various forms of proliferative retinopathy.
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