Association of body mass index with early age at diagnosis of endometrial intraepithelial neoplasia.

OBJECTIVE: Elevated body mass index (BMI) is a risk factor for endometrioid endometrial cancer and its precursor, endometrial intraepithelial neoplasia (EIN). Our objective was to describe the association between BMI and age at EIN diagnosis. METHODS: We conducted a retrospective study of patients diagnosed with EIN from 2010 to 2020 at a large academic medical center. Patient characteristics were stratified by menopausal status and compared using a chi-square or t-test. We used linear regression to determine the parameter estimate (ß) and 95% confidence interval for the association between BMI and age at diagnosis. RESULTS: We identified 513 patients with EIN; 503 (98%) had complete medical records. Premenopausal patients were more likely to be nulliparous and to have polycystic ovary syndrome than postmenopausal patients (both p ≤ 0.001). Postmenopausal patients were more likely to have hypertension, type 2 diabetes, and hyperlipidemia (all p ≤ 0.02). There was a significant linear association between BMI and age at diagnosis in premenopausal patients (ß = -0.19 (95% CI: -0.27, -0.10). In premenopausal patients, for every 1-unit increase in BMI, age at diagnosis decreased by 0.19 years. No association was observed in postmenopausal patients. CONCLUSIONS: In a large cohort of patients with EIN, increasing BMI was associated with an earlier age at diagnosis in premenopausal patients. This data suggests consideration of endometrial sampling in younger patients with known risk factors for excess estrogen exposure.

Feasibility and acceptability of an HPV self-testing strategy: lessons from a research context to assess for ability to implement into primary care at a national level in Botswana.

Background: The WHO strategy for cervical cancer elimination strives to achieve 70% coverage with high-performance cervical screening. While few low- and middle-income countries have achieved this, high-risk human papillomavirus (hrHPV) self-testing creates the possibility to rapidly upscale access to high-performance cervical screening across resource settings. However, effective hrHPV screening requires linkage to follow-up, which has been variable in prior studies. This study developed and tested an implementation strategy aimed at improving screening and linkage to follow-up care in South East District in Botswana. Methods: This study performed primary hrHPV self-testing; those with positive results were referred for a triage visit. Withdrawals for any reason, loss-to follow-up between hrHPV test and triage visit, and number of call attempts to give hrHPV results were also documented. Acceptability of the program to patients was measured as the proportion of patients who completed a triage visit when indicated, meeting the a priori threshold of 80%. Feasibility was defined as the proportion of participants receiving the results and attending follow-up. To assess the associations between participant characteristics and loss-to-follow-up we used log-binomial regressions to estimate risk ratios and 95% confidence intervals (CI). Results: Enrollment of 3,000 women occurred from February 2021 to August 2022. In total, 10 participants withdrew and an additional 33 were determined ineligible after consent, leaving a final cohort of 2,957 participants who underwent self-swab hrHPV testing. Half (50%) of participants tested positive for hrHPV and nearly all (98%) of participants received their hrHPV results, primarily via telephone.  Few calls to participants were required to communicate results: 2,397 (82%) required one call, 386 (13%) required 2 calls, and only 151 (5%) required 3-5 calls. The median time from specimen collection to participant receiving results was 44 days (IQR, 27-65). Of all hrHPV positive participants, 1,328 (90%) attended a triage visit. Discussion: In a large cohort we had low loss-to-follow-up of 10%, indicating that the strategy is acceptable. Telephonic results reporting was associated with high screening completion, required few calls to participants, and supports the feasibility of hrHPV self-testing in primary care followed by interval triage.

Feasibility and Acceptability of Ecological Momentary Assessment of Psychosocial Factors and Self-Management Behaviors Among Veterans With Type 2 Diabetes.

Comorbid symptoms such as post-traumatic stress and pain are common barriers to optimal self-management among veterans with type 2 diabetes. Additionally, self-management behaviors occur in the context of veterans' daily routines and social environments. This study evaluated the feasibility and acceptability of ecological momentary assessment (EMA) among veterans with type 2 diabetes. Ten veterans with type 2 diabetes were asked to respond to random EMA surveys during preprogrammed intervals five times per day for 14 days. EMA surveys were delivered via a mobile application and assessed momentary physical location, activities, social interactions, mood, stress, and pain. The last survey of each day included additional items about daily post-traumatic stress symptoms, diabetes distress, social support, physical activity, self-management behaviors, and functioning. Participants completed interviews assessing their experience in the study and barriers to responding and indicated their likelihood of participating in similar studies. The mean survey response rate was 96%, providing 675 observations. The majority of participants completed the five momentary surveys in <1 minute and the daily EMA surveys in <5 minutes. Results revealed substantial individual day-to-day variability across symptoms and self-management behaviors that is not captured by aggregated means across all participants. Participants generally reported enjoying responding to surveys and experiencing few barriers. Nine of 10 participants reported being "extremely likely" to participate in a similar study. These pilot data suggest that intensive EMA designs are feasible and acceptable for veterans with type 2 diabetes and can inform the design of future larger studies.

Technology-supported Acceptance and Commitment Therapy for chronic health conditions: A systematic review and meta-analysis.

Chronic health conditions (CHCs) are common and associated with functional limitations. Acceptance and commitment therapy (ACT) shows promise in improving functioning, quality of life, and distress across several CHCs. The purpose of this study was to conduct a systematic review of technology-supported ACT for CHCs and perform a meta-analysis on functioning and ACT process outcomes. Multiple databases were systematically searched for randomized controlled trials. A total of 20 unique studies with 2,430 randomized participants were included. CHCs addressed in these studies were chronic pain (k = 9), obesity/overweight (k = 4), cancer (k = 3), hearing loss (k = 1), HIV (k = 1), multiple sclerosis (k = 1), and tinnitus (k = 1). Internet and telephone were the most used technology platforms. All studies included therapist contact with considerable heterogeneity between studies. Random effects meta-analyses found medium effect sizes showing technology-supported ACT outperformed comparator groups on measures of function at post-treatment (Hedges' g = -0.49; p = 0.002) and follow-up (Hedges' g = -0.52; p = 0.02), as well as ACT process outcomes at post-treatment (Hedges' g = 0.48; p < 0.001) and follow-up (Hedges' g = 0.44; p < 0.001). Technology-supported ACT shows promise for improving function and ACT process outcomes across a range of CHCs. Recommendations are provided to optimize technology-supported ACT for CHCs. PROSPERO registration number: CRD42020200230.

Tunable Transcriptional Interference at the Endogenous Alcohol Dehydrogenase Gene Locus in Drosophila melanogaster.

Neighboring sequences of a gene can influence its expression. In the phenomenon known as transcriptional interference, transcription at one region in the genome can repress transcription at a nearby region in cis Transcriptional interference occurs at a number of eukaryotic loci, including the alcohol dehydrogenase (Adh) gene in Drosophila melanogasterAdh is regulated by two promoters, which are distinct in their developmental timing of activation. It has been shown using transgene insertion that when the promoter distal from the Adh start codon is deleted, transcription from the proximal promoter becomes de-regulated. As a result, the Adh proximal promoter, which is normally active only during the early larval stages, becomes abnormally activated in adults. Whether this type of regulation occurs in the endogenous Adh context, however, remains unclear. Here, we employed the CRISPR/Cas9 system to edit the endogenous Adh locus and found that removal of the distal promoter also resulted in the untimely expression of the proximal promoter-driven mRNA isoform in adults, albeit at lower levels than previously reported. Importantly, transcription from the distal promoter was sufficient to repress proximal transcription in larvae, and the degree of this repression was dependent on the degree of distal promoter activity. Finally, upregulation of the distal Adh transcript led to the enrichment of histone 3 lysine 36 trimethylation over the Adh proximal promoter. We conclude that the endogenous Adh locus is developmentally regulated by transcriptional interference in a tunable manner.

Differences in fungicide resistance profiles and multiple resistance to a quinone-outside inhibitor (QoI), two succinate dehydrogenase inhibitors (SDHI), and a demethylation inhibitor (DMI) for two Stagonosporopsis species causing gummy stem blight of cucurbits.

BACKGROUND: Gummy stem blight (GSB) is a devastating disease of cucurbits that has been effectively managed with fungicide applications. However, the Stagonosporopsis spp. that cause GSB have rapidly evolved resistance to multiple classes of fungicides. To better understand the evolution and persistence of fungicide resistance in field populations, resistance profiles of unique and clonal genotypes of 113 Stagonosporopsis citrulli and 19 S. caricae isolates to four different fungicides were determined based on in vitro mycelial growth assays and molecular markers based on genes encoding fungicide targets. RESULTS: All 19 S. caricae isolates screened were resistant to tebuconazole and azoxystrobin, and sensitive to boscalid and fluopyram. All 113 S. citrulli isolates were sensitive to tebuconazole and sensitive to fluopyram, with one exception that was fluopyram-resistant. All isolates of S. citrulli except two were resistant to azoxystrobin. Phenotypic differences in response to boscalid were detected among S. citrulli isolates, but the phenotypes were not associated with multilocus genotypes (MLG) determined by 16 microsatellite loci. Additionally, isolates sharing the same MLG varied by SdhB genotype. A unique mutation of I229V in SdhB, a target of succinate dehydrogenase inhibitor fungicides, was detected for the fluopyram-resistant isolate of S. citrulli. CONCLUSION: Both the lack of association of fungicide resistance profiles with genetic similarity of isolates based on microsatellite loci and the finding that widely distributed MLG varied in fungicide resistance profiles suggest that independent evolutionary events for resistance to boscalid have likely occurred. Frequent genetic recombination within populations may be responsible for resistance to multiple fungicides. This study provides useful information for effectively managing both species of GSB fungi present in the southeastern USA and understanding the evolution of fungicide resistance within populations of plant-pathogenic fungi. © 2019 Society of Chemical Industry.

Bone marrow from blotchy mice is dispensable to regulate blood copper and aortic pathologies but required for inflammatory mediator production in LDLR-deficient mice during chronic angiotensin II infusion.

BACKGROUND: The blotchy mouse caused by mutations of ATP7A develops low blood copper and aortic aneurysm and rupture. Although the aortic pathologies are believed primarily due to congenital copper deficiencies in connective tissue, perinatal copper supplementation does not produce significant therapeutic effects, hinting additional mechanisms in the symptom development, such as an independent effect of the ATP7A mutations during adulthood. METHODS: We investigated if bone marrow from blotchy mice contributes to these symptoms. For these experiments, bone marrow from blotchy mice (blotchy marrow group) and healthy littermate controls (control marrow group) was used to reconstitute recipient mice (irradiated male low-density lipoprotein receptor -/- mice), which were then infused with angiotensin II (1,000 ng/kg/min) for 4 weeks. RESULTS: By using Mann-Whitney U test, our results showed that there was no significant difference in the copper concentrations in plasma and hematopoietic cells between these 2 groups. And plasma level of triglycerides was significantly reduced in blotchy marrow group compared with that in control marrow group (P < 0.05), whereas there were no significant differences in cholesterol and phospholipids between these 2 groups. Furthermore, a bead-based multiplex immunoassay showed that macrophage inflammatory protein (MIP)-1ß, monocyte chemotactic protein (MCP)-1, MCP-3, MCP-5, tissue inhibitor of metalloproteinases (TIMP)-1, and vascular endothelial growth factor (VEGF)-A production was significantly reduced in the plasma of blotchy marrow group compared with that in control marrow group (P < 0.05). More important, although angiotensin II infusion increased maximal external aortic diameters in thoracic and abdominal segments, there was no significant difference in the aortic diameters between these 2 groups. Furthermore, aortic ruptures, including transmural breaks of the elastic laminae in the abdominal segment and lethal rupture in the thoracic segment, were observed in blotchy marrow group but not in control marrow group; however, there was no significant difference in the incidence of aortic ruptures between these 2 groups (P = 0.10; Fisher's exact test). CONCLUSIONS: Overall, our study indicated that the effect of bone marrow from blotchy mice during adulthood is dispensable in the regulation of blood copper, plasma cholesterol and phospholipids levels, and aortic pathologies, but contributes to a reduction of MIP-1ß, MCP-1, MCP-3, MCP-5, TIMP-1, and VEGF-A production and triglycerides concentration in plasma. Our study also hints that bone marrow transplantation cannot serve as an independent treatment option.

Inflammatory mediator profiling reveals immune properties of chemotactic gradients and macrophage mediator production inhibition during thioglycollate elicited peritoneal inflammation.

Understanding of spatiotemporal profiling of inflammatory mediators and their associations with MΦ accumulation is crucial to elucidate the complex immune properties. Here, we used murine thioglycollate elicited peritonitis to determine concentrations of 23 inflammatory mediators in peritoneal exudates and plasma before (day 0) and after (days 1 and 3) thioglycollate administration to peritoneal cavities; these mediators included TNF-α , FGF-9, IFN-γ , IP-10, RANTES, IL-1α , IL-6, IL-7, IL-10, IL-11, IL-12p70, IL-17A, lymphotactin, OSM, KC/GRO, SCF, MIP-1ß , MIP-2, TIMP-1, VEGF-A, MCP-1, MCP-3, and MCP-5. Our results showed that concentrations of most mediators in exudates and plasma reached peak levels on day 1 and were significantly reduced on day 3. Conversely, MΦ numbers started to increase on day 1 and reached peak levels on day 3. Moreover, LPS treatment in vitro significantly induced mediator productions in cell culture media and lysates from MΦ isolated on day 3. Our results also showed that on day 0, concentrations of many mediators in plasma were higher than those in exudates, whereas on day 1, the trend was reversed. Overall, the findings from thioglycollate elicited peritonitis reveal that reversible chemotactic gradients between peritoneal exudates and blood exist in basal and inflamed conditions and the inflammatory mediator production in vivo is disassociated with macrophage accumulation during inflammation resolution.