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BackgroundBroadband access has been highlighted as a national policy priority to improve access to care in rural communities.ObjectiveTo determine whether broadband internet availability was associated with telemedicine adoption among a rural patient population in western Tennessee.MethodsObservational study using electronic medical record data from March 13th, 2019 to March 13th, 2021. Multivariable logistic regression incorporating individual-level characteristics with broadband availability, income, educational attainment, and primary care physician supply at the zip code level, and rural status as determined at the county level.SettingSingle health system in western Tennessee.ParticipantsAdult patients with one or more in-person or remote encounter in a health system in western Tennessee and residing in western Tennessee between March 13th, 2019 and March 13th, 2021 (N = 54,688).Outcome measuresCompletion of one or more video encounters in the year following March 13th, 2020 (N = 3199; 7%). Our primary characteristic of interest was the proportion of residents in each zip code with access to the internet meeting the Federal Communications Commission definition of broadband access, adjusting for age, gender, race, income, educational attainment, insurance type, rural status, and primary care provider supply.ResultsPatients in a rural western Tennessee health system were predominantly white (79%), residing in rural zip codes (73%) with median household incomes ($52,085) less than state and national averages. Patients residing in a zip code where there is 80 to 100% broadband access compared to 0 to 20% were more likely in the year following March 13th, 2020 to have completed both telemedicine and in-person visits ([OR; 95% CI] 1.57; 1.29, 1.94), completed only telemedicine visits (2.26; 1.71, 2.97), less likely to have only completed in-person visits (0.81; 0.74, 0.89), but no more or less likely to have accessed no care (1.07; 0.97, 1.18).DiscussionThe availability of broadband internet was shown to be one of many factors associated with the utilization of telemedicine for a rural, working-class community after March 13th, 2020.ConclusionsAccess to broadband internet is a determinant of access to telemedicine for patients in rural communities and should be a priority for policymakers interested in improving health and access to care for rural patients.

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

Being on the bleeding edge of research requires the use of new and regularly updated software. The result is the occasional and inevitable occurrence of bugs. In the following work we present a case study where a feature request introduced a bug in a neuroimaging software package, which had consequences for the quality of results in a published article. We discuss the process of diagnosis, rectification and analysis replication.

TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1-induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.

Abstract Background Broadband access has been highlighted as a national policy priority to improve access to care in rural communities. Objective To determine whether broadband internet availability was associated with telemedicine adoption among a rural patient population in western Tennessee. Methods Observational study using electronic medical record data from March 13th, 2019 to March 13th, 2021. Multivariable logistic regression incorporating individual-level characteristics with broadband availability, income, educational attainment, and primary care physician supply at the zip code level, and rural status as determined at the county level. Setting Single health system in western Tennessee. Participants Adult patients with one or more in-person or remote encounter in a health system in western Tennessee and residing in western Tennessee between March 13th, 2019 and March 13th, 2021 (N = 54,688). Outcome measures Completion of one or more video encounters in the year following March 13th, 2020 (N = 3199; 7%). Our primary characteristic of interest was the proportion of residents in each zip code with access to the internet meeting the Federal Communications Commission definition of broadband access, adjusting for age, gender, race, income, educational attainment, insurance type, rural status, and primary care provider supply. Results Patients in a rural western Tennessee health system were predominantly white (79%), residing in rural zip codes (73%) with median household incomes ($52,085) less than state and national averages. Patients residing in a zip code where there is 80 to 100% broadband access compared to 0 to 20% were more likely in the year following March 13th, 2020 to have completed both telemedicine and in-person visits ([OR; 95% CI] 1.57; 1.29, 1.94), completed only telemedicine visits (2.26; 1.71, 2.97), less likely to have only completed in-person visits (0.81; 0.74, 0.89), but no more or less likely to have accessed no care (1.07; 0.97, 1.18). Discussion The availability of broadband internet was shown to be one of many factors associated with the utilization of telemedicine for a rural, working-class community after March 13th, 2020. Conclusions Access to broadband internet is a determinant of access to telemedicine for patients in rural communities and should be a priority for policymakers interested in improving health and access to care for rural patients.

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.