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Medically underserved people with type 2 diabetes mellitus face limited access to group-based diabetes care, placing them at risk for poor disease control and complications. Immersive technology and telemedicine solutions could bridge this gap. The purpose of this study was to compare the effectiveness of diabetes medical group visits (DMGVs) delivered in an immersive telemedicine platform versus an in-person (IP) setting and establish the noninferiority of the technology-enabled approach for changes in hemoglobin A (HbA ) and physical activity (measured in metabolic equivalent of task [MET]) at 6 months. This study is a noninferiority randomized controlled trial conducted from February 2017 to December 2019 at an urban safety net health system and community health center. We enrolled adult women (aged ≥18 years) who self-reported African American or Black race or Hispanic or Latina ethnicity and had type 2 diabetes mellitus and HbA ≥8%. Participants attended 8 weekly DMGVs, which included diabetes self-management education, peer support, and clinician counseling using a culturally adapted curriculum in English or Spanish. In-person participants convened in clinical settings, while virtual world (VW) participants met remotely via an avatar-driven, 3D VW linked to video teleconferencing. Follow-up occurred 6 months post enrollment. Primary outcomes were mean changes in HbA and physical activity at 6 months, with noninferiority margins of 0.7% and 12 MET-hours, respectively. Secondary outcomes included changes in diabetes distress and depressive symptoms. Of 309 female participants (mean age 55, SD 10.6 years; n=195, 63% African American or Black; n=105, 34% Hispanic or Latina; n=151 IP; and n=158 in VW), 207 (67%) met per-protocol criteria. In the intention-to-treat analysis, we confirmed noninferiority for primary outcomes. We found similar improvements in mean HbA by group at 6 months (IP: -0.8%, SD 1.9%; VW: -0.5%, SD 1.8%; mean difference 0.3, 97.5% CI -∞ to 0.3; P<.001). However, there were no detectable improvements in physical activity (IP: -6.5, SD 43.6; VW: -9.6, SD 44.8 MET-hours; mean difference -3.1, 97.5% CI -6.9 to ∞; P=.02). The proportion of participants with significant diabetes distress and depressive symptoms at 6 months decreased in both groups. In this noninferiority randomized controlled trial, immersive telemedicine was a noninferior platform for delivering diabetes care, eliciting comparable glycemic control improvement, and enhancing patient engagement, compared to IP DMGVs. ClinicalTrials.gov NCT02726425; https://clinicaltrials.gov/ct2/show/NCT02726425.

Group-based diabetes care, both technology-enabled and in-person, can improve diabetes outcomes in low-income minority women, but the mechanism remains unclear. We tested whether diabetes group medical visits (GMVs) reduced hemoglobin A1c (HbA1c) by mitigating diabetes distress (DD), an emotional response affecting nearly half of adults with type 2 diabetes in community settings. We conducted a mediation and moderation analysis of data from the Women in Control 2.0 comparative effectiveness study, which showed that both technology-enabled and in-person diabetes GMVs improve HbA1c. We tested whether DD mediated the relationship between diabetes GMV engagement and reductions in HbA1c. We also tested whether this relationship was moderated by depressive symptoms and social support. Participants were 309 low-income and minority women. Diabetes GMV engagement was measured using the Group Climate Questionnaire. The mediator, DD, was measured using the Diabetes Distress Screening Scale. The outcome was the 6-month change in HbA1c. Social support was measured using the Medical Outcomes Study Social Support Survey. DD mediated the relationship between engagement and 6-month HbA1c. Specifically, group engagement affected HbA1c by reducing distress associated with the regimen of diabetes self-management (P=.04), and possibly the emotional burden of diabetes (P=.09). The relationship between engagement and 6-month HbA1c was moderated by depressive symptoms (P=.02), and possibly social support (P=.08). Engagement in diabetes GMVs improved HbA1c because it helped reduce diabetes-related distress, especially related to the regimen of diabetes management and possibly related to its emotional burden, and especially for women without depressive symptoms and possibly for women who lacked social support.

BackgroundPrimary care providers (PCPs) often take the lead role in caring for patients with overweight and obesity; however, few PCPs counsel patients about weight loss. Online weight management programs that are integrated within primary care may help address this gap in care.ObjectiveTo identify perceptions of and experience with online weight management programs in general and with a proposed online program, to identify barriers to use, and to improve the design and content of our intervention, which included an online program plus population health management (PHM) support from primary care practices.DesignA mixed qualitative methods study including three patient focus groups and seven semi-structured interviews with healthcare providers.ParticipantsA total of 13 adult patients (age range, 20–70) with body mass index (BMI) 27–35 kg/m2 attended the focus groups. In-person semi-structured interviews were conducted with seven healthcare providers (three PCPs, two population health managers, one primary care nurse, and one registered dietitian).Main MeasuresWe developed and used semi-structured focus groups and interview guides. The focus group and interviews were recorded and transcribed. Using grounded theory, we analyzed the transcripts to identify and extract common concepts and themes.Key ResultsAlthough patients and healthcare providers expressed positive opinions about online weight management programs, few patients had experience with them, and providers stated that such programs are not being widely implemented in primary care settings. Some participants highlighted the flexibility and low cost as strengths of online weight management tools compared with in-person programs. All participants had favorable opinions about our proposed intervention and were overwhelmingly positive about the combination of an online program and PHM support.ConclusionsThis study highlights the potential value of online weight management programs and PHM support in primary care.Clinical Trials RegistrationNCT02656693.

The management of type 2 diabetes mellitus (T2DM) includes mastery of complex care activities, self-management skills, and routine health care encounters to optimize glucose control and achieve good health. Given the lifelong course of T2DM, patients are faced with navigating complex medical and disease-specific information. This health-seeking behavior is a driver of health disparities and is associated with hospitalization and readmission. Given that health-seeking behavior is a potentially intervenable social determinant of health, a better understanding of how people navigate these complex systems is warranted. To address this need, we aimed to develop new patient-reported outcome (PRO) measures that evaluate health-seeking behavior in persons with T2DM. These new PROs were designed to be included in the Re-Engineered Discharge for Diabetes-Computer Adaptive Test (REDD-CAT) measurement system, which includes several other PROs that capture the importance of social determinants of health. Overall, 225 participants with T2DM completed 56 self-report items that examined health-seeking behaviors. Classical Test Theory and Item Response Theory were used for measurement development. Exploratory factor analysis (EFA; criterion ratio of eigenvalue 1 to eigenvalue 2 being >4; variance for eigenvalue 1 ≥40%) and confirmatory factor analysis (CFA; criterion 1-factor CFA loading <.50; 1-factor CFA residual correlation >.20; comparative fit index ≥0.90; Tucker-Lewis index ≥0.90; root mean square error of approximation <0.15) were used to determine unidimensional sets of items. Items with sparse responses, low-adjusted total score correlations, nonmonotonicity, low factor loading, and high residual correlations of high error modification indices were candidates for exclusion. A constrained graded response model was used to examine item misfit, and differential item functioning was examined to identify item bias. Cronbach α was used to examine internal consistency reliability for the new PROs (criterion ≥0.70), and floor and ceiling effects were examined (criterion ≤20%). Four unidimensional sets of items were supported by EFA (all EFA eigenvalue ratios >4; variance for eigenvalue 1=41.4%-67.3%) and CFA (fit statistics all exceeded criterion values). This included (1) \"Health-Seeking Behavior: PCP-Specific\" (6 items); (2) \"Health-Seeking Behavior: General Beliefs\" (13 items); (3) \"Health-Seeking Behavior: Family or Friends-Specific\" (5 items); and (4) \"Health-Seeking Behavior: Internet-Specific\" (4 items). All items were devoid of differential item functioning for age, sex, education, or socioeconomic status factors. \"Health-Seeking Behavior: General Beliefs\" was developed to include both a computer adaptive test and a 6-item short form version; all other PROs were developed as static short forms. The psychometric reliability of these new PROs was supported; internal consistency ranged from acceptable to excellent (Cronbach α=.78-.91), and measures were free of significant floor or ceiling effects (floor effects range: 0%-8.9%; ceiling effects range: 0%-8.4%). The new REDD-CAT Health-Seeking Behavior PROs provide reliable assessments of health-seeking behaviors among those with T2DM.

The Polycomb group (PcG) protein Eed is implicated in regulation of imprinted X-chromosome inactivation in extraembryonic cells but not of random X inactivation in embryonic cells. The Drosophila homolog of the Eed-Ezh2 PcG protein complex achieves gene silencing through methylation of histone H3 on lysine 27 (H3-K27), which suggests a role for H3-K27 methylation in imprinted X inactivation. Here we demonstrate that transient recruitment of the Eed-Ezh2 complex to the inactive X chromosome (Xi) occurs during initiation of X inactivation in both extraembryonic and embryonic cells and is accompanied by H3-K27 methylation. Recruitment of the complex and methylation on the Xi depend on Xist RNA but are independent of its silencing function. Together, our results suggest a role for Eed-Ezh2-mediated H3-K27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3-K27 methylation is not sufficient for silencing of the Xi.

In the last 10 years, it has become increasingly clear that large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions. Consequently, the OXT signaling system forms, like other monoamine axons, a rich functional network across several brain regions. In this manuscript, we review the recently indicated higher order G-protein coupled heteroreceptor complexes of the oxytocin receptor (OXTR), and how these, via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers and their potential impact for brain and behavior. The major focus will be on complexes of the OXTR protomer with the dopamine D2 receptor (D2R) protomer and the serotonin 2A (5-HT2AR) and 2C (5-HT2CR) receptor protomers. Specifically, the existence of D2R-OXTR heterocomplexes in the nucleus accumbens and the caudate putamen of rats has led to a postulated function for this heteromer in social behavior. Next, a physical interaction between OXTRs and the growth hormone secretagogue or ghrelin receptor (GHS-R1a) was demonstrated, which consequently was able to attenuate OXTR-mediated Gαq signaling. This highlights the potential of ghrelin-targeted therapies to modulate oxytocinergic signaling with relevance for appetite regulation, anxiety, depression, and schizophrenia. Similarly, evidence for 5-HT2AR-OXTR heteromerization in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell was demonstrated. This complex may offer new strategies for the treatment of both mental disease and social behavior. Finally, the 5-HT2CR-OXTR heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus. Future work should be done to investigate the precise functional consequence of region-specific OXTR heteromerization in the brain, as well across the periphery, and whether the integration of neuronal signals in the brain may also involve higher order OXTR-GHS-R1a heteroreceptor complexes including the dopamine (DA), noradrenaline (NA) or serotonin (5-HT) receptor protomers or other types of G-protein coupled receptors (GPCRs).

Evolutionarily young genes that serve essential functions represent a paradox; they must perform a function that either was not required until after their birth or was redundant with another gene. How young genes rapidly acquire essential function is largely unknown. We traced the evolutionary steps by which the Drosophila gene Umbrea acquired an essential role in chromosome segregation in D. melanogaster since the gene's origin less than 15 million years ago. Umbrea neofunctionalization occurred via loss of an ancestral heterochromatin-localizing domain, followed by alterations that rewired its protein interaction network and led to species-specific centromere localization. Our evolutionary cell biology approach provides temporal and mechanistic detail about how young genes gain essential function. Such innovations may constantly alter the repertoire of centromeric proteins in eukaryotes.

Osteoporosis is a skeletal disease mainly affecting women over 50 years old and it represents a serious public health problem because of the high socioeconomic burden. This disease is characterized by deterioration of bone microarchitecture, low bone mineral density (BMD), and increased risk of fragility fractures. This study aimed to identify serum useful proteins as biomarkers for the diagnosis and/or prognosis of osteoporosis and fracture risk. We collected 446 serum samples from postmenopausal women aged ≥45 years old. Based on the BMD measurement, we classified the participants into three groups: osteoporotic, osteopenic, and normal. In an initial discovery stage, we conducted a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE). The peptides into the spots of interest were identified through matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF/TOF). Enzyme-linked immunosorbent assay (ELISA) was performed to validate the proteins of interest. We identified 27 spots of interest when comparing low BMD versus normal BMD postmenopausal women. Based on their relevance in bone metabolism, we analyzed three proteins: ceruloplasmin (CP), gelsolin (GSN), and vitamin D-binding protein (VDBP). Our results demonstrated that low serum VDBP levels correlate with low BMD (osteopenic and osteoporotic). Therefore, VDBP could be considered as a novel, potential, and non-invasive biomarker for the early detection of osteoporosis.

Neuronal calcium sensor-1 (NCS-1 Var1) is a calcium-binding protein expressed in most tissues. We examined a poorly characterized variant of NCS-1 (Var2), identified only in humans where the N-terminal 22 amino acid residues of native NCS-1(MGKSNSKLKPEVVEELTRKTY) were replaced with 4 different residues (MATI). Because alterations in the level of expression of NCS-1 Var1 and the expression of NCS-1 variants have been correlated with several neurological diseases, the relative expression and functional role of NCS-1 Var2 was examined. We found that NCS-1 Var2 mRNA levels are not found in mouse tissues and are expressed at levels ~1000-fold lower than NCS-1 Var1 in three different human cell lines (SHSY5Y, HEK293, MB231). Protein expression of both variants was only identified in cell lines overexpressing exogenous NCS-1 Var2. The calcium binding affinity is ~100 times weaker in purified NCS-1 Var2 than NCS-1 Var1. Because truncation of NCS-1 Var1 has been linked to functional changes in neurons, we determined whether the differing properties of the NCS-1 variants could potentially contribute to the altered cell function. In contrast to previous reports showing that overexpression of NCS-1 Var1 increases calcium-dependent processes, functional differences in cells overexpressing NCS-1 Var2 were undetectable in assays for cell growth, cell death and drug (paclitaxel) potency. Our results suggest that NCS-1 Var1 is the primary functional version of NCS-1.

Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo . Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. ATM is a tumor suppressor often mutated in lung adenocarcinoma. In this study, the authors starting from a synthetic lethal screen, demonstrate that tumor cells with mutations in ATM exhibit increased sensitivity to MEK1/2 inhibition through the modulation of the AKT/mTOR pathway.