Implementation and Sustainment of a Statewide Telemedicine Diabetic Retinopathy Screening Network for Federally Designated Safety-Net Clinics

CONTEXT: Diabetic retinopathy (DR) is the leading cause of incident blindness among working-age adults in the United States. Federally designated safety-net clinics (FDSC) often serve as point-of-contact for patients least likely to receive recommended DR screenings, creating opportunity for targeted interventions to increase screening access and compliance. STUDY DESIGN AND METHODS: With such a goal, we implemented and assessed the longitudinal performance of an FDSC-based telemedicine DR screening (TDRS) network of 22 clinical sites providing nonmydriatic fundus photography with remote interpretation and reporting. Retrospective analysis of patient encounters between February 2014 and January 2019 was performed to assess rates of pathology and referral. A generalized estimating equation logistic regression model was used for subset analysis from audits of pre- and post-implementation screening rates. Finally, patient surveys were conducted and assessed as a measure of intervention acceptability. RESULTS: Of the 13,923 individual telescreening encounters (4327 female, 4220 male, and 5376 unspecified; mean [SD] age, 54.9 [12.5] years) studied, 10,540 were of adequate quality to identify 3532 (33.5%) patients with ocular pathology: 2319 (22.0%) patients had some level of DR with 1604 (15.2%) requiring specialist referral, and 808 (7.7%) patients required referral for other ocular pathologies. The mean screening rate for audited clinics in the year prior to program implementation was 29.9% (641/2147), which increased to 47.7% (1012/2124) in the program’s first year, doubling patients’ odds of being screened (OR 2.2; 95% CI: 1.3–3.7; P = .003). These gains were sustained over four years following implementation (OR 1.9; 95% CI: 1.1–3.1; P = .018) despite varied clinic screening performance (4-year averaged range, 22.9–55.1%). Odds of early detection likewise doubled for patients with consecutive screenings (OR 2.2, 95% CI: 2.0–2.4; P \u3c .001). Finally, surveyed patients preferred TDRS to specialist exams (82.5%; 776/941) and would recommend the service to friends (92.7%; 868/936). CONCLUSION AND RELEVANCE: A statewide, FDSC-centered TDRS network was successfully established and sustained in a medically underserved region of the United States. Our results suggest that large TDRS networks in FDSCs can increase screening access and compliance for otherwise unscreened populations, but outcomes can vary greatly among clinics. Further work to optimize program implementation is needed to maximize this model\u27s impact

Adult attachment and relationship satisfaction: The mediating role of gratitude toward the partner

Previous research indicated that insecure attachment, that is, higher levels of attachment avoidance and attachment anxiety, is negatively associated with relationship satisfaction. The present study investigated the mediating role of gratitude toward the partner in this association. In a cross-sectional design, 362 participants (84% female, age range 18–70 years) involved in a romantic relationship completed an online questionnaire assessing attachment avoidance and anxiety, gratitude toward the partner, and relationship satisfaction. Data were analyzed by means of regression and bootstrap analyses. The regression analysis revealed significant negative total and direct effects of both avoidance and anxiety on relationship satisfaction. The bootstrap analyses revealed a significant negative indirect effect of avoidance, but not anxiety, on relationship satisfaction via gratitude toward the partner. Specifically, higher levels of avoidant attachment were related to less gratitude toward the partner, which in turn was associated with lower relationship satisfaction. These findings suggest that it might be valuable applying gratitude interventions to clients high in attachment avoidance attending couples therapy

Circulating MicroRNAs as Non-invasive Biomarkers for Canine Cushing's Syndrome

Canine Cushing's syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, non-invasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as diagnostic (presence of PDH or csACT) and/or prognostic (disease recurrence, histological grade) non-invasive biomarkers for canine Cushing's syndrome. After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre- and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples). In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9x10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of <11. These results indicate that circulating miRNAs have the potential to be non-invasive biomarkers in dogs with Cushing's syndrome that may contribute to clinical decision making

Evaluation of Multi-Level Barriers and Facilitators in a Large Diabetic Retinopathy Screening Program in Federally Qualified Health Centers: A Qualitative Study

BACKGROUND: Recommended annual diabetic retinopathy (DR) screening for people with diabetes has low rates in the USA, especially in underserved populations. Telemedicine DR screening (TDRS) in primary care clinics could expand access and increase adherence. Despite this potential, studies have observed high variability in TDRS rates among clinics and over time, highlighting the need for implementation supports. Previous studies of determinants of TDRS focus on patients\u27 perspectives, with few studies targeting upstream multi-level barriers and facilitators. Addressing this gap, this qualitative study aimed to identify and evaluate multi-level perceived determinants of TDRS in Federally Qualified Health Centers (FQHCs), to inform the development of targeted implementation strategies. METHODS: We developed a theory-based semi-structured interview tool based on the Consolidated Framework for Implementation Research (CFIR). We conducted 22 key informant interviews with professionals involved in TDRS (administrators, clinicians, staff). The interviews were audio-recorded and transcribed verbatim. Reported barriers and facilitators were organized into emergent themes and classified according to CFIR constructs. Constructs influencing TDRS implementation were rated for each study site and compared across sites by the investigators. RESULTS: Professionals identified 21 main barriers and facilitators under twelve constructs of the five CFIR domains. Several identified themes were novel, whereas others corroborated previous findings in the literature (e.g., lack of time and human resources, presence of a champion). Of the 21 identified themes, 13 were classified under the CFIR’s Inner Setting domain, specifically under the constructs Compatibility and Available Resources. Themes under the Outer Setting domain (constructs External Incentives and Cost) were primarily perceived by administrators, whereas themes in other domains were perceived across all professional categories. Two Inner Setting (Leadership Engagement, Goals and Feedback) and two Process (Champion, Engaging) constructs were found to strongly distinguish sites with high versus low TDRS performance. CONCLUSIONS: This study classified barriers and facilitators to TDRS as perceived by administrators, clinicians, and staff in FQHCs, then identified CFIR constructs that distinguished high- and low-performance clinics. Implementation strategies such as academic detailing and collection and communication of program data and successes to leadership; engaging of stakeholders through involvement in implementation planning; and appointment of intervention champions may therefore improve TDRS implementation and sustainment in resource-constrained settings

Heat shock protein expression analysis in canine osteosarcoma reveals HSP60 as a potentially relevant therapeutic target

Heat shock proteins (HSP) are highly conserved across eukaryotic and prokaryotic species. These proteins play a role in response to cellular stressors, protecting cells from damage and facilitating recovery. In tumor cells, HSPs can have cytoprotective effects and interfere with apoptotic cascades. This study was performed to assess the prognostic and predictive values of the gene expression of HSP family members in canine osteosarcoma (OS) and their potential for targeted therapy. Gene expressions for HSP were assessed using quantitative PCR (qPCR) on 58 snap-frozen primary canine OS tumors and related to clinic-pathological parameters. A significant increased expression of HSP60 was found in relation to shorter overall survival and an osteoblastic phenotype. Therefore, the function of HSP60 was investigated in more detail. Immunohistochemical analysis revealed heterogeneous staining for HSP60 in tumors. The highest immunoreactivity was found in tumors of short surviving dogs. Next HSP expression was shown in a variety of canine and human OS cell lines by qPCR and Western blot. In two highly metastatic cell lines HSP60 expression was silenced using siRNA resulting in decreased cell proliferation and induction of apoptosis in both cell lines. It is concluded that overexpression of HSP60 is associated with a poor prognosis of OS and should be evaluated as a new target for therapy

Repositioning the Catalytic Triad Aspartic Acid of Haloalkane Dehalogenase: Effects on Stability, Kinetics, and Structure

Haloalkane dehalogenase (DhlA) catalyzes the hydrolysis of haloalkanes via an alkyl-enzyme intermediate. The covalent intermediate, which is formed by nucleophilic substitution with Asp124, is hydrolyzed by a water molecule that is activated by His289. The role of Asp260, which is the third member of the catalytic triad, was studied by site-directed mutagenesis. Mutation of Asp260 to asparagine resulted in a catalytically inactive D260N mutant, which demonstrates that the triad acid Asp260 is essential for dehalogenase activity. Furthermore, Asp260 has an important structural role, since the D260N enzyme accumulated mainly in inclusion bodies during expression, and neither substrate nor product could bind in the active-site cavity. Activity for brominated substrates was restored to D260N by replacing Asn148 with an aspartic or glutamic acid. Both double mutants D260N+N148D and D260N+N148E had a 10-fold reduced kcat and 40-fold higher Km values for 1,2-dibromoethane compared to the wild-type enzyme. Pre-steady-state kinetic analysis of the D260N+N148E double mutant showed that the decrease in kcat was mainly caused by a 220-fold reduction of the rate of carbon-bromine bond cleavage and a 10-fold decrease in the rate of hydrolysis of the alkyl-enzyme intermediate. On the other hand, bromide was released 12-fold faster and via a different pathway than in the wild-type enzyme. Molecular modeling of the mutant showed that Glu148 indeed could take over the interaction with His289 and that there was a change in charge distribution in the tunnel region that connects the active site with the solvent. On the basis of primary structure similarity between DhlA and other α/β-hydrolase fold dehalogenases, we propose that a conserved acidic residue at the equivalent position of Asn148 in DhlA is the third catalytic triad residue in the latter enzymes.

The coordination of cell growth during fission yeast mating requires Ras1-GTP hydrolysis

The spatial and temporal control of polarity is fundamental to the survival of all organisms. Cells define their polarity using highly conserved mechanisms that frequently rely upon the action of small GTPases, such as Ras and Cdc42. Schizosaccharomyces pombe is an ideal system with which to study the control of cell polarity since it grows from defined tips using Cdc42-mediated actin remodeling. Here we have investigated the importance of Ras1-GTPase activity for the coordination of polarized cell growth during fission yeast mating. Following pheromone stimulation, Ras1 regulates both a MAPK cascade and the activity of Cdc42 to enable uni-directional cell growth towards a potential mating partner. Like all GTPases, when bound to GTP, Ras1 adopts an active conformation returning to an inactive state upon GTP-hydrolysis, a process accelerated through interaction with negative regulators such as GAPs. Here we show that, at low levels of pheromone stimulation, loss of negative regulation of Ras1 increases signal transduction via the MAPK cascade. However, at the higher concentrations observed during mating, hyperactive Ras1 mutations promote cell death. We demonstrate that these cells die due to their failure to coordinate active Cdc42 into a single growth zone resulting in disorganized actin deposition and unsustainable elongation from multiple tips. These results provide a striking demonstration that the deactivation stage of Ras signaling is fundamentally important in modulating cell polarity

Consideration of the bioavailability of metal/metalloid species in freshwaters: experiences regarding the implementation of biotic ligand model-based approaches in risk assessment frameworks

After the scientific development of Biotic Ligand Models (BLMs) in recent decades these models are now considered suitable for implementation in regulatory risk assessment of metals in freshwater bodies. The approach has been developed over several years and has been described in many peer-reviewed publications. The original complex BLMs have been applied in prospective risk assessment reports for metals and metal compounds and are also recommended as suitable concepts for the evaluation of monitoring data in the context of the European Water Framework Directive. Currently, several user-friendly BLM-based bioavailability software tools are available for assessing the aquatic toxicity of a limited number of metals (mainly copper, nickel, and zinc). These tools need only a basic set of water parameters as input (e.g., pH, hardness, dissolved organic matter and dissolved metal concentration). Such tools seem appropriate to foster the implementation in routine water quality assessments. This work aims to review the existing bioavailability-based regulatory approaches and the application of available BLM-based bioavailability tools for this purpose. Advantages and possible drawbacks of these tools (e.g., feasibility, boundaries of validity) are discussed, and recommendations for further implementation are given