Patient preferences in the treatment of stage III/IV classic Hodgkin lymphoma: Results from the CONNECT cross-sectional survey.

We explored patient front-line treatment preferences in newly diagnosed stage III/IV classic Hodgkin lymphoma (cHL). The CONNECT patient survey, administered online from 30 December 2020 to 1 March 2021, examined preferences overall and by age at diagnosis in 182 adult patients diagnosed with stage III/IV cHL within the past 10 years in the United States. At diagnosis, patients' median age was 36 years; 66% of patients were younger (aged 16-41 years) and 34% older (aged 42-85 years). When asked about initial treatment goals, 74% of patients ranked cure as their first or second goal (86% younger vs. 52% older patients; p < 0.001). At diagnosis, 72% of patients preferred aggressive treatment, and 85% were willing to accept more short-term risks in exchange for a better-working therapy long term. For long-term risks, younger versus older patients were significantly more concerned about second cancers (p < 0.001) and fertility issues (p = 0.007), whereas older patients were more concerned about lung damage (p = 0.028) and infections (p < 0.001). Most patients (94%) reported having a caregiver at some point, but 99% of these patients retained some control of treatment decisions. Collectively, these survey results highlight patient treatment preferences and differences in treatment goals and long-term side effect concerns based on patient age.

Physician frontline treatment preferences for stage III/IV classic Hodgkin lymphoma: the real-world US CONNECT study.

Aim: To understand US physicians' frontline (1L) treatment preferences/decision-making for stage III/IV classic Hodgkin lymphoma (cHL). Materials & methods: Medical oncologists and/or hematologists (≥2 years' practice experience) who treat adults with stage III/IV cHL were surveyed online (October-November 2020). Results: Participants (n = 301) most commonly considered trial efficacy/safety data and national guidelines when selecting 1L cHL treatments. Most physicians (91%) rated overall survival (OS) as the most essential attribute when selecting 1L treatment. Variability was seen among regimen selection for hypothetical newly diagnosed patients, with OS cited as the most common reason for regimen selection. Conclusion: While treatment selection varied based on patient characteristics, US physicians consistently cited OS as the top factor considered when selecting a 1L treatment for cHL.

Classic Hodgkin lymphoma (cHL) is a type of cancer that grows in lymph nodes. The researchers created a survey to assess how doctors in the USA choose medicine to treat patients who are newly diagnosed with an advanced stage of cHL (stage 3 or 4 out of 4 stages). We surveyed 301 doctors who treat patients with cHL. When choosing a medicine to treat cHL, most doctors said they consider results from research studies, how well the medicine works, information on the medicine's safety and recommendations in official guidelines. Most doctors said that overall survival (how long the patient survives after being diagnosed with cHL) is the most important outcome they consider when choosing a medicine to treat cHL. During the survey, doctors saw four unique patient profiles. These profiles differed in age, disease stage (how far along the cHL is) and other illnesses the patient has. While medicine choice was different across profiles, overall survival was still the reason for choosing each individual patient's medicine. These survey results show that doctors in the USA highly consider overall survival when choosing medicine for patients newly diagnosed with an advanced stage of cHL.

The impact of classic Hodgkin lymphoma on informal caregivers: results from the CONNECT cross-sectional survey.

PURPOSE: As part of the CONNECT study, we evaluated the caregiver role in treatment decision-making when caring for patients with classic Hodgkin lymphoma (cHL) in the USA. METHODS: The CONNECT caregiver survey was administered online December 2020-March 2021 to self-identified adult caregivers of cHL patients recruited from patient referrals and online panels. The caregiver's role in treatment decision-making, health-related quality of life (HRQoL, PROMIS-Global), and work impacts (WPAI:CG) were assessed. RESULTS: We surveyed 209 caregivers (58% women; median age 47 years; 54% employed; 53% spouse/partner); 69% of patients cared for were diagnosed with cHL in the past 1-2 years, with 48% having stage III/IV cHL and 29% in remission. More spouse/partner than other caregivers were involved in caregiving at symptom onset (61% vs 27%), whereas more other than spouse/partner caregivers began after first treatment (34% vs 5%). Cure, caregivers' top treatment goal (49%), was rated higher by spouse/partner than other caregivers (56% vs 42%). More spouse/partner than other caregivers were involved in treatment option discussions with physicians (52% vs 28%), were involved in patients' treatment decisions (54% vs 23%), and were aligned with patients' treatment goals (93% vs 79%). While caregivers reported HRQoL similar to that of the general population, nearly 30% of employed caregivers reported work impairment. CONCLUSION: Cure was caregivers' top treatment goal. Spouse/partner vs other caregivers were more involved, were involved earlier, and reported greater alignment with patient treatment goals and decision-making. Caregivers reported good HRQoL; however, caregiving impacted work productivity regardless of patient relationship.

Soil salinization and chemically mediated plant-insect interactions in a changing climate.

Increase in soil salinization due to climate change is a global phenomenon that can induce significant changes in plant growth, physiology, and chemistry, exacerbating growing threats to insect biodiversity. Insects that rely on plants are likely to be indirectly impacted by changes in soil salt content through changes in plant chemistry, yet few studies link changes in plant metabolism to impacts on higher trophic levels. Some salinity-mediated changes in specialized metabolites may be predictable due to highly conserved metabolic pathways shared between herbivore defense and stress resistance, but recent studies also suggest substantial variation across plant species and habitats. To date, most of the research on salinity and chemically mediated plant-insect interactions has focused on herbivores, particularly in agricultural systems. Published effects of salinity on pollinators and parasitoids are scarce. Future research will need to focus more on the role of plant chemistry to bridge the divide between studies of plant and insect responses to salinization.

Plant susceptibility to a shared herbivore is reduced by belowground competition with neighbors.

Spatial variation in plant community composition is an important driver of variation in susceptibility to herbivores. In close proximity, certain neighbors can attract or repel herbivores to a focal plant ("associational effects"). Neighboring plants may also compete for resources, modifying their phenotype in ways that affect susceptibility to herbivores. To test whether and how competition contributes to associational effects, we manipulated the sharing of belowground resources among plant neighbors (spotted Joe Pye weed and common boneset) that serve as alternate hosts for an herbivorous beetle. In the field, the beetle Ophraella notata laid more eggs and inflicted more damage on plants of both species that were released from belowground competition with neighbors. Competition also weakened the effects of neighbor identity during field trials, reducing associational susceptibility. When beetles were forced to choose between the two host species in cage trials, competition again reduced beetle use of Joe Pye weed as a secondary host. To test the role of plant traits related to herbivore defense and nutrition, we quantified leaf protein, specific leaf area, and trichomes, and conducted behavioral assays on leaf disks. Beetles did not distinguish between Joe Pye weed treatments at the leaf disk level, and competition did not impact specific leaf area and protein. Trichome density was higher in both species in the preferred treatment. Overall, our results suggest that belowground interactions between plants may mediate the strength of associational effects, as secondary hosts become more attractive when released from competition with primary host plants.

Husimi Dynamics Generated by non-Hermitian Hamiltonians.

The dynamics generated by non-Hermitian Hamiltonians are often less intuitive than those of conventional Hermitian systems. Even for models as simple as a complexified harmonic oscillator, the dynamics for generic initial states shows surprising features. Here we analyze the dynamics of the Husimi distribution in a semiclassical limit, illuminating the foundations of the full quantum evolution. The classical Husimi evolution is composed of two factors: (i) the initial Husimi distribution evaluated along phase-space trajectories and (ii) the final value of the norm corresponding to each phase-space point. Both factors conspire to lead to intriguing dynamical behaviors. We demonstrate how the full quantum dynamics unfolds on top of the classical Husimi dynamics for two instructive examples.

The status of patient portal use among Emergency Department patients experiencing houselessness: A large-scale single-center observational study.

OBJECTIVE: Patient portal (PP) use has rapidly increased in recent years. However, the PP use status among houseless patients is largely unknown. We aim to determine 1) the PP use status among Emergency Department (ED) patients experiencing houselessness, and 2) whether PP use is linked to the increase in patient clinic visits. METHODS: This is a single-center retrospective observational study. From March 1, 2019, to February 28, 2021, houseless patients who presented at ED were included. Their PP use status, including passive PP use (log-on only PP) and effective PP use (use PP of functions) was compared between houseless and non-houseless patients. The number of clinic visits was also compared between these two groups. Lastly, a multivariate logistic regression was analyzed to determine the association between houseless status and PP use. RESULTS: We included a total of 236,684 patients, 13% of whom (30,956) were houseless at time of their encounter. Fewer houseless patients had effective PP use in comparison to non-houseless patients (7.3% versus 11.6%, p < 0.001). In addition, a higher number of clinic visits were found among houseless patients who had effective PP use than those without (18 versus 3, p < 0.001). The adjusted odds ratio of houseless status associated with PP use was 0.48 (95% CI 0.46-0.49, p < 0.001). CONCLUSIONS: Houselessness is a potential risk factor preventing patient portal use. In addition, using patient portals could potentially increase clinic visits among the houseless patient population.

Virtual Town Hall Meetings to Convey Emergency Medicine Residency Program Information to Students.

BACKGROUND: Applying to emergency medicine (EM) residency programs as a medical student is challenging and complicated in a normal year, but the 2020/2021 application cycle was further complicated by the COVID-19 pandemic. Due to the decrease of in-person opportunities for students to connect with residency programs, virtual "town-hall" meetings were developed. In this study our primary objective was to determine whether attendance at a virtual residency program information session improved the perceived knowledge of curriculum information and program exposure to medical students applying to an EM residency. METHODS: Four study sites hosted a total of 12 virtual events consisting of residents, faculty, or both. Standardized pre-event/post-event surveys were conducted to capture medical student perceptions before/after each of the virtual sessions. Apart from measuring the improvement in students' perceived knowledge of a program by gauging their responses to each question, we used a 10-question composite score to compare pre- vs post-event improvement among the participants. RESULTS: The pre-event survey was completed by 195 attendees, and the post-event survey was completed by 123 attendees. The median and mean composite score to this 10-question survey improved from 32.19 to 45, and 31.45 to 44.2, respectively, in the pre- to post-event survey. CONCLUSION: This study showed improvement of medical students' perceived knowledge of residency programs (reflected as increased agreement from pre- to post-event survey). The data demonstrates through question responses that students not only obtained information about the programs but also were able to gain exposure to the culture and "feel" of a program. In a non-traditional application season in which students are unable to pursue their interest in a program through audition rotations, virtual town hall events, along with other asynchronous events, may be a reasonable approach to increasing medical student understanding and awareness of a program and its culture.

Dedicated homeless clinics reduce inappropriate emergency department utilization.

BACKGROUND: The homeless patient population is known to have a high occurrence of inappropriate emergency department (ED) utilization. The study hospital initiated a dedicated homeless clinic targeting patients experiencing homelessness with a combination of special features. We aim to determine whether this mode of care can reduce inappropriate ED utilization among homeless patients. METHODS: We conducted a retrospective observational study from July 1, 2017 to Dec 31, 2017. The study enrolled all homeless patients who visited any hospital regular clinic, dedicated homeless clinic, and ED at least once during the study period. ED homeless patients were divided into four groups (A: no clinic visits; B: those who only visited hospital regular clinic; C: those who only visited dedicated homeless clinic; and D: those who visited both hospital regular clinic and dedicated homeless clinic). The New York University algorithm was used to determine appropriate ED utilization. We compared inappropriate ED utilization among patients from these groups. Multivariate logistic regression was used to determine the risks of different clinical visits in association with inappropriate ED utilization. RESULTS: A total of 16,323 clinic and 8511 ED visits occurred among 5022 unique homeless patients, in which 2450 unique patients were seen in hospital regular clinic, 784 patients in dedicated homeless clinic, 688 patients in both hospital regular clinic and dedicated homeless clinic, and 1110 patients with no clinic visits. Twenty-nine percent (230/784) of patients from dedicated homeless clinic utilized the ED, among which 21% (175/844) of their ED visits were considered inappropriate. In contrast, 40% of patients from hospital regular clinic utilized the ED, among which 29% were inappropriate (P < 0.001). The adjusted odds ratio (OR) was 0.61 (95% confidence interval [CI] = 0.50-0.74, P < 0.001) on dedicated homeless clinic predicting inappropriate ED visits in multivariate logistic regression. CONCLUSION: Implementing a dedicated homeless clinic with these features can reduce ED inappropriate utilization among patients experiencing homelessness.

Prolonged Financial Distress After the Deepwater Horizon Oil Spill Predicts Behavioral Health.

The economic impact of disasters is well known; however, the link between financial loss and behavioral health problems is unknown. Participants included 198 adults of ages 21 to 82, living within 10 miles of the Gulf Coast during the Deepwater Horizon Oil Spill and were involved in the fishing, harvesting, seafood processing, or service/tourism industries. The functional impact of financial resource loss at 2.5 years post spill was measured using the 26-item Financial Life Events Checklist (FLEC). Individuals responded to financial distress by reducing social events and utility bills and changing food-shopping habits. The FLEC significantly predicted higher drug use (Drug Abuse Screening Test), alcohol use (Alcohol Use Disorders Identification Test), mood problems (Profile of Mood States), and depressive symptoms (Beck Depression Inventory II) (p values ≤ 0.05) 4.5 years after the spill. This preliminary study supports the notion that the functional impact of financial loss has a long-term impact on behavioral health after an oil spill.

The negative effects of habitat fragmentation operate at the scale of dispersal.

Habitat loss is often considered the greatest near-term threat to biodiversity. Yet the impact of habitat fragmentation, or the change in habitat configuration for a given amount of habitat loss, has been intensely debated. We isolated effects of habitat loss from fragmentation on the demography, movement, and abundance of wild populations of a specialist herbivore, Chelinidea vittiger, by removing 2,088 patches across 15 landscapes. We compared fragmentation resulting from random loss, which is often considered in theory, to aggregated loss, which is often observed in the real world. When quantifying fragmentation caused by random vs. aggregated loss, aggregated loss led to less fragmented landscapes than random loss based on patch isolation, but more fragmented landscapes when based on isolation at a larger mesoscale scale defined by dispersal distances of C. vittiger. Overall, habitat loss decreased population size and demographic parameters, with thresholds occurring at approximately 70-80% patch loss. Synergistic effects also occurred, where an aggregated pattern of loss had negative effects at low, but not high, amounts of habitat loss. Effects on population size of C. vittiger were driven by reductions in movement and subsequent reproduction. The direction of habitat fragmentation effects from random and aggregated loss treatments, for a given habitat amount, was conflictingly positive or negative depending on the scale at which fragmentation was quantified. Fragmentation quantified at the scale of dispersal for this species best explained population size and highlighted that fragmentation had negative effects at a mesoscale. Our results emphasize the importance of quantifying habitat fragmentation at biologically appropriate scales.

RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells.

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.

Are Patients with Psychogenic Movement Disorders More Likely to be Healthcare Workers?

BACKGROUND: Reported risk factors for the development of a psychogenic movement disorder (PMD) include young age, female gender, history of abuse, current or past psychiatric disorder, lower levels of education and socioeconomic status, and employment as a healthcare worker. Although employment in healthcare is included in several diagnostic criteria for PMD, as well as in many case series, this association has never been validated. METHODS: Using the University of Maryland Movement Disorder Database (UMMDD), we identified PMD cases, as well as patients with isolated focal dystonia as controls. An experienced movement disorder specialist diagnosed all patients, and all cases met criteria for clinically established PMD. Demographic and occupational histories were obtained from medical records and were supplemented by telephone interviews. PMD cases and controls were compared using t tests/χ2 tests. RESULTS: Controls (n = 148) were older than PMD cases (n = 132), with an average age of 61.4 and 52.1 years, respectively (P < 0.001); there were no significant differences between groups with respect to gender, education level, and ethnicity. The proportion of healthcare workers was not significantly different between PMD cases and controls (25% of PMD cases vs. 20% of controls; P = 0.28). CONCLUSIONS: In contrast to traditional teaching, this investigation demonstrates that in our patient population, patients with a PMD were no more likely to be employed as healthcare workers than patients with isolated focal dystonia. This study calls into question the use of employment in healthcare as a reliable criterion to support the diagnosis of PMD.

Bright spots among the world's coral reefs.

Ongoing declines in the structure and function of the world's coral reefs require novel approaches to sustain these ecosystems and the millions of people who depend on them3. A presently unexplored approach that draws on theory and practice in human health and rural development is to systematically identify and learn from the 'outliers'­places where ecosystems are substantially better ('bright spots') or worse ('dark spots') than expected, given the environmental conditions and socioeconomic drivers they are exposed to. Here we compile data from more than 2,500 reefs worldwide and develop a Bayesian hierarchical model to generate expectations of how standing stocks of reef fish biomass are related to 18 socioeconomic drivers and environmental conditions. We identify 15 bright spots and 35 dark spots among our global survey of coral reefs, defined as sites that have biomass levels more than two standard deviations from expectations. Importantly, bright spots are not simply comprised of remote areas with low fishing pressure; they include localities where human populations and use of ecosystem resources is high, potentially providing insights into how communities have successfully confronted strong drivers of change. Conversely, dark spots are not necessarily the sites with the lowest absolute biomass and even include some remote, uninhabited locations often considered near pristine6. We surveyed local experts about social, institutional, and environmental conditions at these sites to reveal that bright spots are characterized by strong sociocultural institutions such as customary taboos and marine tenure, high levels of local engagement in management, high dependence on marine resources, and beneficial environmental conditions such as deep-water refuges. Alternatively, dark spots are characterized by intensive capture and storage technology and a recent history of environmental shocks. Our results suggest that investments in strengthening fisheries governance, particularly aspects such as participation and property rights, could facilitate innovative conservation actions that help communities defy expectations of global reef degradation.

Loss of dE2F compromises mitochondrial function.

E2F/DP transcription factors regulate cell proliferation and apoptosis. Here, we investigated the mechanism of the resistance of Drosophila dDP mutants to irradiation-induced apoptosis. Contrary to the prevailing view, this is not due to an inability to induce the apoptotic transcriptional program, because we show that this program is induced; rather, this is due to a mitochondrial dysfunction of dDP mutants. We attribute this defect to E2F/DP-dependent control of expression of mitochondria-associated genes. Genetic attenuation of several of these E2F/DP targets mimics the dDP mutant mitochondrial phenotype and protects against irradiation-induced apoptosis. Significantly, the role of E2F/DP in the regulation of mitochondrial function is conserved between flies and humans. Thus, our results uncover a role of E2F/DP in the regulation of mitochondrial function and demonstrate that this aspect of E2F regulation is critical for the normal induction of apoptosis in response to irradiation.

Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation.

Epigenetic regulation underlies the robust changes in gene expression that occur during development. How precisely epigenetic enzymes contribute to development and differentiation processes is largely unclear. Here we show that one of the enzymes that removes the activating epigenetic mark of trimethylated lysine 4 on histone H3, lysine (K)-specific demethylase 5A (KDM5A), reinforces the effects of the retinoblastoma (RB) family of transcriptional repressors on differentiation. Global location analysis showed that KDM5A cooccupies a substantial portion of target genes with the E2F4 transcription factor. During ES cell differentiation, knockout of KDM5A resulted in derepression of multiple genomic loci that are targets of KDM5A, denoting a direct regulatory function. In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB-related protein p130, a DREAM complex component. KDM5A was recruited to the transcription start site regions independently of E2F4; however, it cooperated with E2F4 to promote a state of deepened repression at cell cycle genes during differentiation. These findings reveal a critical role of H3K4 demethylation by KDM5A in the transcriptional silencing of genes that are suppressed by RB family members in differentiated cells.

Inhalational or total intravenous anaesthesia: is total intravenous anaesthesia useful and are there economic benefits?

PURPOSE OF REVIEW: The comparison of inhalational and intravenous anaesthesia has been the subject of many controlled trials and meta-analyses. These reported diverse endpoints typically including measures of the speed and quality of induction of anaesthesia, haemodynamic changes, operating conditions, various measures of awakening, postoperative nausea and vomiting and discharge from the recovery area and from hospital as well as recovery of psychomotor function. In a more patient-focused Health Service, measures with greater credibility are overall patient satisfaction, time to return to work and long-term morbidity and mortality. In practice, studies using easier to measure proxy endpoints dominate - even though the limitations of such research are well known. RECENT FINDINGS: Recent study endpoints are more ambitious and include impact on survival from cancer and the possibility of differential neurotoxic impact on the developing brain and implications for neuro-behavioural performance. SUMMARY: Economic analysis of anaesthesia is complex and most published studies are naive, focusing on drug acquisition costs and facility timings, real health economics are much more difficult. Preferred outcome measures would be whole institution costs or the ability to reliably add an extra case to an operating list, close an operating room and reduce the number of operating sessions offered or permanently decrease staffing. Alongside this, however, potential long-term patient outcomes should be considered.

ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells.

Extracellular signal-regulated kinase 5 (ERK5) is activated in response to environmental stress and growth factors. Gene ablation of Erk5 in mice is embryonically lethal as a result of disruption of cardiovascular development and vascular integrity. We investigated vascular endothelial growth factor (VEGF)-mediated ERK5 activation in primary human dermal microvascular endothelial cells (HDMECs) undergoing proliferation on a gelatin matrix, and tubular morphogenesis within a collagen gel matrix. VEGF induced sustained ERK5 activation on both matrices. However, manipulation of ERK5 activity by siRNA-mediated gene silencing disrupted tubular morphogenesis without impacting proliferation. Overexpression of constitutively active MEK5 and ERK5 stimulated tubular morphogenesis in the absence of VEGF. Analysis of intracellular signalling revealed that ERK5 regulated AKT phosphorylation. On a collagen gel, ERK5 regulated VEGF-mediated phosphorylation of the pro-apoptotic protein BAD and increased expression of the anti-apoptotic protein BCL2, resulting in decreased caspase-3 activity and apoptosis suppression. Our findings suggest that ERK5 is required for AKT phosphorylation and cell survival and is crucial for endothelial cell differentiation in response to VEGF.

VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta.

BACKGROUND: Vascular endothelial growth factor (VEGF) has previously been shown to upregulate the expression of the endogenous calcineurin inhibitor, regulator of calcineurin 1, variant 4 (RCAN1.4). The aim of this study was to determine the role and regulation of VEGF-mediated RCAN1.4 expression, using human dermal microvascular endothelial cells (HDMECs) as a model system. METHODOLOGY/PRINCIPAL FINDINGS: We show that VEGF is able to induce RCAN1.4 expression during cellular proliferation and differentiation, and that VEGF-mediated expression of RCAN1.4 was inhibited by the use of inhibitors to protein kinase C (PKC) and calcineurin. Further analysis revealed that siRNA silencing of PKC-delta expression partially inhibited VEGF-stimulated RCAN1.4 expression. Knockdown of RCAN1.4 with siRNA resulted in a decrease in cellular migration and disrupted tubular morphogenesis when HDMECs were either stimulated with VEGF in a collagen gel or in an endothelial/fibroblast co-culture model of angiogenesis. Analysis of intracellular signalling revealed that siRNA mediated silencing of RCAN1.4 resulted in increased expression of specific nuclear factor of activated T-cells (NFAT) regulated genes. CONCLUSIONS/SIGNIFICANCE: Our data suggests that RCAN1.4 expression is induced by VEGFR-2 activation in a Ca(2+) and PKC-delta dependent manner and that RCAN1.4 acts to regulate calcineurin activity and gene expression facilitating endothelial cell migration and tubular morphogenesis.