Navigating care for rare diseases: Caregiver and patient advice for families and clinicians managing care for vascular malformations

OBJECTIVE: Families affected by rare diseases face many challenges finding adequate care and often report poor communication with clinicians. In the current study, we explore patient and caregiver advice for families and clinicians in the context of complex vascular malformations (VMs), a condition that is frequently misunderstood and misdiagnosed. METHODS: We performed semi-structured interviews with 21 adult patients with complex VMs and 24 caregivers of children with VMs. We analyzed the transcripts using thematic analysis. RESULTS: Participants advised patients and caregivers to advocate for care, address mental and emotional well-being, seek social support, and promote self-management and self-care. Participants advised clinicians to show care and concern, show commitment, empower and validate, communicate information clearly, address mental/emotional well-being, acknowledge the broad impact of disease and treatment, acknowledge your limitations, work as a team, and commit to learning. CONCLUSION: Participants\u27 advice revealed challenges related to family-centered communication and patient and caregiver quality of life and demonstrated the importance of self-advocacy and social support. PRACTICE IMPLICATIONS: The result of this study can help newly-diagnosed families overcome challenges related to care and communication. Clinicians can also use the results to support families by offering them our accompanying handout to validate families\u27 experiences and relay this advice

Thrombolysis implementation intervention and clinical outcome : a secondary analysis of a cluster randomized trial

Background: Multiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)"study, which aimed to improve rates of intravenous thrombolysis in Australia. Methods: A posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups. Results: There was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-And post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56-2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active-(odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52). Conclusion: The TIPS multi-component implementation approach was not effective in reducing the odds of post-Treatment severe disability at 90 days, or post-thrombolysis hemorrhage

Thrombolysis ImPlementation in Stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice – protocol for a cluster randomised controlled trial in acute stroke care

BACKGROUND: Stroke is a leading cause of death and disability internationally. One of the three effective interventions in the acute phase of stroke care is thrombolytic therapy with tissue plasminogen activator (tPA), if given within 4.5 hours of onset to appropriate cases of ischaemic stroke. OBJECTIVES: To test the effectiveness of a multi-component multidisciplinary collaborative approach compared to usual care as a strategy for increasing thrombolysis rates for all stroke patients at intervention hospitals, while maintaining accepted benchmarks for low rates of intracranial haemorrhage and high rates of functional outcomes for both groups at three months. METHODS AND DESIGN: A cluster randomised controlled trial of 20 hospitals across 3 Australian states with 2 groups: multi- component multidisciplinary collaborative intervention as the experimental group and usual care as the control group. The intervention is based on behavioural theory and analysis of the steps, roles and barriers relating to rapid assessment for thrombolysis eligibility; it involves a comprehensive range of strategies addressing individual-level and system-level change at each site. The primary outcome is the difference in tPA rates between the two groups post-intervention. The secondary outcome is the proportion of tPA treated patients in both groups with good functional outcomes (modified Rankin Score (mRS <2) and the proportion with intracranial haemorrhage (mRS ≥2), compared to international benchmarks. DISCUSSION: TIPS will trial a comprehensive, multi-component and multidisciplinary collaborative approach to improving thrombolysis rates at multiple sites. The trial has the potential to identify methods for optimal care which can be implemented for stroke patients during the acute phase. Study findings will include barriers and solutions to effective thrombolysis implementation and trial outcomes will be published whether significant or not. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN1261300093979

The Milky Way's circular velocity curve between 4 and 14 kpc from APOGEE data

We measure the Milky Way's rotation curve over the Galactocentric range 4 kpc <~ R <~ 14 kpc from the first year of data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE). We model the line-of-sight velocities of 3,365 stars in fourteen fields with b = 0 deg between 30 deg < l < 210 deg out to distances of 10 kpc using an axisymmetric kinematical model that includes a correction for the asymmetric drift of the warm tracer population (\sigma_R ~ 35 km/s). We determine the local value of the circular velocity to be V_c(R_0) = 218 +/- 6 km/s and find that the rotation curve is approximately flat with a local derivative between -3.0 km/s/kpc and 0.4 km/s/kpc. We also measure the Sun's position and velocity in the Galactocentric rest frame, finding the distance to the Galactic center to be 8 kpc < R_0 < 9 kpc, radial velocity V_{R,sun} = -10 +/- 1 km/s, and rotational velocity V_{\phi,sun} = 242^{+10}_{-3} km/s, in good agreement with local measurements of the Sun's radial velocity and with the observed proper motion of Sgr A*. We investigate various systematic uncertainties and find that these are limited to offsets at the percent level, ~2 km/s in V_c. Marginalizing over all the systematics that we consider, we find that V_c(R_0) 99% confidence. We find an offset between the Sun's rotational velocity and the local circular velocity of 26 +/- 3 km/s, which is larger than the locally-measured solar motion of 12 km/s. This larger offset reconciles our value for V_c with recent claims that V_c >~ 240 km/s. Combining our results with other data, we find that the Milky Way's dark-halo mass within the virial radius is ~8x10^{11} M_sun.Comment: submitted to Ap

A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes

Mitotic chromosomes are compacted laterally by KIF4 and condensin and axially by topoisomerase IIα

© 2012 Samejima et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication dateMitotic chromosome formation involves a relatively minor condensation of the chromatin volume coupled with a dramatic reorganization into the characteristic "X" shape. Here we report results of a detailed morphological analysis, which revealed that chromokinesin KIF4 cooperated in a parallel pathway with condensin complexes to promote the lateral compaction of chromatid arms. In this analysis, KIF4 and condensin were mutually dependent for their dynamic localization on the chromatid axes. Depletion of either caused sister chromatids to expand and compromised the "intrinsic structure" of the chromosomes (defined in an in vitro assay), with loss of condensin showing stronger effects. Simultaneous depletion of KIF4 and condensin caused complete loss of chromosome morphology. In these experiments, topoisomerase IIα contributed to shaping mitotic chromosomes by promoting the shortening of the chromatid axes and apparently acting in opposition to the actions of KIF4 and condensins. These three proteins are major determinants in shaping the characteristic mitotic chromosome morphology

Psychosocial Response to Uncertain Newborn Screening Results for Cystic Fibrosis

Objective To explore the psychosocial implications of diagnostic uncertainty that result from inconclusive results generated by newborn bloodspot screening (NBS) for cystic fibrosis (CF). Study design Using a mixed methods prospective cohort study of children who received NBS for CF, we compared psychosocial outcomes of parents whose children who received persistently inconclusive results with those whose children received true positive or screen-negative results. Results Mothers of infants who received inconclusive results (n = 17), diagnoses of CF (n = 15), and screen-negative results (n = 411) were surveyed; 23 parent interviews were completed. Compared with mothers of infants with true positive/screen-negative results, mothers of infants with inconclusive results reported greater perceived uncertainty (P .05). Qualitatively, parents valued being connected to experts but struggled with the meaning of an uncertain diagnosis, worried about their infant's health-related vulnerability, and had mixed views about surveillance. Conclusion Inconclusive CF NBS results were not associated with anxiety or vulnerability but led to health-related uncertainty and qualitative concerns. Findings should be considered alongside efforts to optimize protocols for CF screening and surveillance. Educational and psychosocial supports are warranted for these families.Peer reviewe

Thrombolysis ImPlementation in Stroke (TIPS): Evaluating the effectiveness of a strategy to increase the adoption of best evidence practice - protocol for a cluster randomised controlled trial in acute stroke care

Background: Stroke is a leading cause of death and disability internationally. One of the three effective interventions in the acute phase of stroke care is thrombolytic therapy with tissue plasminogen activator (tPA), if given within 4.5 hours of onset to appropriate cases of ischaemic stroke.Objectives: To test the effectiveness of a multi-component multidisciplinary collaborative approach compared to usual care as a strategy for increasing thrombolysis rates for all stroke patients at intervention hospitals, while maintaining accepted benchmarks for low rates of intracranial haemorrhage and high rates of functional outcomes for both groups at three months.Methods and design: A cluster randomised controlled trial of 20 hospitals across 3 Australian states with 2 groups: multi- component multidisciplinary collaborative intervention as the experimental group and usual care as the control group. The intervention is based on behavioural theory and analysis of the steps, roles and barriers relating to rapid assessment for thrombolysis eligibility; it involves a comprehensive range of strategies addressing individual-level and system-level change at each site. The primary outcome is the difference in tPA rates between the two groups post-intervention. The secondary outcome is the proportion of tPA treated patients in both groups with good functional outcomes (modified Rankin Score (mR

LATERAL BRANCHING OXIDOREDUCTASE acts in the final stages of strigolactone biosynthesis inArabidopsis

Strigolactones are a group of plant compounds of diverse but related chemical structures. They have similar bioactivity across a broad range of plant species, act to optimize plant growth and development, and promote soil microbe interactions. Carlactone, a common precursor to strigolactones, is produced by conserved enzymes found in a number of diverse species. Versions of the MORE AXILLARY GROWTH1 (MAX1) cytochrome P450 from rice and Arabidopsis thaliana make specific subsets of strigolactones from carlactone. However, the diversity of natural strigolactones suggests that additional enzymes are involved and remain to be discovered. Here, we use an innovative method that has revealed a missing enzyme involved in strigolactone metabolism. By using a transcriptomics approach involving a range of treatments that modify strigolactone biosynthesis gene expression coupled with reverse genetics, we identified LATERAL BRANCHING OXIDOREDUCTASE (LBO), a gene encoding an oxidoreductase-like enzyme of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. Arabidopsis lbo mutants exhibited increased shoot branching, but the lbo mutation did not enhance the max mutant phenotype. Grafting indicated that LBO is required for a graft-transmissible signal that, in turn, requires a product of MAX1. Mutant lbo backgrounds showed reduced responses to carlactone, the substrate of MAX1, and methyl carlactonoate (MeCLA), a product downstream of MAX1. Furthermore, lbo mutants contained increased amounts of these compounds, and the LBO protein specifically converts MeCLA to an unidentified strigolactone-like compound. Thus, LBO function may be important in the later steps of strigolactone biosynthesis to inhibit shoot branching in Arabidopsis and other seed plants

Dynamic changes in the brain protein interaction network correlates with progression of A?42 pathology in Drosophila

Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aβ42 gene. We identified 3093 proteins from flies that were induced to express Aβ42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aβ42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems