Chloroplast microsatellites: measures of genetic diversity and the effect of homoplasy

Chloroplast microsatellites have been widely used in population genetic studies of conifers in recent years. However, their haplotype configurations suggest that they could have high levels of homoplasy, thus limiting the power of these molecular markers. A coalescent-based computer simulation was used to explore the influence of homoplasy on measures of genetic diversity based on chloroplast microsatellites. The conditions of the simulation were defined to fit isolated populations originating from the colonization of one single haplotype into an area left available after a glacial retreat. Simulated data were compared with empirical data available from the literature for a species of Pinus that has expanded north after the Last Glacial Maximum. In the evaluation of genetic diversity, homoplasy was found to have little influence on Nei's unbiased haplotype diversity (H(E)) while Goldstein's genetic distance estimates (D2sh) were much more affected. The effect of the number of chloroplast microsatellite loci for evaluation of genetic diversity is also discussed

Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension.

Systemic hypertension increases cardiac workload causing cardiomyocyte hypertrophy and increased cardiac fibrosis. An underlying feature is increased production of reactive oxygen species. Redox-sensitive ASK1 (apoptosis signal-regulating kinase 1) activates stress-regulated protein kinases (p38-MAPK [mitogen-activated protein kinases] and JNKs [c-Jun N-terminal kinases]) and promotes fibrosis in various tissues. Here, we determined the specificity of ASK1 signaling in the heart, with the hypothesis that ASK1 inhibitors may be used to manage fibrosis in hypertensive heart disease. Using immunoblotting, we established that moderate levels of H2O2 activate ASK1 in neonatal rat cardiomyocytes and perfused rat hearts. ASK1 was activated during ischemia in adult rat hearts, but not on reperfusion, consistent with activation by moderate (not high) reactive oxygen species levels. In contrast, IL (interleukin)-1β activated an alternative kinase, TAK1 (transforming growth factor-activated kinase 1). ASK1 was not activated by IL1β in cardiomyocytes and activation in perfused hearts was due to increased reactive oxygen species. Selonsertib (ASK1 inhibitor) prevented activation of p38-MAPKs (but not JNKs) by oxidative stresses in cultured cardiomyocytes and perfused hearts. In vivo (C57Bl/6J mice with osmotic minipumps for drug delivery), selonsertib (4 mg/[kg·d]) alone did not affect cardiac function/dimensions (assessed by echocardiography). However, it suppressed hypertension-induced cardiac hypertrophy resulting from angiotensin II (0.8 mg/[kg·d], 7d), with inhibition of Nppa/Nppb mRNA upregulation, reduced cardiomyocyte hypertrophy and, notably, significant reductions in interstitial and perivascular fibrosis. Our data identify a specific reactive oxygen species→ASK1→p38-MAPK pathway in the heart and establish that ASK1 inhibitors protect the heart from hypertension-induced cardiac remodeling. Thus, targeting the ASK1→p38-MAPK nexus has potential therapeutic viability as a treatment for hypertensive heart disease

Liver transplantation for type I and type IV glycogen storage disease

Progressive liver failure or hepatic complications of the primary disease led to orthotopic liver transplantation in eight children with glycogen storage disease over a 9-year period. One patient had glycogen storage disease (GSD) type I (von Gierke disease) and seven patients had type IV GSD (Andersen disease). As previously reported [19], a 16.5-year-old-girl with GSD type I was successfully treated in 1982 by orthotopic liver transplantation under cyclosporine and steroid immunosuppression. The metabolic consequences of the disease have been eliminated, the renal function and size have remained normal, and the patient has lived a normal young adult life. A late portal venous thrombosis was treated successfully with a distal splenorenal shunt. Orthotopic liver transplantation was performed in seven children with type N GSD who had progressive hepatic failure. Two patients died early from technical complications. The other five have no evidence of recurrent hepatic amylopectinosis after 1.1–5.8 postoperative years. They have had good physical and intellectual maturation. Amylopectin was found in many extrahepatic tissues prior to surgery, but cardiopathy and skeletal myopathy have not developed after transplantation. Postoperative heart biopsies from patients showed either minimal amylopectin deposits as long as 4.5 years following transplantation or a dramatic reduction in sequential biopsies from one patient who initially had dense myocardial deposits. Serious hepatic derangement is seen most commonly in types T and IV GSD. Liver transplantation cures the hepatic manifestations of both types. The extrahepatic deposition of abnormal glycogen appears not to be problematic in type I disease, and while potentially more threatening in type IV disease, may actually exhibit signs of regression after hepatic allografting

Staff perspectives of a model of access and triage for reducing waiting time in ambulatory services: a qualitative study

BackgroundSpecific Timely Appointments for Triage (STAT) is an intervention designed to reduce waiting time in community outpatient health services, shown to be effective in a large stepped wedge cluster randomised controlled trial. STAT combines initial strategies to reduce existing wait lists with creation of a specific number of protected appointments for new patients based on demand. It offers an alternative to the more traditional methods of demand management for these services using waiting lists with triage systems. This study aimed to explore perceptions of clinicians and administrative staff involved in implementing the model.MethodSemi-structured interviews with 20 staff members who experienced the change to STAT were conducted by an independent interviewer. All eight sites involved in the original trial and all professional disciplines were represented in the sample. Data were coded and analysed thematically.ResultsParticipants agreed that shorter waiting time for patients was the main advantage of the STAT model, and that ongoing management of caseloads was challenging. However, there was variation in the overall weight placed on these factors, and therefore the participants’ preference for the new or previous model of care. Perceptions of whether the advantages outweighed the disadvantages were influenced by five sub-themes: staff perception of how much waiting matters to the patient, prior exposure to the management of waiting list, caseload complexity, approach and attitude to the implementation of STAT and organisational factors.ConclusionsThe STAT model has clear benefits but also presents challenges for staff members. The findings of this study suggest that careful preparation and management of change and active planning for known fluctuations in supply and demand are likely to help to mitigate sources of stress and improve the likelihood of successful implementation of the STAT model for improving waiting times for patients referred to community outpatient services

Return on investment of a model of access combining triage with initial management: an economic analysis

ObjectivesTimely access to outpatient services is a major issue for public health systems. To address this issue, we aimed to establish the return on investment to the health system of the implementation of an alternative model for access and triage (Specific Timely Appointments for Triage: STAT) compared with a traditional waitlist model.DesignUsing a prospective pre–post design, an economic analysis was completed comparing the health system costs for participants who were referred for community outpatient services post-implementation of STAT with a traditional waitlist comparison group.SettingEight community outpatient services of a health network in Melbourne, Australia.ParticipantsAdults and children referred to community outpatient services.InterventionsSTAT combined targeted activities to reduce the existing waiting list and direct booking of patients into protected assessment appointments. STAT was compared with usual care, in which new patients were placed on a waiting list and offered appointments as space became available.OutcomesHealth system costs included STAT implementation costs, outpatient health service use, emergency department presentations and hospital admissions 3 months before and after initial outpatient appointment. Waiting time was the primary outcome. Incremental cost-effectiveness ratios (ICERs) were estimated from the health system perspective.ResultsData from 557 participants showed a 16.9 days or 29% (p&lt;0.001) reduction in waiting time for first appointment with STAT compared with traditional waitlist. The ICER showed a cost of $A10 (95$A4 (95% CI −25 to 32) per day of reduction in waiting, if reduction in waiting times is sustained for 12 months.ConclusionsThere was a significant reduction in waiting time with the introduction of STAT at minimal cost to the health system.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12615001016527).</jats:sec

Mutual Information for the Detection of Crush

Fatal crush conditions occur in crowds with tragic frequency. Event organizers and architects are often criticised for failing to consider the causes and implications of crush, but the reality is that both the prediction and prevention of such conditions offer a significant technical challenge. Full treatment of physical force within crowd simulations is precise but often computationally expensive; the more common method of human interpretation of results is computationally “cheap” but subjective and time-consuming. This paper describes an alternative method for the analysis of crowd behaviour, which uses information theory to measure crowd disorder. We show how this technique may be easily incorporated into an existing simulation framework, and validate it against an historical event. Our results show that this method offers an effective and efficient route towards automatic detection of the onset of crush

Examining a staging model for anorexia nervosa: empirical exploration of a four stage model of severity.

Background: An illness staging model for anorexia nervosa (AN) has received increasing attention, but assessing the merits of this concept is dependent on empirically examining a model in clinical samples. Building on preliminary findings regarding the reliability and validity of the Clinician Administered Staging Instrument for Anorexia Nervosa (CASIAN), the current study explores operationalising CASIAN severity scores into stages and assesses their relationship with other clinical features. Method: In women with DSM-IV-R AN and sub-threshold AN (all met AN criteria using DSM 5), receiver operating curve (ROC) analysis (n = 67) assessed the relationship between the sensitivity and specificity of each stage of the CASIAN. Thereafter chi-square and post-hoc adjusted residual analysis provided a preliminary assessment of the validity of the stages comparing the relationship between stage and treatment intensity and AN sub-types, and explored movement between stages after six months (Time 3) in a larger cohort (n = 171). Results: The CASIAN significantly distinguished between milder stages of illness (Stage 1 and 2) versus more severe stages of illness (Stages 3 and 4), and approached statistical significance in distinguishing each of the four stages from one other. CASIAN Stages were significantly associated with treatment modality and primary diagnosis, and CASIAN Stage at Time 1 was significantly associated with Stage at 6 month follow-up. Conclusions: Provisional support is provided for a staging model in AN. Larger studies with longer follow-up of cases are now needed to replicate and extend these findings and evaluate the overall utility of staging as well as optimal staging models

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Radio Emission from Ultra-Cool Dwarfs

The 2001 discovery of radio emission from ultra-cool dwarfs (UCDs), the very low-mass stars and brown dwarfs with spectral types of ~M7 and later, revealed that these objects can generate and dissipate powerful magnetic fields. Radio observations provide unparalleled insight into UCD magnetism: detections extend to brown dwarfs with temperatures <1000 K, where no other observational probes are effective. The data reveal that UCDs can generate strong (kG) fields, sometimes with a stable dipolar structure; that they can produce and retain nonthermal plasmas with electron acceleration extending to MeV energies; and that they can drive auroral current systems resulting in significant atmospheric energy deposition and powerful, coherent radio bursts. Still to be understood are the underlying dynamo processes, the precise means by which particles are accelerated around these objects, the observed diversity of magnetic phenomenologies, and how all of these factors change as the mass of the central object approaches that of Jupiter. The answers to these questions are doubly important because UCDs are both potential exoplanet hosts, as in the TRAPPIST-1 system, and analogues of extrasolar giant planets themselves.Comment: 19 pages; submitted chapter to the Handbook of Exoplanets, eds. Hans J. Deeg and Juan Antonio Belmonte (Springer-Verlag