Miracle-dz/UniFAR-FTUs huggingface dataset:
Societal perspective on access to publicly subsidised medicines: A cross sectional survey of 3080 adults in Australia

Background Around the world government agencies responsible for the selection and reimbursement of prescribed medicines and other health technologies are considering how best to bring community preferences into their decision making. In particular, community views about the distribution or equity of funding across the population. These official committees and agencies often have access to the best available and latest evidence on clinical effectiveness, safety and cost from large clinical trials and population-based studies. All too often they do not have access to high quality evidence about community views. We therefore, conducted a large and representative population-based survey in Australia to determine what community members think about the factors that do and should influence government spending on prescribed medicines. Methods A choice-based survey was designed to elicit the importance of individual criteria when considering the equity of government spending on prescribed medicines. A representative sample of 3080 adult Australians completed the survey by allocating a hypothetical budget to different combinations of money spent on two patient populations. Societal preferences were inferred from absolute majority responses i.e. populations with more than 50% of respondents’ allocation for a particular allocation criterion. Results This study shows that, all else being equal, severity of disease, diseases for which there is no alternative treatment available on the government formulary, diseases that affect patients who are not financially well off, and life-style unrelated diseases are supported by the public as resource allocation criteria. Where ‘all else is not equal’, participants allocated more resources to the patient population that gained considerable improvement in health and fewer resources to those that gained little improvement in health. This result held under all scenarios except for ‘end-of-life treatments’. Responses to cost (and corresponding number of patients treated) trade-off scenarios indicated a significant reduction in the proportion of respondents choosing to divide resources equally and a shift in preference towards devoting resources to the population that were more costly to treat for all criteria with the exception of severity of disease. Conclusions The general public have clear views on what’s fair in terms of government spending on prescribed medicines. In addition to supporting the application of the ‘rule of rescue’, important considerations for government spending included the severity of disease being treated, diseases for which there is no alternative treatment available on the government formulary, diseases that affect patients who are not financially well off and life-style unrelated diseases. This study shows that the general public are willing to share their views on what constitutes an equitable allocation of the government’s drug budget. The challenge remains to how best to consider those views alongside clinical and economic considerations.
Developmental dyslexia and phonological processing in European Portuguese orthography.

This study analysed the performance of phonological processing, the diagnostic accuracy and the influence on reading in children who were native speakers of an orthography of intermediate depth. Portuguese children with developmental dyslexia (DD; N=24; aged 10-12 years), chronological age (CA)-matched controls (N=24; aged 10-12 years) and reading level (RL)-matched controls (N=24; aged 7-9 years) were tested on measures of phonological processing (phonological awareness, naming speed and verbal short-term memory) and reading. The results indicated that the children with DD performed significantly poorer in all measures compared with the CA and RL. Phonological awareness and naming speed showed a high accuracy (receiver operating characteristics curve analysis) for discriminating the children with DD from the CA and RL, whereas the presence of abnormally low scores in phonological awareness and naming speed was more frequent in the DD group than in the controls and the normative population. Hierarchical linear regression analyses revealed that phonological awareness was the most important predictor of all reading accuracy measures, whereas naming speed was particularly related to text reading fluency.
Stress Physiology and Behavior Problems

Understanding childhood externalizing problems is informative in designing interventions and reducing crime in adulthood because childhood aggression is one of the best predictors for later antisocial behavior. Childhood externalizing problems are typically studied with internalizing problems (e.g., anxiety) given their consistent correlation and seemingly opposite behavior manifestations. This dissertation examined both spectrums of behavior problems to advance our etiological understanding. Adversity and stress have been a focus in criminology research but few studies have incorporated stress physiology, the biological underpinning of how individuals deal with adversity. This dissertation comprised three papers testing the linkage of stress physiology to behavior problems. I examined how the two components of the stress system, namely the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), interact with each other, and together interact with harsh discipline in influencing externalizing and internalizing problems. Data were drawn from a community sample of 11-12 year old children (N = 446). Saliva samples were collected in the initial assessment and later assayed for cortisol (HPA) and salivary alpha-amylase (sAA; ANS). Participants and their caregivers completed questionnaires for child behavior problems initially, 3, 6, and 12 months later. Paper 1 revealed that cortisol was negatively associated with externalizing and internalizing problems but only at low levels of sAA. Paper 2 built on Paper 1 by including harsh discipline as an environmental factor and testing how the combined effect of cortisol and sAA contributed to our understanding of the heterogeneous effect of harsh discipline on behavior problems. Results showed that asymmetry in cortisol and sAA may indicate biological susceptibility to the effect of harsh discipline to develop both externalizing and internalizing problems among boys. Given the similar stress physiological patterns shown in Paper 1 and 2 for externalizing and internalizing problems, Paper 3 further explored and found that the interplay of cortisol and sAA differentiated co-occurrence of behavior problems from other developmental trajectories of behavior problems over a year. Together these findings underscore the significance of stress physiology in behavior problems. Theoretical implications in relation to differential susceptibility hypothesis and practical implications for treatment evaluation and research are discussed. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Criminology First Advisor Adrian Raine
Cortical Oscillatory Activity Is Critical for Working Memory as Revealed by Deficits in Early-Onset Schizophrenia

Impairments in working memory (WM) are a core cognitive deficit in schizophrenia. Neurophysiological models suggest that deficits during WM maintenance in schizophrenia may be explained by abnormalities in the GABAergic system, which will lead to deficits in high-frequency oscillations. However, it is not yet clear which of the three WM phases (encoding, maintenance, retrieval) are affected by dysfunctional oscillatory activity. We investigated the relationship between impairments in oscillatory activity in a broad frequency range (3–100 Hz) and WM load in the different phases of WM in 14 patients with early-onset schizophrenia and 14 matched control participants using a delayed matching to sample paradigm. During encoding, successful memorization was predicted by evoked theta, alpha, and beta oscillatory activity in controls. Patients showed severe reductions in the evoked activity in these frequency bands. During early WM maintenance, patients showed a comparable WM load-dependent increase in induced alpha and gamma activity to controls. In contrast, during the later maintenance phase, patients showed a shift in the peak of induced gamma activity to the lower WM load conditions. Finally, induced theta and gamma activity were reduced in patients during retrieval. Our findings suggest that the WM deficit in schizophrenia is associated with impaired oscillatory activity during all phases of the task and that the cortical storage system reaches its capacity limit at lower loads. Inability to maintain oscillatory activity in specific frequency bands could thus result in the information overload that may underlie both cognitive deficits and psychopathological symptoms of schizophrenia.
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.

PURPOSE To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. MATERIALS AND METHODS From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. RESULTS The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. CONCLUSION The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.
The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model

Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxin–mediated mitotic catastrophe and cell death. [Mol Cancer Ther 2009;8(4):930–9]
Characterization of the Interaction of Full-Length HIV-1 Vif Protein with its Key Regulator CBFβ and CRL5 E3 Ubiquitin Ligase Components

Human immunodeficiency virus-1 (HIV-1) viral infectivity factor (Vif) is essential for viral replication because of its ability to eliminate the host's antiviral response to HIV-1 that is mediated by the APOBEC3 family of cellular cytidine deaminases. Vif targets these proteins, including APOBEC3G, for polyubiquitination and subsequent proteasome-mediated degradation via the formation of a Cullin5-ElonginB/C-based E3 ubiquitin ligase. Determining how the cellular components of this E3 ligase complex interact with Vif is critical to the intelligent design of new antiviral drugs. However, structural studies of Vif, both alone and in complex with cellular partners, have been hampered by an inability to express soluble full-length Vif protein. Here we demonstrate that a newly identified host regulator of Vif, core-binding factor-beta (CBFβ), interacts directly with Vif, including various isoforms and a truncated form of this regulator. In addition, carboxyl-terminal truncations of Vif lacking the BC-box and cullin box motifs were sufficient for CBFβ interaction. Furthermore, association of Vif with CBFβ, alone or in combination with Elongin B/C (EloB/C), greatly increased the solubility of full-length Vif. Finally, a stable complex containing Vif-CBFβ-EloB/C was purified in large quantity and shown to bind purified Cullin5 (Cul5). This efficient strategy for purifying Vif-Cul5-CBFβ-EloB/C complexes will facilitate future structural and biochemical studies of Vif function and may provide the basis for useful screening approaches for identifying novel anti-HIV drug candidates.
Augmentation of Antidepressant Pharmacotherapy: A Preclinical Approach Using the Mouse Forced Swimming Test

Abstract Until recently, several weeks of treatment were required in order to obtain a clinically significant antidepressant response using pharmacotherapy. The present study, using the mouse forced swimming test, investigated possible antidepressant augmentation strategies, together with the probable mechanisms involved in such potentiations. It is clear from this and other similar studies that it is possible to enhance the activity of antidepressant drugs with the addition of other compounds (ie, clonidine, quinine, glyburide, pindolol, or buspirone). These data indicate that direct/indirect manipulation of serotonergic receptor systems potentiates the effect antidepressant drugs (ie, selective serotonergic reuptake inhibitors) in the mouse forced swimming test, and thus establish this model as a reliable preclinical tool for the investigation of possible antidepressant augmentation strategies. It also appears that this model can be used as a method for identifying the mechanisms involved in such treatment strategies.
Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study

Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of general quality of life (QoL), responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65–19.35) score points, P < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55–11.39) score points, P = 0.0003 for 6.5 mg). QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women.
Equilibrium and Welfare in Insurance Markets with Time-Inconsistent Consumers

This paper studies the implications of unobservable consumer naivete on selection and welfare in a competitive insurance market with moral hazard. We identify two distinct forces of sophistication driving the formation of market equilibriums. One is that sophistication helps individuals internalize the incentive to take high effort by adopting some commitment devices, and hence sophisticates are willing to pay a lower premium to increase insurance coverage than naifs. The other is that sophistication helps prevent the optimistic underestimation of loss probability, and thus sophisticates are willing to pay a higher premium to increase insurance coverage than naifs. We show that the above forces of sophistication can produce adverse selection, advantageous selection and the absence of risk-coverage correlation observed in various insurance markets. We also show that sophisticates can adopt some commitment devices to alleviate the externality caused by hidden naivete, and certain incentive insurance clauses such as rebate check are welfare-improving when advantageous selection appears.
The herpes simplex virus type 1 DNA polymerase processivity factor, UL42, does not alter the catalytic activity of the UL9 origin-binding protein but facilitates its loading onto DNA

The herpes simplex virus type 1 UL42 DNA polymerase processivity factor interacts physically with UL9 and enhances its ability to unwind short, partially duplex DNA. In this report, ATP hydrolysis during translocation of UL9 on single-stranded (ss) or partially duplex DNA was examined in the presence and absence of UL42 to determine the effect of UL42 on the catalytic function of UL9. Our studies reveal that a homodimer of UL9 is sufficient for DNA translocation coupled to ATP hydrolysis, and the steady-state ATPase catalytic rate was greater on partially duplex DNA than on ss DNA in the presence or absence of UL42. Although UL42 protein increased the steady-state rate for ATP hydrolysis by UL9 during translocation on either partially duplex or ss DNA, UL42 had no significant effect on the intrinsic ATPase activity of UL9. UL42 also had no effect on the catalytic rate of ATP hydrolysis when UL9 was not limiting but enhanced the steady-state ATPase rate at only subsaturating UL9 concentrations. At subsaturating UL9 to DNA ratios, stoichiometric concentrations of UL42 were shown to increase the amount of UL9 bound to ss DNA at equilibrium. These data support a model whereby UL42 increases the ability of UL9 to load onto DNA, thus increasing its ability to assemble into a functional complex capable of unwinding duplex DNA.
Pancreatic ascites due to rupture of a mucinous cystic neoplasm

of the CSF during an episode of dysarthria but both patients declined consent to a lumbar puncture. In contradiction with this hypothesis is the finding that no CNS-toxicity is reported in over 140 irinotecantreated patients with brain tumours, despite the presence of a clearly disrupted blood-brain barrier in these patients [11 13]. Cytotoxic oedema is unlikely to play an important role in irinotecan induced CNS toxicity since normal diffusion-weighted MR images of the brain were found in one of our patients while experiencing dysarthria. It is also unlikely that irinotecan-mediated CNS toxicity occurs in the context of ACS. Dysarthria can occur in patients without ACS, while administration of atropine does not appear to prevent its (re-)occurrence whereas it effectively deals with ACS. Of importance, pre-clinical toxicology never revealed any CNS-toxicity (Pfizer, data on file) rendering it difficult if not impossible to further study this side effect in animal models. In conclusion, the exact cause of irinotecaninduced CNS toxicity remains unravelled and plasma pharmacokinetics also do not provide an explanation. Therefore, a specific treatment cannot be recommended. Most importantly, since in all cases CNS toxicity was fully reversible, was not exaggerated by rechallenge with irinotecan, and can even decline in severity at repeated exposure; CNS toxicity is not a reason to discontinue irinotecan treatment despite its sometimes impressive and threatening appearance.
Media Coverage of the 2014 West Virginia Elk River Chemical Spill

This study examined how news media framed West Virginia’s 2014 Elk River Chemical Spill, an industrial disaster that began a national discussion about chemical safety. A content analysis of media was conducted to explore disaster coverage. Additionally, in-depth stakeholder interviews were conducted to examine how audiences interpreted and evaluated media coverage. Both content analysis and interview findings highlighted the media’s reliance on the attribution of responsibility news frame, which dominated media coverage, although the dominance of particular frames differed according to media channel and time period.
Neuroendocrine dysfunction in schizophreniform disorder: correlation with six-month clinical outcome.

: The thyrotropin-releasing hormone (TRH) stimulation test and the dexamethasone suppression test (DST) were administered to 21 patients with schizophreniform disorder at the time of admission for acute illness: 9 showed dysregulation on one or the other test. Seventeen patients followed for 6 months were divided into two groups: those with persistent dysfunction and/or psychotic symptoms and those in full remission. Only 1 of 7 patients (14%) with persistent dysfunction in contrast to 7 of 10 patients (70%) in full remission revealed dysregulation on either test. Neuroendocrine challenges may be useful in the early assessment of first-break psychotic patients, and neuroendocrine dysregulation may be a predictor of episodic illness with a better prognosis.