Measuring the Cost of Capital in Australia

The cost of capital is the minimum rate of return that an investment project must earn in order to cover its funding costs and any tax liabilities. Australian studies on this subject have produced a wide range of estimates. This paper demonstrates that a wide range of outcomes can result from often arbitrary assumptions used in constructing measures of the cost of funds. The paper suggests that any conclusions drawn about intertemporal trends or international comparisons of the cost of capital should be treated with care. For managers, it serves as a reminder that the use of simple invariant rules-of-thumb for investment decisions may be inappropriate. In particular, changes of tax regime and inflation should be taken into account in setting ‘hurdle rates’ for investment proposals.

Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine

Background: Longitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed the effects of antidepressants from the serotonin reuptake inhibitor class and usually reporting a single measure. Multimodal neuroimaging assessments were acquired from MDD patients during an acute depressive episode with serial measures during a 12-week treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. Methods: Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI. Results: A significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response. Conclusions: Baseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation. Trial registration: Registered at clinicaltrials.gov (NCT01051466)

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Fear and loathing in the Caribbean: three studies of fear and cancer screening in Brooklyn's immigrant Caribbean subpopulations

Background: Anxiety, worry, and fear are among the most common emotional responses to the threat of disease and several studies have linked various fears to cancer preventive and detection behaviors. Cancer-related worry and fears about screening or its consequences are also characteristics that vary across ethnic groups and may be differentially linked to screening outcomes 1. Limiting the utility of this growing literature are at least two key considerations. First, little attention has been paid to documenting variation in cancer-related fears among subpopulations of persons of African descent, despite evidence that (a) rates of screening may vary among both male 2 and female 3 immigrants from islands in the Caribbean living in the United States and (b) incidence rates for cancers such as those of the prostate may be very high in men from Jamaica 4, Guadaloupe 5 and Trinidad and Tobago 6, as well as in immigrant groups in both the United Kingdom 7 and United States 8. Second, findings regarding the relations anxiety, cancer worry, and screening fear hold with screening behavior seen thus far have been inconsistent, in our view because anxieties stemming from different sources have different relations with behavior. In the emotions theory view, understanding the role of fear in health behavior in diverse groups is predicated on understanding the object or source of the fear 91011 for the simple reason that anxiety motivates avoidance of particular elicitors 1012. Research conducted within the U54 Comprehensive Cancer Partnership between Long Island University and Columbia University has produced several studies documenting differences in breast and prostate cancer screening frequencies among Caribbean subpopulations living in Brooklyn, New York 11213. A major concentration in this program of behavioral research has investigated whether trait anxiety, cancer worry, and screening-related fears vary across Caribbean subpopulations and whether these highly differentiated emotional responses independently predict screening behavior in multivariate models 12121314. Consistent with theory, we expected that fears pertaining to the screening context (e.g., fear of pain or the psychological implications of certain screens), would predict avoidance of the fear-inducing situation and thus be associated with less frequent screening. Conversely, where fears relate to the disease itself, greater fear should predict more frequent screening. Methods: Because of our overarching interest in the links between cancer and cancer-screening-related fears and cancer screening behaviors among the diverse groups of men and women living in Brooklyn, New York, we combined data from three community-based studies. Although measures and samples varied somewhat across studies, each study investigated the link between emotions and screening outcome in ethnic groups that included immigrants from islands in the Caribbean. Because of our interest in examining differences within traditional racial categories, we used a combination of (a) self-categorization based on a the traditional racial categories offered in the US Census together with (b) information regarding country of origin. Allowing a combination of self-reported racial categorization (tapping aspects of identity and minority status) in concert with shared birthplace to influence groupings increases the likelihood that participants share cultural and developmental characteristics thought to form part of ethnicity 15. We distinguished between Black men born in the United States (hereafter, U.S.-born African Americans), and those originating from countries in the English-speaking Caribbean (e.g., Trinidad & Tobago, Jamaica, Barbados). Immigrant and non-immigrant minority groups were contrasted with men self-identifying as "European or White/Non-Hispanic" who were born in the United States (hereafter, U.S.-born European American). In Study 1, stratified cluster-sampling was used to recruit 1364 women (aged between 50–70 years) from six ethnic groups: US-born African American, US-born European American, immigrants from islands in the English-speaking Caribbean (Jamaica, Barbados, Trinidad and Tobago), the Dominican Republic, Haiti, and Eastern Europe 1. In Study 2, 180 US-born African American, US-born European American and immigrant Jamaican men (aged between 40–70 years) were recruited using convenience sampling 13. In Study 3, 533 men (aged between 45–70 years) from four groups – US-born African American, US-born European American, and immigrant men from Jamaica and from Trinidad and Tobago – were recruited 12. In each study, participants provided background data, reported on screening history for either breast or prostate cancer, and completed a measure of trait anxiety, cancer worry, and/or screening fears. Results: As expected, we found differences among groups of African descent from the United States and the Caribbean. Although women from all groups screened at rates below those recommended, data from Study 1 showed that English-speaking Caribbean, Haitian and Dominican women screened less frequently than US-born African Americans and European Americans and that immigrant Eastern European women were also infrequent screeners (see Figure 1). Conversely, however, there were no differences in rates of self-reported prostate screening among men from the English-speaking Caribbean, US-born African Americans, or US-born European Americans in either Study 2 or Study 3. As expected, cancer-related emotional characteristics also varied across subpopulations (see Figure 2). Cancer worry was generally lower among women from the various Caribbean immigrant groups (Study 1) than it was among US-born African Americans or US-born European Americans. Fears regarding screening, however, varied somewhat differently. Fear of screening was higher among US-born African Americans and immigrant men from the English-speaking Caribbean (Studies 2 and 3) than among US-born European Americans. Consistent with the need to carefully measure fear-related constructs in the context of cancer behavior, however, our data also demonstrated that a specific fear related to concerns regarding threats to masculinity in the context of male screening strongly characterized the attitudes of men from the English-speaking Caribbean compared to the views of US-born European and US-born African Americans (Study 2). Finally, a combination of multiple regression and ANOVAs in each study showed that emotional characteristics independently predicted screening, in most cases even when background characteristics were controlled. Across studies, greater cancer worry predicted more frequent screening while fear of screening predicted less frequent screening. Figure 1 Number of cancer screens in prior 10 years Number of cancer screens in prior 10 years. DRE = digital rectal examination, PSA = prostate specific antigen test, Mamm = mammogram, CBE = clinical breast exam. Figure 2 Emotion characteristics related to screening Emotion characteristics related to screening. Trait = trait anxiety, Worry = cancer worry, Scr. Fr. = screening fear, and Em. Con. = emasculation concern. Conclusion: Data from three large-scale studies in Brooklyn, New York suggest that members of immigrant Caribbean subpopulations screen for breast and prostate cancer at very low rates; in most cases lower than those of either US-born African or US-born European Americans. Groups of Caribbean men and women also vary in the emotions they report regarding cancer and the screening process, generally revealing a pattern that is predictive of poorer screening. Coupled with the fact that emotion characteristics predicted screening outcomes even when controlling for other factors, data from these three studies suggest that the emotional responses Caribbean groups place them at risk for poor screening. Interventions that address these responses may offer the prospect of improving screening frequency in these disadvantaged groups. Competing interests: The authors declare that they have no competing interests. Authors' contributions: NSC and CM was involved in study design, analysis, interpretation/write up and critical revision of the manuscript. BA and DH in the analysis, interpretation and write up. AKJ, TU and LNB were involved in the interpretation and write up. PMR was part of the study design, analysis and interpretation/write up. JMM and AIN had part in the study design, analysis and critical revision whilst JSJ took part in critical revision

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Temporal Comparison of PBDEs, OH-PBDEs, PCBs, and OH-PCBs in the Serum of Second Trimester Pregnant Women Recruited from San Francisco General Hospital, California

Prenatal exposures to polybrominated diphenyl ethers (PBDEs) can harm neurodevelopment in humans and animals. In 2003–2004, PentaBDE and OctaBDE were banned in California and phased-out of US production; resulting impacts on human exposures are unknown. We previously reported that median serum concentrations of PBDEs and their metabolites (OH-PBDEs) among second trimester pregnant women recruited from San Francisco General Hospital (2008–2009; n=25) were the highest among pregnant women worldwide. We recruited another cohort from the same clinic in 2011–2012 (n=36) and now compare serum concentrations of PBDEs, OH-PBDEs, polychlorinated biphenyl ethers (PCBs) (structurally similar compounds banned in 1979), and OH-PCBs between two demographically similar cohorts. Between 2008–2009 and 2011–2012, adjusted least square geometric mean (LSGM) concentrations of ΣPBDEs decreased 65% (95% CI: 18, 130) from 90.0 ng/g lipid (95% CI: 64.7,125.2) to 54.6 ng/g lipid (95% CI: 39.2, 76.2) (p=0.004); Σ OH-PBDEs decreased six-fold (p<0.0001); and BDE-47, -99, and -100 declined more than BDE-153. There was a modest, non-significant (p=0.13) decline in LSGM concentrations of ΣPCBs and minimal differences in ΣOH-PCBs between 2008–2009 and 2011–2012. PBDE exposures are likely declining due to regulatory action, but the relative stability in PCB exposures suggests PBDE exposures may eventually plateau and persist for decades