Survival Analysis as a Basis for Testing Hypotheses when Using Quantitative Ordinal Scale Disease Severity Data.

Disease severity in plant pathology is often measured by the amount of a plant or plant part that exhibits disease symptoms. This is typically assessed using a numerical scale, which allows a standardized, convenient, and quick method of rating. These scales, known as quantitative ordinal scales (QOS), divide the percentage scale into a predetermined number of intervals. There are various ways to analyze these ordinal data, with traditional methods involving the use of midpoint conversion to represent the interval. However, this may not be precise enough, as it is only an estimate of the true value. In this case, the data may be considered interval-censored, meaning that we have some knowledge of the value but not an exact measurement. This type of uncertainty is known as censoring, and techniques that address censoring, such as survival analysis (SA), use all available information and account for this uncertainty. To investigate the pros and cons of using SA with QOS measurements, we conducted a simulation based on three pathosystems. The results showed that SA almost always outperformed midpoint conversion with data analyzed using a t test, particularly when data were not normally distributed. Midpoint conversion is currently a standard procedure. In certain cases, the midpoint approach required a 400% increase in sample size to achieve the same power as the SA method. However, as the mean severity increases, fewer additional samples are needed (approximately an additional 100%), regardless of the assessment method used. Based on these findings, we conclude that SA is a valuable method for enhancing the power of hypothesis testing when analyzing QOS severity data. Future research should investigate the wider use of survival analysis techniques in plant pathology and their potential applications in the discipline.

Metabolomic profiles of ovariectomized mice and their associations with body composition and frailty-related parameters in postmenopausal women.

BACKGROUND: Menopause, a dramatical estrogen-deficient condition, is considered the most significant milestone in women's health. PURPOSE: To investigate the metabolite changes attributed to estrogen deficiency using random forest (RF)-based machine learning (ML) modeling strategy in ovariectomized (OVX) mice as well as determine the clinical relevance of selected metabolites in older women. METHODS AND RESULTS: Untargeted and targeted metabolomic analyses revealed that metabolites related to TCA cycle, sphingolipids, phospholipids, fatty acids, and amino acids, were significantly changed in the plasma and/or muscle of OVX mice. Subsequent ML classifiers based on RF algorithm selected alpha-ketoglutarate (AKG), arginine, carnosine, ceramide C24, phosphatidylcholine (PC) aa C36:6, and PC ae C42:3 in plasma as well as PC aa 34:1, PC aa C34:3, PC aa C36:5, PC aa C32:1, PC aa C36:2, and sphingosine in muscle as top featured metabolites that differentiate the OVX mice from the sham-operated group. When circulating levels of AKG, arginine, and carnosine, which showed the most significant changes in OVX mice blood, were measured in postmenopausal women, higher plasma AKG levels were associated with lower bone mass, weak grip strength, poor physical performance, and increased frailty risk. CONCLUSIONS: Metabolomics- and ML-based methods identified the key metabolites of blood and muscle that were significantly changed after ovariectomy in mice, and the clinical implication of several metabolites was investigated by looking at their correlation with body composition and frailty-related parameters in postmenopausal women. These findings provide crucial context for understanding the diverse physiological alterations caused by estrogen deficiency in women.

Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

Surrogacy: beyond the commercial/altruistic distinction.

In this article, I critique the commonly accepted distinction between commercial and altruistic surrogacy arrangements. The moral legitimacy of surrogacy, I claim, does not hinge on whether it is paid ('commercial') or unpaid ('altruistic'); rather, it is best determined by appraisal of virtue-abiding conditions constitutive of the surrogacy arrangement. I begin my article by problematising the prevailing commercial/altruistic distinction; next, I demonstrate that an assessment of the virtue-abiding or non-virtue-abiding features of a surrogacy is crucial to navigating questions about the moral legitimacy of surrogacy; in the final part, I reject other moral heuristics that might be proposed as alternatives to the commercial/altruistic dichotomy, and reiterate that a virtue-ethical framework is the most suitable way forward.

Who should provide the uterus? The ethics of live donor recruitment for uterus transplantation.

Uterus transplantation (UTx) is an experimental surgery likely to face the issue of organ shortage. In my article, I explore how this issue might be addressed by changing the prevailing practices around live uterus donor recruitment. Currently, women with children - often the mothers of recipients - tend to be overrepresented as donors. Yet, other potentially eligible groups who may have an interest in providing their uterus - such as transgender men, or cisgender women who do not wish to gestate or to have children - tend to be excluded as potential donors. Moving forward, I recommend that donor inclusion criteria for UTx be broadened to be more inclusive of these latter groups.

Psychometric properties of measures designed to assess common mental health problems and wellbeing in adults with intellectual disabilities: a systematic review.

BACKGROUND: Multiple measures of mental health problems and mental wellbeing for adults with intellectual disabilities are available, but investigations into their reliability and validity are still in the early stages. The aim of this systematic review was to provide an update to previous evaluations of measures of common mental health problems and wellbeing in adults with mild to moderate intellectual disabilities (ID). METHODS: A systematic search was performed across three databases (MEDLINE, PsycINFO and SCOPUS). The literature search was limited to the years from 2009 to 2021 and to the original English versions. Ten papers evaluating nine measures were reviewed, and the psychometric properties of these measures were discussed using the Characteristics of Assessment Instructions for Psychiatric Disorders in Persons with Intellectual Developmental Disorders as a framework. RESULTS: Four measures had at least one rating of 'good' across both dimensions of reliability and at least one dimension of validity and were deemed to have promising psychometric properties: the Clinical Outcomes in Routine Evaluation-Learning Disabilities, Impact of Events Scale-Intellectual Disabilities, Lancaster and Northgate Trauma Scales and Self-Assessment and Intervention (self-report section). Additionally, these measures were developed through consultations with mental health professionals and/or people with IDs and thus were deemed to have good content validity. CONCLUSIONS: This review informs measurement choice for researchers and clinicians while highlighting a need for continued research efforts into the quality of measures available for people with IDs. The results were limited by incomplete psychometric evaluations of measures available. A paucity of psychometrically robust measures of mental wellbeing was observed.

Self-esteem and its relationship with depression and anxiety in adults with intellectual disabilities: a systematic literature review.

BACKGROUND: In the general population, low self-esteem has been linked with poorer mental and physical health. This systematic literature review aimed to summarise and evaluate the findings of studies that examined self-esteem in adults with intellectual disabilities and links with mental health outcomes. METHOD: A systematic search of PsycINFO, Web of Science and CINAHL was conducted to identify studies published between 1990 and 2021. The studies were appraised using the QualSyst tool. RESULTS: Twenty-six articles were identified of which two studies were removed from the review due to low quality. Studies reported mixed evidence regarding levels of self-esteem compared with the general population. Engagement in activities appeared to be linked with positive self-esteem, and perception of negative interpersonal life events as having a negative impact was associated with lower self-esteem. There was evidence of co-occurrence of low self-esteem and depression, but no studies examined the relationship between self-esteem and anxiety. CONCLUSION: Reviewed studies provided mixed evidence on levels of self-esteem in this population, suggesting that factors such as engagement in life were related to higher self-esteem and demonstrating the co-occurrence of low self-esteem and depression. However, clear causal links have yet to be identified, and more research is needed using longitudinal designs to answer questions about trajectory.

Development and initial psychometric properties of the Warwick-Edinburgh Mental Wellbeing Scale-Intellectual Disability version.

BACKGROUND: The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS; Tennant et al., 2007) is yet to be validated in the intellectual disability (ID) population. The aim of this study was to report the development process and assess the psychometric properties of a newly adapted version of the WEMWBS and the Short WEMWBS for individuals with mild to moderate IDs (WEMWBS-ID/SWEMWBS-ID). METHOD: The WEMWBS item wordings and response options were revised by clinicians and researchers expert in the field of ID, and a visual aid was added to the scale. The adapted version was reviewed by 10 individuals with IDs. The measure was administered by researchers online using screenshare, to individuals aged 16+ years with mild to moderate IDs. Data from three UK samples were collated to evaluate the WEMWBS-ID (n = 96). A subsample (n = 22) completed the measure again 1 to 2 weeks later to assess test-retest reliability, and 95 participants additionally completed an adapted version of the adapted Rosenberg Self-Esteem Scale to examine convergent validity. Additional data from a Canadian sample (n = 27) were used to evaluate the SWEMWBS-ID (n = 123). RESULTS: The WEMWBS-ID demonstrated good internal consistency (ω = 0.77-0.87), excellent test-retest reliability [intraclass correlation coefficient (ICC) = .88] and good convergent validity with the self-esteem scale (r = .48-.60) across samples. A confirmatory factor analysis for a single factor model demonstrated an adequate fit. The SWEMWBS-ID showed poor to good internal consistency (ω = 0.36-0.74), moderate test-retest reliability (ICC = .67) and good convergent validity (r = .48-.60) across samples, and a confirmatory factor analysis indicated good model fit for a single factor structure. CONCLUSIONS: The WEMWBS-ID and short version demonstrated promising psychometric properties, when administered virtually by a researcher. Further exploration of the scales with larger, representative samples is warranted.

The limitations of liberal reproductive autonomy.

The common liberal understanding of reproductive autonomy - characterized by free choice and a principle of non-interference - serves as a useful way to analyse the normative appeal of having certain choices open to people in the reproductive realm, especially for issues like abortion rights. However, this liberal reading of reproductive autonomy only offers us a limited ethical understanding of what is at stake in many kinds of reproductive choices, particularly when it comes to different uses of reproductive technologies and third-party reproduction. This is because the liberal framework does not fully capture who benefits from which reproductive options, the extent of the risks and harms involved in various reproductive interventions, and the reasons for why people are driven to make certain reproductive choices.

Observation of Coulomb-Assisted Nuclear Bound State of Ξ

In an emulsion-counter hybrid experiment performed at J-PARC, a Ξ^{-} absorption event was observed which decayed into twin single-Λ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as Ξ^{-}+^{14}N→_{Λ}^{10}Be+_{Λ}^{5}He. For the binding energy of the Ξ^{-} hyperon in the Ξ^{-}-^{14}N system a value of 1.27±0.21 MeV was deduced. The energy level of Ξ^{-} is likely a nuclear 1p state which indicates a weak ΞN-ΛΛ coupling.

Mutations in genes encoding desmosomal proteins: spectrum of cutaneous and extracutaneous abnormalities.

The desmosome is a type of intercellular junction found in epithelial cells, cardiomyocytes and other specialized cell types. Composed of a network of transmembranous cadherins and intracellular armadillo, plakin and other proteins, desmosomes contribute to cell-cell adhesion, signalling, development and differentiation. Mutations in genes encoding desmosomal proteins result in a spectrum of erosive skin and mucosal phenotypes that also may affect hair or heart. This review summarizes the molecular pathology and phenotypes associated with desmosomal dysfunction with a focus on inherited disorders that involve the skin/hair, as well as associated extracutaneous pathologies. We reviewed the relevant literature to collate studies of pathogenic human mutations in desmosomes that have been reported over the last 25 years. Mutations in 12 different desmosome genes have been documented, with mutations in nine genes affecting the skin/mucous membranes (DSG1, DSG3, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP) and eight resulting in hair abnormalities (DSG4, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP). Mutations in three genes can result in cardiocutaneous syndromes (DSC2, JUP, DSP), although mutations have been described in five genes in inherited heart disorders that may lack any dermatological manifestations (DSG2, DSC2, JUP, PKP2, DSP). Understanding the diverse nature of these clinical phenotypes, as well as the desmosome gene mutation(s), has clinical value in managing and counselling patients, as well as demonstrating the biological role and activity of specific components of desmosomes in skin and other tissues.

Shear-wave velocity for colorectal cancer liver metastases as a potential prognostic factor after chemotherapy: a preliminary study.

AIM: To evaluate whether shear-wave velocity (SWV) can be used for predicting the prognoses of patients with colorectal cancer liver metastases (CRLMs) after chemotherapy. MATERIALS AND METHODS: Our institutional review board approved this prospective study, and written informed consent was obtained. SWV of CRLMs were obtained using point shear-wave elastography using acoustic radiation force impulse from 25 patients prior to and 2, 7, and 14 days after chemotherapy. Progression-free survival (PFS) after chemotherapy was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to determine significant predictive factors for PFS. For measurement reproducibility, an additional 37 patients with CRLMs were enrolled and assessed using intraclass correlation coefficients (ICCs). RESULTS: After chemotherapy, 10 and 15 patients were classified into responder and non-responder groups, respectively. The estimated 1- and 3-year PFS values in the whole cohort were 36% and 8%, respectively. A decrease in the SWV value on day 2 relative to the initial value was a significant predictive factor for better PFS outcome (hazard ratio = 0.20, 95% confidence interval = 0.07-0.57, p=0.003). The estimated 1 and 3-year PFS rates were 66.7% and 22.2%, respectively, in nine patients with decreased SWV values on day 2 and significantly higher than 18.8% and 0% of 16 patients with increased SWV values on day 2. The ICC value of SWV of CRLMs in the additional 37 patients was 0.823 (95% CI = 0.685-0.905), indicating good agreement. CONCLUSION: SWV values of CRLMs could provide prognostic information in patients with CRLMs treated with chemotherapy, as decreased SWV values on day 2 after chemotherapy was a significant predictive factor for better PFS.

Both cardiovascular and cerebrovascular events are decreased following long-term narrowband ultraviolet B phototherapy in patients with vitiligo: a propensity score matching analysis.

BACKGROUND: Systemic effects of long-term narrowband ultraviolet B (NB-UVB) phototherapy have not been well studied in vitiligo patients. An 11-year nationwide population-based retrospective cohort study was conducted using the Korean National Health Insurance claims database (2007-2017). OBJECTIVES: To investigate the effects of long-term NB-UVB phototherapy on the risk of cardiovascular and cerebrovascular events in vitiligo patients. METHODS: This study included vitiligo patients with ≥100 phototherapy sessions (phototherapy group, n = 3229) and <3 phototherapy sessions (no phototherapy group, n = 9687), in which covariables with age, sex, insurance type and comorbidities such as diabetes, hypertension and hyperlipidemia were matched by 1 : 3 propensity score matching. The outcomes of interest were cardiovascular (ischaemic heart disease and myocardial infarction) and cerebrovascular events (cerebrovascular infraction and haemorrhage). Cox proportional hazards models were used to assess the associations between NB-UVB phototherapy and each event. RESULTS: The risk of cardiovascular or cerebrovascular events was significantly decreased in the phototherapy group compared with the no phototherapy group [hazard ratio (HR) 0.637, 95% confidence interval (CI) 0.523-0.776]. Subgroup analysis revealed that the risk of cardiovascular (HR: 0.682, 95% CI: 0.495-0.940) and cerebrovascular events (HR: 0.601, 95% CI: 0.470-0.769) were significantly lower in the phototherapy group than the no phototherapy group, respectively. CONCLUSIONS: Our findings suggest that long-term NB-UVB phototherapy could decrease the risk of cardiovascular and cerebrovascular events in patients with vitiligo.

Association of low skeletal muscle mass with the presence of advanced colorectal neoplasm: integrative analysis using three skeletal muscle mass indices.

AIM: This study aimed to evaluate an association between colorectal neoplasm (CRN) and skeletal muscle mass using three widely accepted skeletal muscle mass indices (SMIs) in a large population at average risk. METHOD: We performed a cross-sectional study using a screening colonoscopy database of 33 958 asymptomatic subjects aged 40-75 years. Appendicular skeletal muscle mass (ASM) was measured using a bioelectrical impedance analyser. ASM adjusted for height squared (ASM/ht2 ), weight (ASM/wt) and body mass index (ASM/BMI) were used as indices for muscle mass. Logistic regression models were used to evaluate the association between SMIs and CRN. RESULTS: In a multivariable-adjusted model, the risk of an advanced CRN increased linearly with decreasing quartiles for all three SMIs. The adjusted odds ratios (ORs) for advanced CRN in quartiles 1, 2 and 3 of ASM/wt compared with that in quartile 4 were 1.279, 1.196 and 1.179, respectively (Ptrend  = 0.017); for ASM/BMI, ORs were 1.307, 1.144 and 1.091, respectively (Ptrend  = 0.002); and for ASM/ht2 , ORs were 1.342, 1.169 and 1.062, respectively (Ptrend  = 0.002). The risk of distally located advanced CRN was higher in quartile 1 than in quartile 4 for all three SMIs (ASM/wt, OR = 1.356; ASM/BMI, OR = 1.383; ASM/ht2 , OR = 1.430). CONCLUSION: Our study demonstrated that low skeletal muscle mass was consistently associated with the presence of advanced CRN in a population at average risk regardless of the operational definition of the SMI, and it was particularly associated with distal advanced CRN.

Differentiation of dural arteriovenous fistula from reflux venous flow on 3D TOF-MR angiography: identifying asymmetric enlargement of external carotid artery branches.

AIM: To differentiate dural arteriovenous fistula (DAVF) from reflux venous flow (RVF) by assessment of asymmetric enlargement of external carotid artery (ECA) branches on three-dimensional (3D) time-of-flight magnetic resonance angiography (TOF-MRA). MATERIALS AND METHODS: Nineteen patients with DAVF and 27 patients with RVF were included from September 2007 to April 2019. The locations of DAVF were the cavernous (n=9) and sigmoid-transverse (n=6) sinuses, and the jugular (n=3) and sphenoparietal (n=1) veins. Two radiologists visually assessed asymmetric enlargement of the ascending pharyngeal artery (ASP), middle meningeal artery (MMA), accessory meningeal artery (AMA), artery of the foramen rotundum, and occipital artery. MMA size was also measured quantitatively. RESULTS: More frequent asymmetric enlargement of the ASP and MMA were seen in DAVF than in RVF (17 of 19 versus 3 of 27 for ASP; 16 of 19 versus 1 of 27 for MMA, p<0.01). The AMA, artery of the foramen rotundum, and occipital arteries were not visualised in RVF patients. The ipsilateral MMA size was significantly larger in DAVF than in RVF (2.14 versus 0.64 mm2, p< 0.01). The diagnostic performance of ipsilateral MMA size for DAVF was good, with an area under the receiver operating characteristic curve of 0.89, with a sensitivity of 84.2% and a specificity of 81.5% at a cut-off of 1.08 mm2. CONCLUSIONS: DAVF showed significantly larger ECA branches than RVF on 3D TOF-MRA. Therefore, thorough evaluation of ECA branches could help to differentiate DAVF from RVF.

Effects of skin abrasion in immersion challenge with Vibrio harveyi in Asian seabass Lates calcarifer fingerlings.

Skin abrasions often occur in farmed fish following handling by labourers, injury by farm facilities, cannibalism and ectoparasites. Vibrio spp. are opportunistic pathogens that can invade host fish through damaged tissues and cause outbreaks of vibriosis. This study describes the effect of skin abrasions on the infectivity of V. harveyi using Asian seabass Lates calcarifer (Bloch, 1790) fingerlings as a case example and compares bacterial load and fish survival following immersion challenge with different doses. In total, 315 fish (6.67 ± 1.8 g) were divided into 3 treatments: skin abrasion followed by immersion infection, immersion infection only and an uninfected, uninjured control. Fish in the infection treatments were divided into 3 subgroups and exposed in triplicate to a 7 d immersion challenge with 106, 107 and 108 CFU ml-1 of live V. harveyi. No mortalities were observed in the control and immersion infection groups. However, fish in the skin abrasion treatment group that were infected with 108 CFU ml-1 of live V. harveyi showed signs of progressing disease throughout the experiment, which resulted in mortalities. Significantly higher bacterial loads (p < 0.05) were recorded in the intestine, liver and gills of the fish in this group. Fish in the skin abrasion treatment that were exposed to 107 and 108 CFU ml-1 of V. harveyi showed 100% mortality by Days 5 and 4, respectively. These findings confirm that skin injuries increase the susceptibility of seabass fingerlings to V. harveyi infection.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Search for a Dark Matter-Induced Annual Modulation Signal in NaI(Tl) with the COSINE-100 Experiment.

We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.

First Direct Search for Inelastic Boosted Dark Matter with COSINE-100.

A search for inelastic boosted dark matter (IBDM) using the COSINE-100 detector with 59.5 days of data is presented. This relativistic dark matter is theorized to interact with the target material through inelastic scattering with electrons, creating a heavier state that subsequently produces standard model particles, such as an electron-positron pair. In this study, we search for this electron-positron pair in coincidence with the initially scattered electron as a signature for an IBDM interaction. No excess over the predicted background event rate is observed. Therefore, we present limits on IBDM interactions under various hypotheses, one of which allows us to explore an area of the dark photon parameter space that has not yet been covered by other experiments. This is the first experimental search for IBDM using a terrestrial detector.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.