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Abstract Aim Illicitly manufactured fentanyl and its analogs are the primary drivers of opioid overdose deaths in the United States (U.S.). People who use drugs may be exposed to fentanyl or its analogs intentionally or unintentionally. This study sought to identify strategies used by rural people who use drugs to reduce harms associated with unintentional fentanyl exposure. Methods This analysis focused on 349 semi-structured qualitative interviews across 10 states and 58 rural counties in the U.S conducted between 2018 and 2020. Interview guides were collaboratively standardized across sites and included questions about drug use history (including drugs currently used, frequency of use, mode of administration) and questions specific to fentanyl. Deductive coding was used to code all data, then inductive coding of overdose and fentanyl codes was conducted by an interdisciplinary writing team. Results Participants described being concerned that fentanyl had saturated the drug market, in both stimulant and opioid supplies. Participants utilized strategies including: (1) avoiding drugs that were perceived to contain fentanyl, (2) buying drugs from trusted sources, (3) using fentanyl test strips, 4) using small doses and non-injection routes, (5) using with other people, (6) tasting, smelling, and looking at drugs before use, and (7) carrying and using naloxone. Most people who used drugs used a combination of these strategies as there was an overwhelming fear of fatal overdose. Conclusion People who use drugs living in rural areas of the U.S. are aware that fentanyl is in their drug supply and use several strategies to prevent associated harms, including fatal overdose. Increasing access to harm reduction tools (e.g., fentanyl test strips, naloxone) and services (e.g., community drug checking, syringe services programs, overdose prevention centers) should be prioritized to address the polysubstance-involved overdose crisis. These efforts should target persons who use opioids and other drugs that may contain fentanyl.

Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years’ PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation.Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years’ PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation.

Abstract Background The steep rise in substance use and substance use disorder (SUD) shows an urgency to assess its prevalence using valid measures. This systematic review summarizes the validity of measures to assess the prevalence of substance use and SUD in the US estimated in population and sub-population-based surveys. Methods A literature search was performed using nine online databases. Studies were included in the review if they were published in English and tested the validity of substance use and SUD measures among US adults at the general or sub-population level. Independent reviews were conducted by the authors to complete data synthesis and assess the risk of bias. Results Overall, 46 studies validating substance use/SUD (n = 46) measures were included in this review, in which 63% were conducted in clinical settings and 89% assessed the validity of SUD measures. Among the studies that assessed SUD screening measures, 78% examined a generic SUD measure, and the rest screened for specific disorders. Almost every study used a different survey measure. Overall, sensitivity and specificity tests were conducted in over a third of the studies for validation, and 10 studies used receiver operating characteristics curve. Conclusion Findings suggest a lack of standardized methods in surveys measuring and reporting prevalence of substance use/SUD among US adults. It highlights a critical need to develop short measures for assessing SUD that do not require lengthy, time-consuming data collection that would be difficult to incorporate into population-based surveys assessing a multitude of health dimensions. Systematic review registration PROSPERO CRD42022298280.

Diabetes has become one of the largest global health-care problems of the 21st century. According to the Centers for Disease Control and Prevention, the population prevalence of diabetes in the US is approaching 10% and is increasing by 5% each year. Diabetic neuropathy is the most common complication associated with diabetes mellitus. Diabetes causes a broad spectrum of neuropathic complications, including acute and chronic forms affecting each level of the peripheral nerve, from the root to the distal axon. This review will focus on the most common form, distal symmetric diabetic polyneuropathy. There has been an evolution in our understanding of the pathophysiology and the management of diabetic polyneuropathy over the past decade. We highlight these new perspectives and provide updates from the past decade of research.

Background and objective: The risk of first recurrence beyond 5 yr for patients with low-grade (LG) Ta non–muscle-invasive bladder cancer (NMIBC) is low enough to consider discontinuing cystoscopic surveillance at that point. However, a positive urinary dipstick test for haematuria (UDH) during and beyond the period of cystoscopic surveillance can disrupt plans to cease surveillance because the association between UDH positivity and recurrence in LG Ta NMIBC is unknown. In a two-stage study, we evaluated this association and explored the role of UDH negativity in predicting the absence of recurrence. Methods: Because of previously demonstrated changes in recurrence patterns over time, two prospective cohorts were assessed: an “exploratory” cohort (January 2007–March 2008) and a “validation” cohort (November 2017–August 2018). UDH was performed before flexible cystoscopy. Patient, operative, and surveillance data have been recorded prospectively using standard pro forma sheets since 1978 in our institution. Only patients with primary LG Ta pTa NMIBC were included for analysis. Key findings and limitations: We assessed 231 patients in the exploratory group and 293 in the validation group. The proportion of smokers (67% vs 70%; p = 0.5) and mean follow-up (72.2 vs 79.9 mo; p = 0.2) were similar between the groups. The recurrence rate was higher in the exploratory group (19% vs 11%; p = 0.009), as was the UDH positivity rate (37% vs 11%; p

This interview study offers educators practical tips on using tools to improve online learning experiences. Eleven instructors, professors, and instructional designers were interviewed about the challenges they faced designing and teaching online university courses in Florida. This study aimed to explore how educators and instructional designers innovated learning design to improve instructor presence, engagement, and interactivity. In the wake of a pandemic that expedited the adoption of online learning, this paper is intended to offer advice for educators transitioning from emergency remote learning to strategic online course design that integrates emerging technology. This paper is intended to share what educators learned by experimenting with interactive 360-degree multimedia, virtual reality, videography, and visual design in learning management systems. Some of the tools featured in this paper include Roblox, Flipside, Plotagon, Articulate 360, Canvas, Kaltura, and video conferencing apps.

Climate-induced sea-level rise threatens the world’s coastal populations, critical infrastructure, and ecosystems. The science of sea-level rise (SLR) has developed to inform understanding of global climate mitigation and adaptation challenges, but there is much less engagement with practitioners to discern their climate services needs and support the development of adaptation planning and action on the ground. In addition, adaptation planning and implementation processes for SLR are relatively new and practitioners developing leading practices are seeking interaction with their peers and the SLR science community. To address these gaps, we co-produced online global workshops with sixty-nine practitioners from twenty-six countries. These workshops aimed to increase understanding of the state of SLR adaptation planning practice worldwide, gather information on practitioners' existing knowledge and service needs to advance their adaptation efforts, and facilitate exchange between practitioners engaged with coastal adaptation and the SLR science community. The workshops uncovered commonalities across contexts and identified consistent needs from scientists and other technical experts amongst the practitioner community. These needs include generating more localized SLR impact data, understanding of compound risk, creating data timelines for decision making, and developing clarity about uncertainties and probabilities. We also observed important differences between urban and rural locations and between places with different economic resources. To meet their needs, practitioners identified three crucial next steps: 1) Develop more online engagement opportunities, 2) Establish a global practitioner community of practice, and 3) Scale and improve the provision of climate services.

BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Background: Living donor kidney transplantation (LDKT) is the optimal treatment for eligible patients with kidney failure, although it is underutilized. Contextually tailored patient- and family-centered interventions may be effective to increase LDKT. Objective: We outline a protocol to test the feasibility of the Multidisciplinary Support To Access living donor Kidney Transplant (MuST AKT) intervention designed to increase LDKT. Design: Non-blinded single-center pilot randomized controlled trial with a qualitative interview component. Setting: Academic transplant referral center in Northern Alberta Region with a population of more than 2 million in its catchment area. Patients: English-speaking patients of the age range 18 to 75 years who are referred for kidney transplantation are eligible to participate. Measurements: Feasibility will be assessed by indicators of recruitment, retention, and completion rates, treatment fidelity, adherence to intervention, engagement in intervention, and acceptability. Methods: Participants will be randomly assigned 1:1 to either standard care (control) or the experimental group who receive standard care plus the MuST AKT intervention, a person-centered program designed to assist and enable the kidney transplant candidate to achieve what is required to receive an LDKT. The intervention consists of an introductory session and 4 intervention sessions delivered in-person or virtually. Limitations: Inferences cannot be drawn regarding the efficacy/effectiveness of the MuST AKT intervention. This study is non-blinded. Conclusions: This pilot study is the first step in our broader initiative to increase LDKT in our health care jurisdiction. The results of this study will be used to inform the development of a future definitive randomized controlled trial. Trial registration number: NCT04666545.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Yuki Kihara is a globally accomplished, award-winning interdisciplinary Pacific artist, researcher, and curator. She is of Samoan and Japanese heritage and identifies as Fa'afafine, a third gender meaning 'in the [...]

Using the pollen loads carried by floral visitors to infer their floral visitation behavior is a powerful technique to explore the foraging of wild pollinators. Interpreting these pollen records, however, requires assumptions about the underlying pollen dynamics. To compare visitor foraging across flower species, the most important assumption is that pollen is picked up and retained on the visitor at similar rates. Given differences in pollen presentation traits such as grain number or stickiness even among flowers with similar morphologies, however, the generality of this assumption is unclear. We investigated pollen accumulation on the hawkmoth Manduca sexta, testing the degree to which accumulation differed among flower species and how pollen stickiness affected this accumulation. In no-choice floral visitation assays to six plant species visited by long-tongued hawkmoths in the wild, M. sexta individuals were allowed to visit flowers 1, 2, or 5 times, after which the pollen on their proboscises was removed and counted. We found that the six plant species varied orders of magnitude in the number of pollen grains deposited on the moths, with some placing thousands of grains after a single visit and other placing none after five. Plant species with sticky pollen adhesion mechanisms placed more pollen on the moths and had relatively less pollen accumulation over successive visits than non-sticky plants. Intriguingly, moths carried fewer pollen grains after 5 visits than after 2 visits, suggesting that both sticky and non-sticky pollen was lost during foraging. Together, our results suggest that interpretation of pollen load data should be made cautiously, especially when comparing across plant species.

BackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.MethodsRare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.ResultsCNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.ConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P

Rationale & Objective: For patients requiring in-center hemodialysis, suboptimal transportation arrangements are commonly cited as a source of ongoing stress and anxiety and have been associated with a reduced quality of life and increased mortality risk. Transportation-related problems are especially pronounced in Canada given its size, low population density, and long, often snowy winters. We aimed to identify and better understand transportation options for hemodialysis patients in Canada and to describe stakeholder experiences. Study Design: We used a qualitative descriptive research design to explore stakeholder experiences and perspectives of transportation to and from dialysis facilities. Setting & Participants: We recruited participants from a large urban hemodialysis program in Western Canada and included 11 participants from a project group, 45 participants from an open forum, and a survey of 8 social workers. Data collection occurred at a series of project group meetings and an open forum (n=45). In addition, we asked 8 renal social workers based in major cities across Canada to comment on the provision of transport for patients in their area via email or telephone consult. Analytical Approach: We used conventional content analysis to explore stakeholder experiences. Results: Traveling to and from dialysis facilities remains a source of stress and anxiety for many patients and their families. Patients described several factors contributing to these feelings including: the challenges of physically getting to the treatment center, particularly in adverse weather conditions; being a burden on family and friends; difficulties accessing the treatment facility; issues with public transport; and financial worries related to high costs. Limitations: Findings may not be relevant in low- and middle-income countries and those with a warmer climate. Conclusions: Without a concerted and collaborative approach to address the barriers identified here, it is likely that travel to and from in-center hemodialysis will continue to adversely affect patients’ quality of life.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Abstract Background Despite advances in the care of women and their babies in the past century, an estimated 1.7 million babies are born still each year throughout the world. A robust method to estimate a pregnant woman’s individualized risk of late-pregnancy stillbirth is needed to inform decision-making around the timing of birth to reduce the risk of stillbirth from 35 weeks of gestation in Australia, a high-resource setting. Methods This is a protocol for a cross-sectional study of all late-pregnancy births in Australia (2005–2015) from 35 weeks of gestation including 5188 stillbirths among 3.1 million births at an estimated rate of 1.7 stillbirths per 1000 births. A multivariable logistic regression model will be developed in line with current T ransparent R eporting of a multivariable prediction model for I ndividual P rognosis or D iagnosis (TRIPOD) guidelines to estimate the gestation-specific probability of stillbirth with prediction intervals. Candidate predictors were identified from systematic reviews and clinical consultation and will be described through univariable regression analysis. To generate a final model, elimination by backward stepwise multivariable logistic regression will be performed. The model will be internally validated using bootstrapping with 1000 repetitions and externally validated using a temporally unique dataset. Overall model performance will be assessed with R 2 , calibration, and discrimination. Calibration will be reported using a calibration plot with 95% confidence intervals (α = 0.05). Discrimination will be measured by the C-statistic and area underneath the receiver-operator curves. Clinical usefulness will be reported as positive and negative predictive values, and a decision curve analysis will be considered. Discussion A robust method to predict a pregnant woman’s individualized risk of late-pregnancy stillbirth is needed to inform timely, appropriate care to reduce stillbirth. Among existing prediction models designed for obstetric use, few have been subject to internal and external validation and many fail to meet recommended reporting standards. In developing a risk prediction model for late-gestation stillbirth with both providers and pregnant women in mind, we endeavor to develop a validated model for clinical use in Australia that meets current reporting standards.

Abstract Background Bipolar disorder has been associated with several personality traits, cognitive styles and affective temperaments. Women who have bipolar disorder are at increased risk of experiencing postpartum psychosis, however little research has investigated these traits and temperaments in relation to postpartum psychosis. The aim of this study is to establish whether aspects of personality, cognitive style and affective temperament that have been associated with bipolar disorder also confer vulnerability to postpartum psychosis over and above their known association with bipolar disorder. Methods Personality traits (neuroticism, extraversion, schizotypy and impulsivity), cognitive styles (low self-esteem and dysfunctional attitudes) and affective temperaments (including cyclothymic and depressive temperaments) were compared between two groups of parous women with DSM-IV bipolar I disorder: i) 284 with a lifetime history of postpartum psychosis within 6 weeks of delivery (PP group), ii) 268 without any history of mood episodes with onset during pregnancy or within 6 months of delivery (no perinatal mood episode, No PME group). Results After controlling for current mood state, and key demographic, clinical and pregnancy-related variables, there were no statistically significant differences between the PP and No PME groups on any of the personality, cognitive style or affective temperament measures. Conclusions Personality traits, cognitive styles and affective temperaments previously shown to be associated with bipolar disorder in general were not specifically associated with the occurrence of postpartum psychosis. These factors may not be relevant for predicting risk of postpartum psychosis in women with bipolar disorder.

Introduction The aim of the cervical ripening at home or in-hospital—prospective cohort study and process evaluation (CHOICE) study is to compare home versus in-hospital cervical ripening to determine whether home cervical ripening is safe (for the primary outcome of neonatal unit (NNU) admission), acceptable to women and cost-effective from the perspective of both women and the National Health Service (NHS).Methods and analysis We will perform a prospective multicentre observational cohort study with an internal pilot phase. We will obtain data from electronic health records from at least 14 maternity units offering only in-hospital cervical ripening and 12 offering dinoprostone home cervical ripening. We will also conduct a cost-effectiveness analysis and a mixed methods study to evaluate processes and women/partner experiences. Our primary sample size is 8533 women with singleton pregnancies undergoing induction of labour (IOL) at 39+0 weeks’ gestation or more. To achieve this and contextualise our findings, we will collect data relating to a cohort of approximately 41 000 women undergoing IOL after 37 weeks. We will use mixed effects logistic regression for the non-inferiority comparison of NNU admission and propensity score matched adjustment to control for treatment indication bias. The economic analysis will be undertaken from the perspective of the NHS and Personal Social Services (PSS) and the pregnant woman. It will include a within-study cost-effectiveness analysis and a lifetime cost–utility analysis to account for any long-term impacts of the cervical ripening strategies. Outcomes will be reported as incremental cost per NNU admission avoided and incremental cost per quality adjusted life year gained.Research ethics approval and dissemination CHOICE has been funded and approved by the National Institute of Healthcare Research Health Technology and Assessment, and the results will be disseminated via publication in peer-reviewed journals.Trial registration number ISRCTN32652461.