Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis.

Alterations in hippocampal volume are a known marker for first-episode psychosis (FEP) as well as for the clinical high-risk state. The Polygenic Schizophrenia-related Risk Score (PSRS), derived from a large case-control study, indicates the polygenic predisposition for schizophrenia in our clinical sample. A total of 65 at-risk mental state (ARMS) and FEP patients underwent structural magnetic resonance imaging. We used automatic segmentation of hippocampal volumes using the FSL-FIRST software and an odds-ratio-weighted PSRS based on the publicly available top single-nucleotide polymorphisms from the Psychiatric Genomics Consortium genome-wide association study (GWAS). We observed a negative association between the PSRS and hippocampal volumes (ß=-0.42, P=0.01, 95% confidence interval (CI)=(-0.72 to -0.12)) across FEP and ARMS patients. Moreover, a higher PSRS was significantly associated with a higher probability of an individual being assigned to the FEP group relative to the ARMS group (ß=0.64, P=0.03, 95% CI=(0.08-1.29)). These findings provide evidence that a subset of schizophrenia risk variants is negatively associated with hippocampal volumes, and higher values of this PSRS are significantly associated with FEP compared with the ARMS. This implies that FEP patients have a higher genetic risk for schizophrenia than the total cohort of ARMS patients. The identification of associations between genetic risk variants and structural brain alterations will increase our understanding of the neurobiology underlying the transition to psychosis.

Women's interpretation of and responses to potential gynaecological cancer symptoms: a qualitative interview study.

OBJECTIVE: To explore women's experiences of symptoms potentially indicative of gynaecological cancer in a community-based sample without imposing a cancer perspective. DESIGN: A qualitative interview study with thematic analysis of transcripts. PARTICIPANTS: 26 women aged ≥30 years, who had experienced a symptom that might indicate gynaecological cancer in the past 3 months, were recruited using a screening questionnaire distributed online and in community settings. SETTING: London, UK. RESULTS: Women attributed gynaecological symptoms to existing illnesses/conditions or considered themselves to be predisposed to them, either through their 'genes' or previous personal experience. Normalising symptoms by attributing them to demographic characteristics (eg, age, sex) was common, as was considering them a side effect of hormonal contraception. When women raised cancer as a possible cause, they often dismissed it as unlikely. Responses to symptoms included self-management (eg, self-medicating, making lifestyle changes), adopting a 'lay system of care', or consulting a healthcare professional. Triggers to help-seeking included persistent, painful or debilitating symptoms, concern about symptom seriousness, and feeling that help-seeking was legitimised. Barriers to help-seeking included lack of concern, vague symptoms, unusual symptom location, competing time demands, previous negative experiences with the healthcare system, and not wanting to be perceived as a time-waster. CONCLUSIONS: Attributions of symptoms potentially indicative of a gynaecological cancer were varied, but most often involved women fitting symptoms into their expectations of what was 'normal'. Normalising acted as a barrier to seeking help from a healthcare professional, alongside competing time demands and negative attitudes towards help-seeking. These barriers may lead to later diagnosis and poorer cancer survival. Our findings could be used to inform the development of interventions to encourage appropriate help-seeking.

Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK.

BACKGROUND: Not recognising a symptom as suspicious is a common reason given by cancer patients for delayed help-seeking; but inevitably this is retrospective. We therefore investigated associations between recognition of warning signs for breast, colorectal and lung cancer and anticipated time to help-seeking for symptoms of each cancer. METHODS: Computer-assisted telephone interviews were conducted with a population-representative sample (N=6965) of UK adults age ≥ 50 years, using the Awareness and Beliefs about Cancer scale. Anticipated time to help-seeking for persistent cough, rectal bleeding and breast changes was categorised as >2 vs ≤ 2 weeks. Recognition of persistent cough, unexplained bleeding and unexplained lump as cancer warning signs was assessed (yes/no). Associations between recognition and help-seeking were examined for each symptom controlling for demographics and perceived ease of health-care access. RESULTS: For each symptom, the odds of waiting for >2 weeks were significantly increased in those who did not recognise the related warning sign: breast changes: OR=2.45, 95% CI 1.47-4.08; rectal bleeding: OR=1.77, 1.36-2.30; persistent cough: OR=1.30, 1.17-1.46, independent of demographics and health-care access. CONCLUSION: Recognition of warning signs was associated with anticipating faster help-seeking for potential symptoms of cancer. Strategies to improve recognition are likely to facilitate earlier diagnosis.

Experience of symptoms indicative of gynaecological cancers in UK women.

BACKGROUND: Gynaecological cancers account for ∼12% of female cancer incidence in the United Kingdom. Encouraging prompt help-seeking for potential symptoms could help improve outcomes. However, before developing help-seeking interventions, it is important to estimate the number of women with symptoms potentially indicative of a gynaecological cancer to help estimate the impact of such interventions on primary care. METHODS: As part of a face-to-face, population-based survey, women aged ≥16 (n=911) were shown a list of symptoms potentially indicative of a gynaecological cancer and were asked to indicate any experienced in the last 3 months. Those who reported symptoms were asked about their responses to one randomly selected index symptom. RESULTS: Just under half (44%) of the respondents reported a symptom, with 35% reporting a frequent and/or severe symptom. Younger (P<0.001), lower socioeconomic status (P<0.01) and non-White women (P<0.05) were significantly more likely to report symptoms. Few (14%) respondents were both older (≥45 years) and had a frequent and/or severe symptom. Of these women, 38% had seen a GP. CONCLUSION: Symptoms that potentially indicate a gynaecological cancer, even if limited to those that are frequent and/or severe, appear to be common. Consequently, encouraging prompt help-seeking may increase the burden on primary care. However, targeting those at increased risk (older women with frequent or severe symptoms) should avoid unmanageable increases in primary care consultations for gynaecological conditions.

Differences in cancer awareness and beliefs between Australia, Canada, Denmark, Norway, Sweden and the UK (the International Cancer Benchmarking Partnership): do they contribute to differences in cancer survival?

BACKGROUND: There are wide international differences in 1-year cancer survival. The UK and Denmark perform poorly compared with other high-income countries with similar health care systems: Australia, Canada and Sweden have good cancer survival rates, Norway intermediate survival rates. The objective of this study was to examine the pattern of differences in cancer awareness and beliefs across these countries to identify where these might contribute to the pattern of survival. METHODS: We carried out a population-based telephone interview survey of 19079 men and women aged ≥ 50 years in Australia, Canada, Denmark, Norway, Sweden and the UK using the Awareness and Beliefs about Cancer measure. RESULTS: Awareness that the risk of cancer increased with age was lower in the UK (14%), Canada (13%) and Australia (16%) but was higher in Denmark (25%), Norway (29%) and Sweden (38%). Symptom awareness was no lower in the UK and Denmark than other countries. Perceived barriers to symptomatic presentation were highest in the UK, in particular being worried about wasting the doctor's time (UK 34%; Canada 21%; Australia 14%; Denmark 12%; Norway 11%; Sweden 9%). CONCLUSION: The UK had low awareness of age-related risk and the highest perceived barriers to symptomatic presentation, but symptom awareness in the UK did not differ from other countries. Denmark had higher awareness of age-related risk and few perceived barriers to symptomatic presentation. This suggests that other factors must be involved in explaining Denmark's poor survival rates. In the UK, interventions that address barriers to prompt presentation in primary care should be developed and evaluated.

Communication about colorectal cancer screening in Britain: public preferences for an expert recommendation.

BACKGROUND: Informed decision-making approaches to cancer screening emphasise the importance of decisions being determined by individuals' own values and preferences. However, advice from a trusted source may also contribute to autonomous decision-making. This study examined preferences regarding a recommendation from the NHS and information provision in the context of colorectal cancer (CRC) screening. METHODS: In face-to-face interviews, a population-based sample of adults across Britain (n=1964; age 50-80 years) indicated their preference between: (1) a strong recommendation to participate in CRC screening, (2) a recommendation alongside advice to make an individual decision, and (3) no recommendation but advice to make an individual decision. Other measures included trust in the NHS and preferences for information on benefits and risks. RESULTS: Most respondents (84%) preferred a recommendation (47% strong recommendation, 37% recommendation plus individual decision-making advice), but the majority also wanted full information on risks (77%) and benefits (78%). Men were more in favour of a recommendation than women (86% vs 81%). Trust in the NHS was high overall, but the minority who expressed low trust were less likely to want a recommendation. CONCLUSION: Most British adults want full information on risks and benefits of screening but they also want a recommendation from an authoritative source. An 'expert' view may be an important part of autonomous health decision-making.

Awareness of cancer risk factors among ethnic minority groups in England.

OBJECTIVE: To explore awareness of cancer risk factors in ethnic minority men and women living in England. STUDY DESIGN: Cross-sectional survey. METHODS: Men and women were recruited from the six largest ethnic minority groups in the UK proportional to the population distribution: Indian (n = 467); Pakistani (n = 333); Bangladeshi (n = 126); Caribbean (n = 252); African (n = 216); and Chinese (n = 106). Participants responded to an open-ended question about cancer risk factors. Analyses were adjusted for age, gender, socio-economic class and language. RESULTS: The most commonly cited cancer risk factors were smoking (55%), diet (20%), genetics (20%), drinking alcohol (19%) and lifestyle (17%). On average, participants who were able to name cancer risk factors (91% of respondents) cited 2.13 factors. There were some differences between broad ethnic groups (Asian, Black and Chinese), but fewer differences within them (e.g. between Indian, Pakistani and Bangladeshi, or African and Caribbean). CONCLUSIONS: Awareness of risk factors (particularly diet and exercise) was lower in this sample than in previous population representative samples in the UK. Interventions aimed at raising awareness of cancer risk factors are likely to be beneficial across the whole ethnic minority population. Any ethnically targeted interventions should consider risk factor awareness levels as well as cancer risk.

Do the British public recognise differences in survival between three common cancers?

BACKGROUND: The recognition that cancer is not a single entity, rather that different cancers have different causes and trajectories, has been a key development in the scientific understanding of cancer. However, little is known about the British public's awareness of differences between cancers. This study examined differences in perceived survivability for three common cancers with widely disparate survival rates (breast, colorectal and lung). METHOD: In a population-based survey, using home interviews (N=2018), respondents answered a quantitative (numeric) question on 5-year survival and a qualitative (non-numeric) question on curability, for each of the three cancers. RESULTS: British adults correctly recognised that 5-year survival for breast cancer was higher than for colorectal cancer (CRC), which in turn was recognised to be higher than for lung cancer. Similarly, curability was perceived to be higher for breast than CRC, and both were perceived to be more curable than lung cancer. Awareness of survival differences did not vary by sex, age or socioeconomic status. In terms of absolute values, there was a tendency to underestimate breast cancer survival and overestimate lung cancer survival. CONCLUSION: The British public appear to be aware that not all cancers are equally fatal.

HD 181068: a red giant in a triply eclipsing compact hierarchical triple system.

Hierarchical triple systems comprise a close binary and a more distant component. They are important for testing theories of star formation and of stellar evolution in the presence of nearby companions. We obtained 218 days of Kepler photometry of HD 181068 (magnitude of 7.1), supplemented by ground-based spectroscopy and interferometry, which show it to be a hierarchical triple with two types of mutual eclipses. The primary is a red giant that is in a 45-day orbit with a pair of red dwarfs in a close 0.9-day orbit. The red giant shows evidence for tidally induced oscillations that are driven by the orbital motion of the close pair. HD 181068 is an ideal target for studies of dynamical evolution and testing tidal friction theories in hierarchical triple systems.

Disease stage and psychosocial outcomes in colorectal cancer.

OBJECTIVE: Disease stage is a strong predictor of cancer survival and is therefore assumed to influence psychosocial outcomes. However, existing findings are inconsistent, perhaps reflecting limited sample sizes, especially among patients with advanced disease. There has also been an emphasis on breast cancer, resulting in a focus on outcomes among women. The present study investigated associations between disease stage and psychosocial wellbeing in 128 patients (52% male, 48% female) diagnosed with colorectal cancer. METHOD: Patients diagnosed within the past year in a single hospital were invited to participate in a questionnaire study and give permission for staging information to be obtained from their medical records. The questionnaire included measures of anxiety, depression, quality of life, social support, social difficulties and quality of medical interactions. RESULTS: Patients with more advanced disease were more anxious (P < 0.01) and depressed (P < 0.001), perceived their social support as lower (P < 0.01), and had a worse quality of life (P < 0.01). Women with advanced disease had more severe colorectal symptoms (P < 0.01), and worse physical (P < 0.01) and emotional (P < 0.05) quality of life than men. CONCLUSION: Patients with advanced colorectal cancer have unmet psychosocial needs. Women may be more strongly affected by advanced disease than men.

Examining the relationship between pubertal stage, adolescent health behaviours and stress.

BACKGROUND: This paper examines the associations between puberty and three important health behaviours (smoking, food intake and exercise) and explores whether these associations are mediated by puberty's relationship to stress and psychological difficulties. METHOD: Data were taken from the first year of the ongoing, 5-year, Health and Behaviours in Teenagers Study (HABITS). This is a school-based study set in 36 schools in London. In the first year of the study, 4320 students (2578 boys, 1742 girls) in their first year of secondary education took part. RESULTS: Among girls, being more pubertally advanced was associated with a greater likelihood of having tried smoking. Among boys, being more pubertally advanced was associated with a greater likelihood of having tried smoking, a higher intake of high-fat food and higher levels of exercise. More pubertally advanced girls experienced more stress but not more psychological difficulties. There were no associations between puberty and either stress or psychological difficulties in boys. Stress and psychological difficulties were associated with health behaviours in girls and boys, but neither of these factors mediated the relationship between pubertal stage and health behaviours found in girls. CONCLUSIONS: These results suggest that the onset of puberty has a marked effect on the development of health behaviours. Puberty was related to an acceleration of the development of unhealthy behaviours, except for exercise behaviour in boys, where advanced puberty was associated with more exercise. These changes were unrelated to adolescent issues of stress and a causal explanation for these associations must be sought elsewhere.

Socioeconomic disparities in cancer-risk behaviors in adolescence: baseline results from the Health and Behaviour in Teenagers Study (HABITS).

BACKGROUND: This study explores the association between socioeconomic deprivation and five factors associated with long-term risk of cancer, in adolescents. METHODS: BMI, fat intake, fruit and vegetable intake, smoking, and exercise were assessed in 4320 students ages 11 to 12, from 36 schools, in the first year of a 5-year longitudinal study of the development of health behaviors (HABITS study). Neighborhood socioeconomic deprivation for each student's area of residence was matched to their postcode (zip code). We used multiple logistic regression analyses to investigate the relationship between risky behaviors and socioeconomic circumstances. RESULTS: Univariate analyses showed boys and girls from more deprived neighborhoods were more likely to have tried smoking, to eat a high fat diet, and to be overweight. Girls living in more deprived areas were also less likely to eat five servings of fruit and vegetables or to exercise at the weekend. Most differences persisted after controlling for ethnicity. A clear deprivation gradient emerged for each risk factor, indicating the linear nature of the relationship. CONCLUSIONS: This study demonstrates the influence of deprivation on engaging in cancer-risk health behaviors. These patterns may set young people from more socioeconomically deprived social environments on a trajectory leading to increased cancer mortality in adult life.

In vivo and in vitro characterization of an RNA replication enhancer in a satellite RNA associated with turnip crinkle virus.

RNA replication enhancers are cis-acting elements that can stimulate replication or transcription of RNA viruses. Turnip crinkle virus (TCV) and satC, a parasitic RNA associated with TCV infections, contain stem-loop structures that are RNA replication enhancers (P. Nagy, J. Pogany, and A. E. Simon, EMBO J. 1999, 18, 5653-5665). We have found that replacement of 28 nt of the satC enhancer, termed the motif1-hairpin, with 28 randomized bases reduced satC accumulation 8- to 13-fold in Arabidopsis thaliana protoplasts. Deletion of single-stranded flanking sequences at either side of the hairpin also affected RNA accumulation with combined alterations at both sides of the hairpin showing the most detrimental effect in protoplasts. In vitro analysis with a partially purified TCV RdRp preparation demonstrated that the motif1-hairpin in its minus-sense orientation was able to stimulate RNA synthesis from the satC hairpin promoter (located at the 3' end of plus strands) by almost twofold. This level of RNA synthesis stimulation is approximately fivefold lower than that observed with a linear promoter, suggesting that a highly stable hairpin promoter is less responsive to the presence of the motif1-hairpin enhancer than a linear promoter. The motif1-hairpin in its plus-sense orientation was only 60% as active in enhancing transcription from the hairpin promoter. Since the motif1-hairpin is a hotspot for RNA recombination during plus-strand synthesis and since satC promoters located on the minus-strand are all short linear sequences, these findings support the hypothesis that the motif1-hairpin is primarily involved in enhancing plus-strand synthesis.

Prodromes of first-episode psychosis: how can we challenge nonspecificity?

Prevention of functional psychosis is a major concern of modern psychiatry. The aim is to avoid biological and psychosocial deterioration at the earliest possible stage of the illness. The term "prodrome" has become crucial for identification of the very early stage. Recent years have yielded intensive research effort in defining prodromal signs and symptoms; however, the conclusion of most researchers is that they are nonspecific. We present the descriptive and phenomenological findings of the prodrome concept. Although prodromes are nonspecific, their discrepancy with persisting social impairment over time is a frequently encountered and highly alarming feature in young at-risk individuals. The inclusion of phenomenological findings may suggest the presence of psychosis-like inner experiences already as early as the prodromal phase, and thus bears in itself the question of the starting point for psychopharmacological and psychosocial treatment. Finally, a decision pathway for clinicians is proposed in their difficult task of identifying young individuals at risk.

Polymerization of nontemplate bases before transcription initiation at the 3' ends of templates by an RNA-dependent RNA polymerase: an activity involved in 3' end repair of viral RNAs.

The 3' ends of RNAs associated with turnip crinkle virus (TCV), including subviral satellite (sat)C, terminate with the motif CCUGCCC-3'. Transcripts of satC with a deletion of the motif are repaired to wild type (wt) in vivo by RNA-dependent RNA polymerase (RdRp)-mediated extension of abortively synthesized oligoribonucleotide primers complementary to the 3' end of the TCV genomic RNA. Repair of shorter deletions, however, are repaired by other mechanisms. SatC transcripts with the 3' terminal CCC replaced by eight nonviral bases were repaired in plants by homologous recombination between the similar 3' ends of satC and TCV. Transcripts with deletions of four or five 3' terminal bases, in the presence or absence of nonviral bases, generated progeny with a mixture of wt and non-wt 3' ends in vivo. In vitro, RdRp-containing extracts were able to polymerize nucleotides in a template-independent fashion before using these primers to initiate transcription at or near the 3' end of truncated satC templates. The nontemplate additions at the 5' ends of the nascent complementary strands were not random, with a preference for consecutive identical nucleotides. The RdRp was also able to initiate transcription opposite cytidylate, uridylate, guanylate, and possibly adenylate residues without exhibiting an obvious preference, flexibility previously unreported for viral RdRp. The unexpected existence of three different repair mechanisms for TCV suggests that 3' end reconstruction is critical to virus survival.

Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases.

BACKGROUND: Risperidone and olanzapine are atypical antipsychotics that are now widely used in clinical practice. METHOD: A MEDLINE search (1966-1999) showed that, following the introduction of these agents in recent years, 26 cases of induced hypomanic and manic syndromes have been reported during standard olanzapine (N = 10) or risperidone (N = 16) treatment. RESULTS: A critical analysis of these case reports reveals that the effects on mood were sometimes insufficiently documented and that in about half of them (N = 16) evidence is highly suggestive of a causative role of risperidone or olanzapine in the induction of (hypo)manic symptomatology. CONCLUSION: Despite limitations, the available literature confirms intriguing effects of these 2 antipsychotics on mood. The risk factors as well as the mechanisms of action underlying these effects remain to be clarified.

CCA initiation boxes without unique promoter elements support in vitro transcription by three viral RNA-dependent RNA polymerases.

It has previously been observed that the only specific requirement for transcriptional initiation on viral RNA in vitro by the RNA-dependent RNA polymerase (RdRp) of turnip yellow mosaic virus is the CCA at the 3' end of the genome. We now compare the abilities of this RdRp, turnip crinkle virus RdRp, and Qbeta replicase, an enzyme capable of supporting the complete viral replication cycle in vitro, to transcribe RNA templates containing multiple CCA boxes but lacking specific viral sequences. Each enzyme is able to initiate transcription from several CCA boxes within these RNAs, and no special reaction conditions are required for these activities. The transcriptional yields produced from templates comprised of multiple CCA or CCCA repeats relative to templates derived from native viral RNA sequences vary between 2:1 and 0.1:1 for the different RdRps. Control of initiation by such redundant sequences presents a challenge to the specificity of viral transcription and replication. We identify 3'-preferential initiation and sensitivity to structural presentation as two specificity mechanisms that can limit initiation among potential CCA initiation sites. These two specificity mechanisms are used to different degrees by the three RdRps. The finding that three viral RdRps representing two of the three supergroups within the positive-strand RNA viral RdRp phylogeny support substantial transcription in the absence of unique promoters suggests that this phenomenon may be common among positive-strand viruses. A framework is presented arguing that replication of viral RNA in the absence of unique promoter elements is feasible.

3'-End stem-loops of the subviral RNAs associated with turnip crinkle virus are involved in symptom modulation and coat protein binding.

Many plant RNA viruses are associated with one or more subviral RNAs. Two subviral RNAs, satellite RNA C (satC) and defective interfering RNA G (diG) intensify the symptoms of their helper, turnip crinkle virus (TCV). However, when the coat protein (CP) of TCV was replaced with that of the related Cardamine chlorotic fleck virus (CCFV), both subviral RNAs attenuated symptoms of the hybrid virus TCV-CP(CCFV). In contrast, when the translation initiation codon of the TCV CP was altered to ACG and reduced levels of CP were synthesized, satC attenuated symptoms while diG neither intensified nor attenuated symptoms. The determinants for this differential symptom modulation were previously localized to the 3'-terminal 100 bases of the subviral RNAs, which contain six positional differences (Q. Kong, J.-W. Oh, C. D. Carpenter, and A. E. Simon, Virology 238:478-485, 1997). In the current study, we have determined that certain sequences within the 3'-terminal stem-loop structures of satC and diG, which also serve as promoters for complementary strand synthesis, are critical for symptom modulation. Furthermore, the ability to attenuate symptoms was correlated with weakened binding of TCV CP to the hairpin structure.

Incidence of atrial fibrillation after mild or moderate hypothermic cardiopulmonary bypass.

OBJECTIVES: Atrial fibrillation remains a significant source of morbidity after coronary artery bypass grafting (CABG). Whether cardiopulmonary bypass (CPB) temperature influences the occurrence of postoperative atrial fibrillation in CABG patients has not been specifically examined. In the present study, we reviewed postoperative data from patients who were prospectively randomized to mild or moderate hypothermic CPB for elective CABG to determine the incidence of postoperative atrial fibrillation. DESIGN: Randomized, single center, observational study. SETTING: Tertiary university medical center. PATIENTS: Adults undergoing elective CABG surgery. INTERVENTIONS: Enrolled patients were prospectively randomized to mild (34 degrees C [93.2 degrees F]) or moderate (28 degrees C [82.4 degrees F]) hypothermic CPB. MEASUREMENTS AND MAIN RESULTS: The incidence of postoperative atrial fibrillation was determined by review of ICU and hospital records. There was a significantly higher incidence of atrial fibrillation in the moderate compared with the mild hypothermic CPB group. Patients who had postoperative atrial fibrillation were significantly older than those without atrial fibrillation. Furthermore, a significant increase in the relative risk of developing postoperative atrial fibrillation was found for both age and CPB temperature. CONCLUSIONS: Our results indicate that the temperature of systemic cooling during CPB is an important factor in the development of atrial fibrillation after CABG surgery. In addition, this study confirms that increasing age is a significant determinant of postoperative atrial fibrillation.