Longitudinal structure-function analysis of molecularly-confirmed CYP4V2 Bietti Crystalline Dystrophy

Objectives: Bietti Crystalline Dystrophy (BCD) is an autosomal recessive progressive retinal disease caused by mutations in CYP4V2. We have characterised the natural history including structural and functional measures to identify potential outcome metrics for future clinical trials. Methods: Molecularly-confirmed BCD patients with biallelic variants in CYP4V2 were retrospectively identified from Moorfields Eye Hospital (UK). Clinical details including results of molecular genetic testing, best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (OCT) scans were extracted. From OCT scans, ellipsoid zone (EZ) measures, foveal thickness of the whole retina, outer retina and choroid were measured. Age-related changes of clinical parameters were assessed with linear mixed models. Results: Twenty-eight BCD patients were identified, with median age at baseline of 37 years (interquartile range [IQR]: 30–49.5). Median follow-up was 7.7 years (IQR: 3.4–14.5). Most patients (41.7%) showed chorioretinal atrophy at baseline. All OCT parameters showed significant age-related loss (p < 0.05), with EZ measures and choroidal thickness displaying the most rapid degeneration (2.3–3.3% per year vs 0.6–1.5% per year). Median BCVA was 0.2 LogMAR (IQR: 0–0.5) at baseline and showed small age-related loss ( + 0.016 LogMAR per year, p = 0.0019). Patients exhibited substantial phenotypic variability. Conclusions: BCD presents between age 25 and 40, and slowly progresses to an advanced chorioretinal atrophy and vision loss by age 60. BCVA may be preserved until late, and is seemingly poorly representative of disease progression. OCT parameters capturing EZ and choroid changes may afford more suitable trial outcome measures

Perception of Risk and Terrorism-Related Behavior Change: Dual Influences of Probabilistic Reasoning and Reality Testing

The present study assessed the degree to which probabilistic reasoning performance and thinking style influenced perception of risk and self-reported levels of terrorism-related behaviour change. A sample of 263 respondents, recruited via convenience sampling, completed a series of measures comprising probabilistic reasoning tasks (perception of randomness, base rate, probability, and conjunction fallacy), the Reality Testing subscale of the Inventory of Personality Organization (IPO-RT), the Domain-Specific Risk-Taking Scale, and a terrorism-related behaviour change scale. Structural equation modelling examined three progressive models. Firstly, the Independence Model assumed that probabilistic reasoning, perception of risk and reality testing independently predicted terrorism-related behaviour change. The Mediation Model supposed that probabilistic reasoning and reality testing correlated, and indirectly predicted terrorism-related behaviour change through perception of risk. Lastly, the Dual-Influence Model proposed that probabilistic reasoning indirectly predicted terrorism-related behaviour change via perception of risk, independent of reality testing. Results indicated that performance on probabilistic reasoning tasks most strongly predicted perception of risk, and preference for an intuitive thinking style (measured by the IPO-RT) best explained terrorism-related behaviour change. The combination of perception of risk with probabilistic reasoning ability in the Dual-Influence Model enhanced the predictive power of the rational-analytical route, with conjunction fallacy having a significant indirect effect on terrorism-related behaviour change via perception of risk. The Dual-Influence Model possessed superior fit and reported similar predictive relations between intuitive-experiential and analytical-rational routes and terrorism-related behaviour change. The discussion critically examines these findings in relation to dual-processing frameworks. This includes considering the limitations of current operationalisations and recommendations for future research that align outcomes and subsequent work more closely to specific dual-process models

Psychometric Assessment of Shortened Mental Toughness Questionnaires (MTQ): Factor Structure of the MTQ-18 and the MTQ-10

The 18-item Mental Toughness Questionnaire (MTQ-18) is a brief, widely used measure of mental toughness. The MTQ-18 derives from the longer MTQ-48, which comprises four independent but correlated factors (Challenge, Commitment, Control and Confidence). Despite sampling items from across MTQ-48 dimensions, the MTQ-18 (as intended) provides a global, unidimensional score. Researchers have recently developed a further abridged version of the MTQ-18, the MTQ-10, which has demonstrated promising psychometric performance. The current paper assessed the factorial structure, reliability, predictive validity and invariance of the MTQ-18 and MTQ-10 in a sample of 944 students from English independent schools (year 11, aged 16 years). Respondents completed the MTQ-18 items online alongside the Satisfaction with Life Scale. Confirmatory factor analysis revealed that the MTQ-10 was a superior general measure, because the MTQ-18 possessed additional variance to that accounted for by a unidimensional solution. Additionally, the MTQ-10 evidenced higher factor loadings and demonstrated better data-model fit. Tests of concurrent validity revealed the MTQ-10 was a stronger predictor of well-being (life satisfaction). Both the MTQ-18 and MTQ-10 demonstrated gender invariance at the configural, metric and scalar level. Overall, although the MTQ-18 was a psychometrically acceptable measure, the MTQ-10 was a superior unidimensional measure of MT

The Relationship Between Mental Toughness, Job Loss, and Mental Health Issues During the COVID-19 Pandemic

Concerns toward public well-being and mental health are increasing considering the COVID-19 pandemic's global societal and individual impact. The present study builds on the current body of COVID-19 literature by examining the role of mental toughness (MT) in predicting negative affective states (depression, anxiety and stress) during the pandemic. The study also examined the effects of changes in employment on mental health and MT. Participants (N = 723) completed a battery of questionnaires including the Mental Toughness Questionnaire 48-item, The State-Trait Anxiety Inventory, and the Depression, Anxiety and Stress Scale – 21 items. Participants reported relatively higher levels of depression, stress and anxiety in comparison to pre-COVID-19 samples from previous research, with respondents who had lost their jobs during the pandemic reporting higher levels of negative affective states. Despite this, mentally tough individuals appeared to report lower levels of depression, anxiety and stress. Moreover, moderation analyses identified some interaction between MT and employment status when predicting depression, anxiety and stress. Our findings suggest that MT may have some utility in reducing the adverse mental health effects of the pandemic on individuals, however, further longitudinal research is needed to support these implications

Tandem quadruplication of HMA4 in the zinc (Zn) and cadmium (Cd) hyperaccumulator noccaea caerulescens

Zinc (Zn) and cadmium (Cd) hyperaccumulation may have evolved twice in the Brassicaceae, in Arabidopsis halleri and in the Noccaea genus. Tandem gene duplication and deregulated expression of the Zn transporter, HMA4, has previously been linked to Zn/Cd hyperaccumulation in A. halleri. Here, we tested the hypothesis that tandem duplication and deregulation of HMA4 expression also occurs in Noccaea. A Noccaea caerulescens genomic library was generated, containing 36,864 fosmid pCC1FOSTM clones with insert sizes ~20–40 kbp, and screened with a PCR-generated HMA4 genomic probe. Gene copy number within the genome was estimated through DNA fingerprinting and pooled fosmid pyrosequencing. Gene copy numbers within individual clones was determined by PCR analyses with novel locus specific primers. Entire fosmids were then sequenced individually and reads equivalent to 20-fold coverage were assembled to generate complete whole contigs. Four tandem HMA4 repeats were identified in a contiguous sequence of 101,480 bp based on sequence overlap identities. These were flanked by regions syntenous with up and downstream regions of AtHMA4 in Arabidopsis thaliana. Promoter-reporter b-glucuronidase (GUS) fusion analysis of a NcHMA4 in A. thaliana revealed deregulated expression in roots and shoots, analogous to AhHMA4 promoters, but distinct from AtHMA4 expression which localised to the root vascular tissue. This remarkable consistency in tandem duplication and deregulated expression of metal transport genes between N. caerulescens and A. halleri, which last shared a common ancestor >40 mya, provides intriguing evidence that parallel evolutionary pathways may underlie Zn/Cd hyperaccumulation in Brassicaceae

The Moderating Effect of Mental Toughness: Perception of Risk and Belief in the Paranormal

This research demonstrates that higher levels of mental toughness provide cognitive-perceptual processing advantages when evaluating risk. No previous research, however, has examined mental toughness in relation to perception of risk and paranormal belief (a variable associated with distorted perception of causality and elevated levels of perceived risk). Accordingly, the present paper investigated relationships between these factors. A sample of 174 participants completed self-report measures assessing mental toughness, general perception of risk, and paranormal belief. Responses were analyzed via correlations and moderation analyses. Results revealed that mental toughness correlated negatively with perception of risk and paranormal belief, whereas paranormal belief correlated positively with perception of risk. For the moderation effects, simple slopes analyses indicated that high levels of MT and subfactors of commitment and confidence reduced the strength of association between paranormal belief and perceived risk. Therefore, MT potentially acts as a protective factor among individuals who believe in the paranormal, reducing the tendency to perceive elevated levels of risk

Cometary diversity and cometary families

Comets are classified from their orbital characteristics into two separate classes: nearly-isotropic, mainly long-period comets and ecliptic, short-period comets. Members from the former class are coming from the Oort cloud. Those of the latter class were first believed to have migrated from the Kuiper belt where they could have been accreted in situ, but recent orbital evolution simulations showed that they rather come from the trans-Neptunian scattered disc. These two reservoirs are not where the comets formed: they were expelled from the inner Solar System following interaction with the giant planets. If comets formed at different places in the Solar System, one would expect they show different chemical and physical properties. In the present paper, I review which differences are effectively observed: chemical and isotopic compositions, spin temperatures, dust particle properties, nucleus properties... and investigate whether these differences are correlated with the different dynamical classes. The difficulty of such a study is that long-period, nearly-isotropic comets from the Oort cloud are better known, from Earth-based observations, than the weak nearly-isotropic, short-period comets. On the other hand, only the latter are easily accessed by space missions.Comment: Proceedings of the XVIIIemes Rencontres de Blois: Planetary Science: Challenges and Discoveries, 28th May - 2nd June 2006, Blois, Franc

The lancet weight determines wheal diameter in response to skin prick testing with histamine

BACKGROUND:Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization. OBJECTIVE:Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort. METHODS:Accurate weight-controlled SPT was performed on the volar forearms and backs of 20 healthy subjects. Four predetermined lancet weights were applied (25 g, 85 g, 135 g and 265 g) using two positive control histamine solutions (1 mg/mL and 10 mg/mL) and one negative control (saline). A total of 400 SPTs were conducted. The outcome parameters were: wheal size, neurogenic inflammation (measured by superficial blood perfusion), frequency of bleeding, and the lancet provoked pain response. RESULTS:The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm. CONCLUSION AND CLINICAL RELEVANCE:The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease

Background: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. Objectives: To assess effects of increasing PUFA intake on cardiovascular disease (CVD) and all-cause mortality in adults. Search method: We searched CENTRAL, MEDLINE and Embase to April 2017 and ClinicalTrials.com and World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. Selection criteria: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without CVD that assessed effects over ≥12 months. We included full-text, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, CVD mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. Data collection and analysis: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included studies for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. Main result: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Twelve included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA. Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 3.4% vs 3.3% in primary prevention, 11.7% vs 11.5% in secondary prevention, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 24 trials in 19290 participants), but probably reduces risk of CVD events from 5.8% to 4.9% in primary prevention, 23.3% to 20.8% in secondary prevention (RR 0.89, 95% CI 0.79 to 1.01, 20 trials in 17,073 participants), both moderate quality evidence. Increasing PUFA may reduce risk of CHD events from 13.4% to 7.1% primary prevention, 14.3% to 13.7% secondary prevention (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants), CHD death (5.2% to 4.4% primary prevention, 6.8% to 6.1% secondary prevention, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) and may slightly reduce stroke risk (2.1% to 1.5% primary prevention, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, I2 31%, 16 trials, 15,107 participants) all low quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality. Event outcomes were all downgraded for indirectness, as most events occurred in men in westernised countries. Increasing PUFA intake reduces total cholesterol (MD -0.12 mmol/L, 95% CI -0.23 to -0.02, I2 79%, 8072 participants, 26 trials) and probably decreases triglycerides (TG, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, I2 50%, 3905 participants, 20 trials), but has little or no effect on HDL (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, I2 0%, 4674 participants, 18 trials) and LDL (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, I2 44%, 3362 participants, 15 trials). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, I2 59%, 7100 participants, 12 trials). Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. Authors' conclusions: Increasing PUFA intake probably reduces risk of CVD events, may reduce risk of CHD events and CHD mortality,and may slightly reduce stroke risk, but has little or no effect on all-cause or CVD mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease

Background: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. Objectives: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. Search methods: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. Selection criteria: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. Data collection and analysis: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. Main results: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and it may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low-quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence), and probably reduces risk of CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs), and arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear. Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression. There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, although LCn3 slightly reduced triglycerides and increased HDL. ALA probably reduces HDL (high- or moderate-quality evidence). Authors' conclusions: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event risk, CHD mortality and arrhythmia