Native myocardial T1 and right ventricular size by CMR predict outcome in systemic sclerosis-associated pulmonary hypertension.

OBJECTIVES: Measures of right heart size and function are prognostic in systemic sclerosis-associated pulmonary hypertension (SSc-PH), but the importance of myocardial tissue characterisation remains unclear. We aimed to investigate the predictive potential and interaction of cardiovascular magnetic resonance (CMR) myocardial tissue characterisation and right heart size and function in SSc-PH. METHODS: A retrospective, single-centre, observational study of 148 SSc-PH patients confirmed by right heart catheterization who underwent clinically-indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2023 was performed. RESULTS: Sixty-six (45%) patients died during follow-up (median 3.5 years, range 0.1-7.3). Patients who died were older (65 vs 60 years, p= 0.035) with more dilated (RVEDVi and RVESVi, p< 0.001), hypertrophied (RVMi, p= 0.013) and impaired (RVEF, p< 0.001) right ventricles, more dilated right atria (RAi, p= 0.043) and higher native myocardial T1 (p< 0.001).After adjustment for age, RVESVi (p = 0.0023) and native T1 (p = 0.0024) were independent predictors of all-cause mortality. Both RVESVi and native T1 remained independently predictive after adjusting for age and PH subtype (RVESVi p < 0.001, T1 p = 0.0056). Optimal prognostic thresholds for RVESVi and native T1 were ≤38 mL/m2 and ≤1119 ms, respectively (p < 0.001). Patients with RVESVi ≤ 38 mL/m2 and native T1 ≤ 1119 ms had significantly better outcomes than all other combinations (p < 0.001). Furthermore, patients with RVESVi > 38mL/m2 and native T1 ≤ 1119 ms had significantly better survival than patients with RVESVi > 38mL/m2 and native T1 > 1119ms (p = 0.017). CONCLUSION: We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside RV function confers added value in SSc-PH and may represent an additional treatment target.

Artificial intelligence and machine learning for clinical pharmacology.

Artificial intelligence (AI) will impact many aspects of clinical pharmacology, including drug discovery and development, clinical trials, personalized medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation in clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner. This review serves as an introduction to AI for the clinical pharmacologist, highlighting current applications, aspects of model development and issues surrounding evaluation and deployment. The aim of this article is to empower clinical pharmacologists to embrace and lead on the safe and effective use of AI within healthcare.

Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis.

OBJECTIVES: We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc). METHODS: S100A4 protein concentration was measured by ELISA in serum of SSc (n=94) and healthy controls (n=15). Protein expression in skin fibroblast cultures from diffuse cutaneous SSc (SScF, n=6) and healthy controls (normal fibroblasts (NF), n=6) was assessed. Recombinant S100A4 and a high affinity anti-S100A4 neutralising monoclonal antibody (AX-202) were tested on SScF and NF. RESULTS: Median (range) S100A4 (ng/mL) was higher in serum of SSc (89.9 (15.0-240.0)) than healthy controls (71.4 (7.9-131.8); p=0.027). There was association with SSc-interstitial lung disease (p=0.025, n=55), scleroderma renal crisis (p=0.026, n=4). Median (range) S100A4 (ng/mL) was higher in culture supernatants of SScF (4.19 (0.52-8.42)) than NF controls (0.28 (0.02-3.29); p<0.0001). AX-202 reduced the constitutive profibrotic gene and protein expression phenotype of SScF. Genome-wide RNA sequencing analysis identified an S100A4 activated signature in NF overlapping the hallmark gene expression signature of SScF. Thus, 464 differentially expressed genes (false discovery rate (FDR) <0.001 and fold change (FC) >1.5) induced in NF by S100A4 were also constitutively overexpressed, and downregulated by AX-202, in SScF. Pathway mapping of these S100A4 dependent genes in SSc showed the most significant enriched Kegg pathways (FDR <0.001) were regulation of stem cell pluripotency (4.6-fold) and metabolic pathways (1.9-fold). CONCLUSION: Our findings provide compelling evidence for a profibrotic role for S100A4 in SSc and suggest that serum level may be a biomarker of major organ manifestations and disease severity. This study supports examining the therapeutic potential of targeting S100A4 in SSc.

Characteristics of adults with type 1 diabetes and treatment-resistant problematic hypoglycaemia: a baseline analysis from the HARPdoc RCT.

AIMS/HYPOTHESIS: Problematic hypoglycaemia still complicates insulin therapy for some with type 1 diabetes. This study describes baseline emotional, cognitive and behavioural characteristics in participants in the HARPdoc trial, which evaluates a novel intervention for treatment-resistant problematic hypoglycaemia. METHODS: We documented a cross-sectional baseline description of 99 adults with type 1 diabetes and problematic hypoglycaemia despite structured education in flexible insulin therapy. The following measures were included: Hypoglycaemia Fear Survey II (HFS-II); Attitudes to Awareness of Hypoglycaemia questionnaire (A2A); Hospital Anxiety and Depression Index; and Problem Areas In Diabetes. k-mean cluster analysis was applied to HFS-II and A2A factors. Data were compared with a peer group without problematic hypoglycaemia, propensity-matched for age, sex and diabetes duration (n = 81). RESULTS: The HARPdoc cohort had long-duration diabetes (mean ± SD 35.8 ± 15.4 years), mean ± SD Gold score 5.3 ± 1.2 and a median (IQR) of 5.0 (2.0-12.0) severe hypoglycaemia episodes in the previous year. Most individuals had been offered technology and 49.5% screened positive for anxiety (35.0% for depression and 31.3% for high diabetes distress). The cohort segregated into two clusters: in one (n = 68), people endorsed A2A cognitive barriers to hypoglycaemia avoidance, with low fear on HFS-II factors; in the other (n = 29), A2A factor scores were low and HFS-II high. Anxiety and depression scores were significantly lower in the comparator group. CONCLUSIONS/INTERPRETATION: The HARPdoc protocol successfully recruited people with treatment-resistant problematic hypoglycaemia. The participants had high anxiety and depression. Most of the cohort endorsed unhelpful health beliefs around hypoglycaemia, with low fear of hypoglycaemia, a combination that may contribute to persistence of problematic hypoglycaemia and may be a target for adjunctive psychological therapies.

Autoantibody predictors of gastrointestinal symptoms in systemic sclerosis.

OBJECTIVES: To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics. METHODS: Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses. RESULTS: Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease. CONCLUSION: There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective.

Verdict spotting: investigating the effects of juror bias, evidence anchors and verdict system in jurors.

The Scottish verdict of not proven represents a second acquittal verdict which is not legally defined. Existing research into the influence of the not proven verdict on jury decision making is modest. The main aim of the current study was therefore to investigate the influence of verdict systems (two vs three) on juror decision making. The effect of pre-trial bias and evidence anchors on juror judgements were also examined. One-hundred and twenty-eight mock jurors listened to two homicide vignettes and were asked to rate their belief of guilt of the accused and to give a verdict in both trials. The results suggest that pre-trial bias was a significant predictor of both verdict choice and belief of guilt, whereas evidence anchors were not a significant predictor of either. Finally, both guilty and not guilty verdicts were given with increased frequency in the two-verdict system when compared to the three-verdict system.

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.

Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer.

Threshold point utilisation in juror decision-making.

This study aims to identify whether a model of juror decision-making (i.e. the threshold point model) that encompasses both rational and intuitive decision-making exists. A total of 60 participants were selected who are eligible for jury duty in Scotland. These individuals read nine vignettes and rated the evidence of each vignette separately by placing the evidence in either a guilty, a not guilty or a not proven (a verdict type specific to Scotland) counter. Participants were asked after being presented with each piece of information to state how likely they thought the suspect was of being guilty, on a scale from 1 to 100. The data are best described using a flexible model (i.e. a diffusion model) that allows for information integration. Future research should examine whether or not the diffusion model can explain cognitive fallacies, such as confirmation bias, that are commonly studied in decision science.

Life satisfaction in people with post-traumatic stress disorder.

BACKGROUND/AIMS: There is limited research on the association between post-traumatic stress disorder (PTSD) and life satisfaction in community samples. We set out to investigate levels of life satisfaction and its demographic, trauma related and clinical predictors in a sample of people with PTSD (n = 46). METHODS: Participants completed a battery of standardised self-report measures including Satisfaction with Life Scale, the PTSD Checklist and The Hospital Anxiety and Depression Scale. RESULTS: Our results indicated that people with moderately severe PTSD in the community are likely to experience lower levels of life satisfaction compared with those with other psychiatric conditions or those without any diagnoses. Multivariate analysis revealed that marital status and trauma symptoms were the only significant predictors of life satisfaction. In specific, being married and presenting with less severe posttraumatic symptomatology were both significantly associated with higher levels of life satisfaction in people with PTSD. CONCLUSIONS: The strong association between traumatic symptomatology and life satisfaction may indicate that routine assessment for life satisfaction or similar positive constructs in people with PTSD, referred for psychological therapies might be useful. Information on positive psychology constructs may facilitate capitalising on clients' strengths and not just on pathology.

Clinician perception of pathological narcissism in females: a vignette-based study.

The DSM-5 reports that up to 75% of those diagnosed with Narcissistic Personality Disorder (NPD) are males, which denotes that narcissism is a clinical phenomenon that operates differently in men and women. Vulnerable narcissism, which tends to be more prevalent in females and is currently under-appreciated in the DSM-5, may be diagnosed as other "vulnerable" disorders (e.g., Borderline Personality Disorder; BPD). The current study investigated gender differences in clinicians' perceptions of narcissistic pathology. Adopting an online vignette-based study, clinicians (N = 108; 79 females) read clinical case vignettes of hypothetical patients and provided diagnostic ratings of existing personality disorders. Clinicians' diagnostic ratings of NPD were concurrent with the vignette containing grandiose narcissism symptoms, irrespective of patient gender. However, when presented with a vulnerable narcissism vignette, clinicians were significantly more likely to attribute a BPD diagnosis in female patients, compared to male patients. Clinicians with a psychodynamic approach and more experience in practice were also more likely to label vulnerable narcissism symptoms as NPD, compared to those with a CBT approach and less experience in practice. The clinical implications of these results support the shift toward assessing personality dysfunction based on dimensional trait domains.

A Phenome-Wide Association Study of Drugs and Comorbidities Associated With Gastrointestinal Dysfunction in Systemic Sclerosis.

OBJECTIVE: To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data. METHODS: Twelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIBO]) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire. RESULTS: One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs. CONCLUSION: Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.

Improving outcomes in carcinoid heart disease - learning from a single centre.

INTRODUCTION: A significant proportion of patients with carcinoid syndrome develop carcinoid heart disease (CHD). Valve degeneration can lead to right heart failure, and worsening prognosis. Replacement of affected valves is an effective therapy. We reviewed patients treated with valve replacement to assess prognostic factors. METHODS: CHD patients records who underwent valve replacement from 2003-2019 were reviewed. RESULTS: Twenty-six patients underwent valve replacement. Mean (SD) age was 61 (11) years, 54% female. Eleven tumours were grade G1, with the remaining G2. NYHA pre-surgery mean (SD) 2.0 (0.7); post-surgery mean 1.2; follow-up mean (SD) 1.6 (0.8). Mean NYHA score difference from pre- to post-surgery -0.71 ( P  = 0.002). 88.5% two (PR & TR), 3.9% one, 3.9% three and 3.9% four valves replaced. 13 patients received Lu177 oxodotreotide; 27% completed four cycles. Mortality at 1 and 5 years follow up was 42% and 50% respectively. Cox proportional hazards model of survival from surgery, adjusting for age [hazard ratio (HR) 0.96 (0.89-1.03) ( P  = 0.25)], four cycles of Lu177 oxodotreotide demonstrated HR 0.087 (0.0079-0.95) ( P  = 0.045) indicating improved survival. DISCUSSION: Surgical patients were often NYHA grade II, and symptoms improved post-surgery. Four cycles of Lu177 oxodotreotide improved survival, although the confidence interval was wide. Further studies should be performed to assess Lu177 oxodotreotide in CHD.

Distinct cardiovascular phenotypes are associated with prognosis in systemic sclerosis: a cardiovascular magnetic resonance study.

AIMS: Cardiovascular involvement in systemic sclerosis (SSc) is heterogeneous and ill-defined. This study aimed to: (i) discover cardiac phenotypes in SSc by cardiovascular magnetic resonance (CMR); (ii) provide a CMR-based algorithm for phenotypic classification; and (iii) examine for associations between phenotypes and mortality. METHODS AND RESULTS: A retrospective, single-centre, observational study of 260 SSc patients who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2019 was performed. Agglomerative hierarchical clustering using only CMR variables revealed five clusters of SSc patients with shared CMR characteristics: dilated right hearts with right ventricular failure (RVF); biventricular failure dilatation and dysfunction (BVF); and normal function with average cavity (NF-AC), normal function with small cavity (NF-SC), and normal function with large cavity (NF-LC) sizes. Phenotypes did not co-segregate with clinical or antibody classifications. A CMR-based decision tree for phenotype classification was created. Sixty-three (24%) patients died during a median follow-up period of 3.4 years. After adjustment for age and presence of pulmonary hypertension (PH), independent CMR predictors of all-cause mortality were native T1 (P < 0.001) and right ventricular ejection fraction (RVEF) (P = 0.0032). NF-SC and NF-AC groups had more favourable prognoses (P≤0.036) than the other three groups which had no differences in prognoses between them (P > 0.14). Hazard ratios (HR) were statistically significant for RVF (HR = 8.9, P < 0.001), BVF (HR = 5.2, P = 0.006), and NF-LC (HR = 4.9, P = 0.002) groups. The NF-LC group remained significantly predictive of mortality after adjusting for RVEF, native T1, and PH diagnosis (P = 0.0046). CONCLUSION: We identified five CMR-defined cardiac SSc phenotypes that did not co-segregate with clinical data and had distinct outcomes, offering opportunities for a more precision-medicine based management approach.

Female Narcissism: Assessment, Aetiology, and Behavioural Manifestations.

Despite putative gender differences in the expression of narcissism, prominent theories have virtually dismissed the role of females in the development and manifestation of narcissism. The contention that narcissism is a pathology of the self that may partly differ in males and females is further evident in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-5 reports that up to 75% of those diagnosed with Narcissistic Personality Disorder (NPD) are men. Such figures suggest that the representation of narcissism as codified in the DSM-5 may only be marginally applicable to females, given its prominent focus and nature on capturing grandiose themes which closely resemble commonly masculine norms. The overemphasis on grandiose features extends to the empirical literature which defines narcissism as a normative personality trait and is widely assessed using the Narcissistic Personality Inventory (NPI), on which males obtain significantly higher scores than females. As this review will demonstrate, one limitation frequently occurring in the literature is the attempt to comprehend narcissistic manifestations in females through the lens of what has commonly been defined as narcissism (DSM/NPI). In this review, the literature concerning the diagnostic assessment and conceptualisation of narcissistic personality disorder, aetiological factors, aggression, and partner violence perpetration will be discussed in relation to the importance of gender. This is followed by a review of existing gaps in theory and research, and suggestions for fruitful directions that can aid a richer and more meaningful literature on narcissism inclusive of gender issues.

Hypoglycemia Subtypes in Type 1 Diabetes: An Exploration of the Hypoglycemia Fear Survey-II.

OBJECTIVE: The Hypoglycemia Fear Survey-II (HFS-II) is a well-validated measure of fear of hypoglycemia in people with type 1 diabetes. The aim of this study was to explore the relationships between hypoglycemia worries, behaviors, and cognitive barriers to hypoglycemia avoidance and hypoglycemia awareness status, severe hypoglycemia, and HbA1c. RESEARCH DESIGN AND METHODS: Participants with type 1 diabetes (n = 178), with the study population enriched for people at risk for severe hypoglycemia (49%), completed questionnaires for assessing hypoglycemia fear (HFS-II), hyperglycemia avoidance (Hyperglycemia Avoidance Scale [HAS]), diabetes distress (Problem Areas In Diabetes [PAID]), and cognitive barriers to hypoglycemia avoidance (Attitudes to Awareness of Hypoglycemia [A2A]). Exploratory factor analysis was applied to the HFS-II. We sought to establish clusters based on HFS-II, A2A, Gold, HAS, and PAID using k-means clustering. RESULTS: Four HFS-II factors were identified: Sought Safety, Restricted Activity, Ran High, and Worry. While Sought Safety, Restricted Activity, and Worry increased with progressively impaired awareness and recurrent severe hypoglycemia, Ran High did not. With cluster analysis we outlined four clusters: two clusters with preserved hypoglycemia awareness were differentiated by low fear/low cognitive barriers to hypoglycemia avoidance (cluster 1) versus high fear and distress and increased Ran High behaviors (cluster 2). Two clusters with impaired hypoglycemia awareness were differentiated by low fear/high cognitive barriers (cluster 3) as well as high fear/low cognitive barriers (cluster 4). CONCLUSIONS: This is the first study to define clusters of hypoglycemia experience by worry, behaviors, and cognitive barriers to hypoglycemia avoidance. The resulting subtypes may be important in understanding and treating problematic hypoglycemia.

Assessing Cognitive Bias in Forensic Decisions: A Review and Outlook.

In recent years, a number of studies have demonstrated that forensic examiners can be biased by task-irrelevant contextual information. However, concerns relating to methodological flaws and ecological validity attenuate how much the current body of knowledge can be applied to real-life operational settings. The current review takes a narrative approach to synthesizing the literature across forensic science. Further, the review considers three main issues: (i) primary research on contextual bias within forensic science; (ii) methodological criticisms of this research; (iii) an alternative perspective that task-irrelevant contextual information does not always lead to error. One suggestion for future research is outlined, which is that studies on contextual bias in forensic decisions should be conducted in collaboration between forensic scientists and cognitive psychologists. Only then can rigorous and ecological valid experiments be created that will be able to assess how task-irrelevant contextual information influences forensic analysis and judgments in operationally valid settings.

Trialstreamer: A living, automatically updated database of clinical trial reports.

OBJECTIVE: Randomized controlled trials (RCTs) are the gold standard method for evaluating whether a treatment works in health care but can be difficult to find and make use of. We describe the development and evaluation of a system to automatically find and categorize all new RCT reports. MATERIALS AND METHODS: Trialstreamer continuously monitors PubMed and the World Health Organization International Clinical Trials Registry Platform, looking for new RCTs in humans using a validated classifier. We combine machine learning and rule-based methods to extract information from the RCT abstracts, including free-text descriptions of trial PICO (populations, interventions/comparators, and outcomes) elements and map these snippets to normalized MeSH (Medical Subject Headings) vocabulary terms. We additionally identify sample sizes, predict the risk of bias, and extract text conveying key findings. We store all extracted data in a database, which we make freely available for download, and via a search portal, which allows users to enter structured clinical queries. Results are ranked automatically to prioritize larger and higher-quality studies. RESULTS: As of early June 2020, we have indexed 673 191 publications of RCTs, of which 22 363 were published in the first 5 months of 2020 (142 per day). We additionally include 304 111 trial registrations from the International Clinical Trials Registry Platform. The median trial sample size was 66. CONCLUSIONS: We present an automated system for finding and categorizing RCTs. This yields a novel resource: a database of structured information automatically extracted for all published RCTs in humans. We make daily updates of this database available on our website (https://trialstreamer.robotreviewer.net).

Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes. METHODS: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. FINDINGS: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. INTERPRETATION: Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new 'precision medicine' for carriers of these inactive ALDH2.

The bastard verdict and its influence on jurors.

The Scottish legal system is a unique jurisdiction, as jurors are able to give not proven verdicts in addition to the well-known Anglo-American verdicts (guilty and not guilty). The not proven verdict has never been legally defined, meaning that currently legal practitioners can only estimate why a not proven verdict has been given. The main aim of this study was to investigate if jurors violate the regularity principle, which is commonly incorporated in many rational choice models, by testing if the introduction of the not proven verdict has an impact on the outcomes given by jurors. In addition, this study aimed to test if the introduction of the not proven verdict has an impact upon how the not guilty verdict is perceived by jurors. In this study, 128 participants listened to two vignettes centred on homicide trials. Jurors could give one of two verdicts in one of the vignettes and one of three verdicts in the other vignette. The vignettes were counterbalanced in regard to how many verdicts could be given at the end of them. It was found that jurors in a three-verdict system were less likely to give a not guilty verdict in comparison to jurors in a two-verdict system, showing that jurors violate the regularity principle and that the not proven verdict may change how the not guilty verdict is perceived. The findings of this research have implications in relation to juror communication, article 6 of the European Convention of Human Rights and juror rationality.

Faith in thy threshold.

The current study focussed on the decision-making processes of jurors. The study investigated how jurors make a decision, if they integrate information within their decision-making process and if cue utilisation thresholds promote confirmation bias. To do this, 108 participants listened to one of nine cases. These participants were asked to give a likelihood of guilt rating after each piece of evidence, to state what the last piece of information was that they needed to make a decision and to give a final verdict at the end of a trial. The results highlighted that threshold decision making was being utilised, that information integration may allow thresholds to be reached and that thresholds may promote confirmation bias to reduce cognitive dissonance. In conclusion, this suggests that jurors integrate information until they reach a leading verdict, then the evaluation of information is distorted to support the leading threshold. Implications relate to legal instructions for jurors.