The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.

Trends in mortality from pneumonia in the Europe union: a temporal analysis of the European detailed mortality database between 2001 and 2014.

BACKGROUND: Pneumonia is responsible for approximately 230,000 deaths in Europe, annually. Comprehensive and comparable reports on pneumonia mortality trends across the European Union (EU) are lacking. METHODS: A temporal analysis of national mortality statistics to compare trends in pneumonia age-standardised death rates (ASDR) of EU countries between 2001 and 2014 was performed. International Classification of Diseases version 10 (ICD-10) codes were used to extract data from the World Health Organisation European Detailed Mortality Database and trends were analysed using Joinpoint regression. RESULTS: Median pneumonia mortality across the EU for the last recorded observation was 19.8 / 100,000 and 6.9 / 100,000 for males and females, respectively. Mortality was higher in males across all EU countries, most notably in Estonia and Lithuania where the ratio of male to female ASDR was 4.0 and 3.7, respectively. Gender mortality differences were lowest in the UK and Demark with ASDR ratios of 1.1 and 1.5, respectively. Pneumonia mortality across all countries decreased by a median of 31.0% over the observation period. Countries that demonstrated an increase in pneumonia mortality were Poland (males + 33.1%, females + 10.2%), and Lithuania (males + 6.0%). CONCLUSIONS: Mortality from pneumonia is improving in most EU countries, however substantial variation in trends remains between countries and between genders.

Discrepancy Between Achieved and Vendor-Predicted Ablation Zones in the Lung: Contributing Factors.

PURPOSE: Several factors are known to affect lung ablation zones. Questions remain as to why there are discrepancies between achieved and vendor-predicted ablation zones and what contributing factors can be modified to balance therapeutic effects with avoidance of complications. This retrospective study of lung tumour microwave ablation analyses day 1 post-treatment CT to assess the effects of lesion-specific and operator-dependent factors on ablation zones. METHODS AND MATERIALS: Consecutive patients treated at a tertiary centre from 2018 to 2021 were included. All ablations were performed using a single microwave ablation device under lung isolation. The lung tumours were categorised as primary or secondary, and their "resistance" to ablation was graded according to their locations. Intraprocedural pulmonary inflation was assessed as equal to or less than the contralateral non-isolated lung. Ablation energy was categorised as high, medium, or low. Ablation zone dimensions were measured on day 1 CT and compared to vendor reference charts. Ablations with multiple needle positions or indeterminate boundaries were excluded. RESULTS: A total of 47 lesions in 31 patients were analysed. Achieved long axes are longer than predicted by 5 mm or 14% (p < 0.01) without overall short axis discrepancy. Secondary tumours (p = 0.020), low-resistance location (p < 0.01), good lung inflation (p < 0.01), low (p = 0.003) and medium (p = 0.038) total energy produce lengthened long axes by 4-6 mm or 10-19%. High total energy results in shorter than predicated short axes by 6 mm or 18% (p = 0.010). CONCLUSION: We identified several factors affecting ablation zone dimensions which may have implications for ablation planning and the avoidance of complications.

Future Interventional Radiologists and Where to Find Them-Insights from Five UK Interventional Radiology Symposia for Junior Doctors and Medical Students.

BACKGROUND: The interventional radiology (IR) trainee recruitment in the UK is lagging behind the pace of service expansion and is potentially hindered by underrepresented undergraduate curricula. Understanding the contributing factors that encourage junior doctors and medical students to consider an IR career will help the IR community to better focus the efforts on recruiting and nurturing the next generation. METHODS: Anonymised questionnaires on undergraduate and postgraduate IR exposure were distributed to attendees of five UK IR symposia between 2019 and 2020. RESULTS: 220 responses were received from 103 (47%) junior doctors and 117 (53%) medical students. Prior IR exposure strongly correlates with individuals' positive views towards an IR career (Pearson's R = 0.40, p < 0.001), with involvement in clinical activities as the most important independent contributor (OR 3.6, 95%CI 1.21-10.50, p = 0.021). Longer time spent in IR (especially as elective modules) and IR-related portfolio-building experiences (such as participating in research, attending conferences and obtaining career guidance) demonstrate strong association with willingness to pursue an IR career for the more motivated (p values < 0.05). The symposia had overall positive effects on subjective likelihood to pursue an IR career, particularly among junior doctors who face near-term career choices (p < 0.001). CONCLUSION: Our study, focusing on a self-selected cohort, identified contributing factors to individuals' willingness to pursue an IR career. Symposia have additional recruitment effects in extra-curricular settings. Active engagement with junior doctors and medical students through clinical activities and non-clinical portfolio-related experiences are key to generate informed and motivated candidates for the future of IR.

Feasibility of combined screening for upper gastrointestinal adenocarcinoma risk by serology and Cytosponge testing: the SUGAR study.

AIMS: Aim was to assess the feasibility of serum markers to identify individuals at risk for gastro-oesophageal adenocarcinoma to reduce the number of individuals requiring invasive assessment by endoscopy. METHODS: Blood samples from 56 patients with Barrett's oesophagus and 202 non-Barrett controls who previously took part in a trial assessing the accuracy of the Cytosponge for Barrett's oesophagus were assessed for serum pepsinogen (PG) 1 and 2, gastrin-17, trefoil factor 3 (TFF3) and Helicobacter pylori infection. RESULTS: PG1 was pathological (<50 ng/mL) in 26 patients (10.1%), none of whom had Barrett's oesophagus (p<0.001). Smoking and drinking had no influence on these results. Pathological PG1 was associated with stomach pain (p=0.029), disruption of sleep (p=0.027) and disruption of diet by symptoms (p=0.019). Serum TFF3 was not associated with any clinical parameter. CONCLUSIONS: Assessment of serum PG1 could be combined with a test for Barrett's oesophagus to identify additional patients requiring endoscopy.