Asymmetric bulges within hairpin RNA transgenes influence small RNA size, secondary siRNA production and viral defence.

Small RNAs (sRNAs) are essential for normal plant development and range in size classes of 21-24 nucleotides. The 22nt small interfering RNAs (siRNAs) and miRNAs are processed by Dicer-like 2 (DCL2) and DCL1 respectively and can initiate secondary siRNA production from the target transcript. 22nt siRNAs are under-represented due to competition between DCL2 and DCL4, while only a small number of 22nt miRNAs exist. Here we produce abundant 22nt siRNAs and other siRNA size classes using long hairpin RNA (hpRNA) transgenes. By introducing asymmetric bulges into the antisense strand of hpRNA, we shifted the dominant siRNA size class from 21nt of the traditional hpRNA to 22, 23 and 24nt of the asymmetric hpRNAs. The asymmetric hpRNAs effectively silenced a ß-glucuronidase (GUS) reporter transgene and the endogenous ethylene insensitive-2 (EIN2) and chalcone synthase (CHS) genes. Furthermore, plants containing the asymmetric hpRNA transgenes showed increased amounts of 21nt siRNAs downstream of the hpRNA target site compared to plants with the traditional hpRNA transgenes. This indicates that these asymmetric hpRNAs are more effective at inducing secondary siRNA production to amplify silencing signals. The 22nt asymmetric hpRNA constructs enhanced virus resistance in plants compared to the traditional hpRNA constructs.

G-U base-paired hpRNA confers potent inhibition of small RNA function in plants.

MicroRNA (miRNA) target mimicry technologies, utilizing naturally occurring miRNA decoy molecules, represent a potent tool for analyzing miRNA function. In this study, we present a highly efficient small RNA (sRNA) target mimicry design based on G-U base-paired hairpin RNA (hpG:U), which allows for the simultaneous targeting of multiple sRNAs. The hpG:U constructs consistently generate high amounts of intact, polyadenylated stem-loop (SL) RNA outside the nuclei, in contrast to traditional hairpin RNA designs with canonical base pairing (hpWT), which were predominantly processed resulting in a loop. By incorporating a 460-bp G-U base-paired double-stranded stem and a 312-576 nt loop carrying multiple miRNA target mimicry sites (GUMIC), the hpG:U construct displayed effective repression of three Arabidopsis miRNAs, namely miR165/166, miR157, and miR160, both individually and in combination. Additionally, a GUMIC construct targeting a prominent cluster of siRNAs derived from cucumber mosaic virus (CMV) Y-satellite RNA (Y-Sat) effectively inhibited Y-Sat siRNA-directed silencing of the chlorophyll biosynthetic gene CHLI, thereby reducing the yellowing symptoms in infected Nicotiana plants. Therefore, the G-U base-paired hpRNA, characterized by differential processing compared to traditional hpRNA, acts as an efficient decoy for both miRNAs and siRNAs. This technology holds great potential for sRNA functional analysis and the management of sRNA-mediated diseases.

Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. METHODS: APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 µmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days -1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). FINDINGS: APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (-63%, SD 20) compared with placebo (1%, 29; least squares mean change -395·9 µmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. INTERPRETATION: Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. FUNDING: PTC Therapeutics.

Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Nutritional assessment and management in acute pancreatitis: Ongoing lessons of the NCEPOD report.

INTRODUCTION: Acute pancreatitis (AP) is a medical emergency that is common, poorly understood and carries a significant risk of death. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) undertook a comprehensive report into the current management of AP in the UK. The study aimed to provide a more detailed analysis of the findings related to nutritional assessment and support. METHODS: The data presented here were analysed from the core dataset used in the NCEPOD study. Adult patients admitted between January and June 2014 with a coded diagnosis of AP were included. A clinical and organisational questionnaire was used to collect data and submitted case notes subjected to peer review. Nutritional data, including assessment and provision of support, were analysed. RESULTS: One hundred and forty-seven out of 168 (87.5%) hospitals had a nutrition team in place. A screening nutritional assessment was performed in only 67.4% (368/546) of patients. Subsequent referral to a dietitian and nutrition team input occurred in 39% (201/521) and 25% (143/572) of patients, respectively. Supplemental nutrition was considered and used in 240/555 (43.2%) patients. Overall management of the patients' nutrition was considered adequate by the case reviewers in only 281/332 (85%) of cases and by the clinicians in 77% (421/555) of cases. CONCLUSIONS: Many patients do not receive adequate nutritional assessment and, in up to 23% of cases, nutritional intervention is not adequate. Pancreatic exocrine insufficiency is likely under recognised and undertreated. Nutritional strategies to support early intervention and to support clinicians outside of tertiary pancreatic centres are warranted.

Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. METHODS: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 µg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. RESULTS: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; p < 0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (area under receiver operating characteristic curve KP54: 1.0, 95% CI 1.0-1.0; GnRH: 0.88, 95% CI 0.76-0.99). Indeed, all CHH men had an LH rise <2.0 iU/L following KP54, whereas all healthy men had an LH rise >4.0 iU/L. Anosmic men with CHH (i.e., Kallmann syndrome) had even lower LH rises after KP54 than did normosmic men with CHH (p = 0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH rises after KP54 than other men with CHH (p = 0.035). CONCLUSION: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with CHH.

Evaluating co-created patient-facing materials to increase understanding of genetic test results.

Patients often have difficulty understanding genetic test reports. Technical language and jargon can impede comprehension and limit patients using results to act on findings. One potential way to improve patient understanding of genetic test reports is to provide patient-facing materials. This study aimed to examine understandability and actionability of co-created patient-facing materials for genetic test results in a research context. We combined interprofessional perspectives and patient engagement to co-create patient-facing materials for patients undergoing research genetic testing for congenital hypogonadotropic hypogonadism (Kallmann syndrome). The iterative development process was guided by principles of health literacy and human-centered design (i.e., design thinking). Readability was assessed using eight validated algorithms. Patients and parents evaluated materials using a web-based survey. The gold standard Patient Education Materials Assessment Tool for print materials (PEMAT-P) was employed to measure understandability (content, style, use of numbers, organization, design, use of visual aids) and actionability. PEMAT-P scores >80% were considered high quality. Results were analyzed descriptively and correlations performed to identify relationships between education/health literacy and PEMAT-P ratings. A consensus score of eight algorithms indicated the materials were an 8th -9th grade reading level. Our findings are consistent with the U.S. Department of Health and Human Services 'average difficulty' classification (i.e., 7th-9th grade). In total, 61 patients/parents evaluated the materials. 'Visual Aids' received the lowest mean PEMAT-P rating (89%). All other parameters scored 90%-97%. PEMAT-P scores did not differ according to educational attainment (less than college vs. college or more, p = 0.28). Participants with adequate health literacy were more likely to approve of the 'organization' of information (p < 0.05). Respondents with low health literacy had more favorable views of 'visual aids' (p < 0.01). Involving patients in a co-creation process can produce high-quality patient-facing materials that are easier to understand.

Management of venous thromboembolism in patients experiencing direct oral anticoagulant treatment failure: a single-center review of practice and outcomes.

Direct oral anticoagulants (DOACs) have gained in popularity over vitamin K antagonists for the treatment of venous thromboembolism, however their efficacy is not routinely monitored. It is therefore a clinical challenge to know how to respond when treatment with DOACs fails, and there is little formal guidance on how to manage these patients. We sought to characterize VTE patients who experienced DOAC failure at our institution, and rationalize subsequent treatment strategies. We collated the details of 54 consecutive patients with suboptimal response or breakthrough thrombosis on a DOAC, from our large specialist-led thrombosis clinic. Initial treatment changes were recorded, as well as long-term anticoagulation therapy and treatment outcomes. On first recognition of DOAC failure, 69% of patients were temporarily switched to therapeutic-dose low molecular weight heparin; most of the remaining patients were treated with an alternative DOAC regimen. After a limited period of parenteral treatment, 84% of patients returned to oral anticoagulation, the majority of whom experienced no further treatment failures. By the end of follow-up, 72% of patients were either on long-term DOAC therapy or had completed treatment altogether. In the absence of evidence or guidelines, brief rescue of anticoagulation with parenteral therapy can be an effective strategy when treatment with a DOAC fails.

An open-label, randomised controlled trial on the effectiveness of the Orve + wrap® versus Forced Air Warming in restoring normothermia in the postanaesthetic care unit.

AIMS AND OBJECTIVES: To determine the clinical effectiveness and safety of the Orve + wrap® thermal blanket. BACKGROUND: Inadvertent perioperative hypothermia is a common problem in postanaesthetic care units and can have significant effects on patients' postoperative morbidity. Despite its commercial availability, there is no clinical evidence on the effectiveness of Orve + wrap®. DESIGN: A single centre prospective, open-label, noninferiority randomised controlled trial. METHODS: Postoperative hypothermic (35.0-35.9°C) patients who had undergone elective surgery were randomised to receive either Orve + wrap® or Forced Air Warming during their PACU stay. Patient temperatures were recorded every 10 min using zero-heat-flux thermometry. This study is reported using CONSORT Extension checklist for noninferiority and equivalence trials. RESULTS: Between December 2016-October 2018, 129 patients were randomised to receive either Orve + wrap® blanket (n = 65, 50.3%) or Forced Air Warming (n = 64, 49.7%). The mean 60-min postoperative temperature of patients receiving Orve + wrap® blanket was 36.2 and 36.3°C for the patients receiving Forced Air Warming. The predefined noninferiority margin of a mean difference in temperature of 0.3°C was not reached between the groups at 60 min. Additionally, there were no statistical differences between adverse event rates across these groups. CONCLUSIONS: In the context of this study, warming patients with the Orve + wrap® was noninferior to Forced Air Warming. There were comparable rates of associated postoperative consequences of warming (shivering, hypotension, arrhythmias or surgical site infections), between the groups. RELEVANCE TO CLINICAL PRACTICE: The Orve + wrap® potentially provides an alternative warming method to Forced Air Warming for patients requiring short-term postoperative warming. However, there are still a number of unknowns regarding the Orve + wrap® performance and further exploration is required.

Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers.

Tetrahydrobiopterin (BH4) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH4, is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH4 as a pharmacological agent for diseases associated with BH4-deficient conditions. We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5-80 mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean Cmax 0.58-2.92 ng/mL) and BH4 (mean Cmax 57-312 ng/mL). Maximum plasma concentrations were achieved in about 1-2 h (sepiapterin) or about 4 h (BH4) after CNSA-001 oral intake. Increases in plasma BH4 were substantially larger in absolute terms and on a dose-for-dose basis following treatment with CNSA-001 vs. sapropterin dihydrochloride, a synthetic form of BH4. The pharmacokinetics of plasma sepiapterin and BH4 were similar before and after seven days of repeat daily dosing with CNSA-001 at 5, 20 or 60 mg/kg indicating little or no drug accumulation. Oral administration of CNSA-001 resulted in higher concentrations of sepiapterin in fasted vs. fed subjects, but overall BH4 plasma exposure following CNSA-001 intake increased by 1.7-1.8-fold in fed subjects. CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH4 in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH4 deficiencies and other diseases associated with deficient BH4 metabolism.

The composition of precarity: 'emerging' composers' experiences of opportunity culture in contemporary classical music.

This paper examines the precarious working lives of 'emerging' composers attempting to build a career in the world of new classical music in the UK. This topic is approached by considering the 'composition opportunity', success in which is seen as an important element in 'making it' in this sphere. We argue that such schemes in fact manifest a crucial tension in the nature of artistic labour, and are, at the very least, problematic in their function as conduits towards full professional identity. They may instead act to maintain the precarious working situation of composers in a neoliberal age. The working lives of artists are all too rarely illuminated, and new music composers are no exception; this survey of 47 emerging composers is the largest study of such individuals in the UK.

An Olympic Legacy? Did the Urban Regeneration Associated With the London 2012 Olympic Games Influence Adolescent Mental Health?

Public expenditure on large events such as the London 2012 Olympic Games is often justified by the potential legacy of urban regeneration and its associated health and well-being benefits for local communities. In the Olympic Regeneration in East London Study, we examined whether there was an association between urban regeneration related to the 2012 Games and improved mental health in young people. Adolescents aged 11-12 years attending schools in the Olympic host borough of Newham in London or in 3 adjacent comparison London boroughs completed a survey before the 2012 Games and 6 and 18 months after the Games (in 2013 and 2014, respectively). Changes in depressive symptoms and well-being between baseline and each follow-up were examined. A total of 2,254 adolescents from 25 randomly selected schools participated. Adolescents from Newham were more likely to have remained depressed between baseline and the 6- and 18-month follow-up surveys (for 6-month follow-up, relative risk = 1.78, 95% confidence interval: 1.12, 2.83; for 18-month follow-up, relative risk = 1.93, 95% confidence interval: 1.01, 3.70) than adolescents from the comparison boroughs. No differences in well-being were observed. There was little evidence that urban regeneration had any positive influence on adolescent mental health and some suggestion that regeneration may have been associated with maintenance of depressive symptoms. Such programs may have limited short-term impact on the mental health of adolescents.

Mis-use of antibiotics in acute pancreatitis: Insights from the United Kingdom's National Confidential Enquiry into patient outcome and death (NCEPOD) survey of acute pancreatitis.

BACKGROUND: International guidelines for the management of acute pancreatitis state that antibiotics should only be used to treat infectious complications. Antibiotic prophylaxis is not recommended. The aim of this study was to analyse antibiotic use, and its appropriateness, from a national review of acute pancreatitis. METHODS: Data were collected from The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) study into the management of acute pancreatitis. Adult patients admitted to hospitals in England and Wales between January and June 2014 with a coded diagnosis of acute pancreatitis were included. Clinical and organisational questionnaires were used to collect data and these submissions subjected to peer review. Antibiotic use, including indication and duration were analysed. RESULTS: 439/712 (62%) patients received antibiotics, with 891 separate prescriptions and 23 clinical indications. A maximum of three courses of antibiotics were prescribed, with 41% (290/712) of patients receiving a second course and 24% (174/712) a third course. For the first antibiotic prescription, the most common indication was "unspecified" (85/439). The most common indication for the second course was sepsis (54/290), "unspecified" was the most common indication for the third course (50/174). In 72/374 (19.38%) the indication was deemed inappropriate by the clinicians and in 72/393 (18.3%) by case reviewers. CONCLUSIONS: Inappropriate use of antibiotics in acute pancreatitis is common. Healthcare providers should ensure that antimicrobial policies are in place as part of an antimicrobial stewardship process. This should include specific guidance on their use and these policies must be accessible, adherence audited and frequently reviewed.

Associations between home and school neighbourhood food environments and adolescents' fast-food and sugar-sweetened beverage intakes: findings from the Olympic Regeneration in East London (ORiEL) Study.

OBJECTIVE: To examine associations between availability of fast-food restaurants and convenience stores in the home and school neighbourhoods, considered separately and together, and adolescents' fast-food and sugar-sweetened beverage (SSB) intakes. DESIGN: Cross-sectional observational study. SETTING: East London, UK. SUBJECTS: Adolescents (n 3089; aged 13-15 years) from the Olympic Regeneration in East London (ORiEL) Study self-reported their weekly frequency of fast-food and SSB consumption. We used food business addresses collected from local authority registers to derive absolute (counts) and relative (proportions) exposure measures to fast-food restaurants and convenience stores within 800 m from home, school, and home and school combined. Associations between absolute and relative measures of the food environment and fast-food and SSB intakes were assessed using Poisson regression models with robust standard errors. RESULTS: Absolute exposure to fast-food restaurants or convenience stores in the home, school, or combined home and school neighbourhoods was not associated with any of the outcomes. High SSB intake was associated with relative exposure to convenience stores in the residential neighbourhood (risk ratio=1·45; 95 % CI 1·08, 1·96) and in the home and school neighbourhoods combined (risk ratio=1·69; 95 % CI 1·11, 2·57). CONCLUSIONS: We found no evidence of an association between absolute exposure to fast-food restaurants and convenience stores around home and school and adolescents' fast-food and SSB intakes. Relative exposure, which measures the local diversity of the neighbourhood food environment, was positively associated with SSB intake. Relative measures of the food environment may better capture the environmental risks for poor diet than absolute measures.

Nicotiana small RNA sequences support a host genome origin of cucumber mosaic virus satellite RNA.

Satellite RNAs (satRNAs) are small noncoding subviral RNA pathogens in plants that depend on helper viruses for replication and spread. Despite many decades of research, the origin of satRNAs remains unknown. In this study we show that a ß-glucuronidase (GUS) transgene fused with a Cucumber mosaic virus (CMV) Y satellite RNA (Y-Sat) sequence (35S-GUS:Sat) was transcriptionally repressed in N. tabacum in comparison to a 35S-GUS transgene that did not contain the Y-Sat sequence. This repression was not due to DNA methylation at the 35S promoter, but was associated with specific DNA methylation at the Y-Sat sequence. Both northern blot hybridization and small RNA deep sequencing detected 24-nt siRNAs in wild-type Nicotiana plants with sequence homology to Y-Sat, suggesting that the N. tabacum genome contains Y-Sat-like sequences that give rise to 24-nt sRNAs capable of guiding RNA-directed DNA methylation (RdDM) to the Y-Sat sequence in the 35S-GUS:Sat transgene. Consistent with this, Southern blot hybridization detected multiple DNA bands in Nicotiana plants that had sequence homology to Y-Sat, suggesting that Y-Sat-like sequences exist in the Nicotiana genome as repetitive DNA, a DNA feature associated with 24-nt sRNAs. Our results point to a host genome origin for CMV satRNAs, and suggest novel approach of using small RNA sequences for finding the origin of other satRNAs.

Are Treatment Outcomes Determined by Type of Gambling? A UK Study.

One of the main difficulties faced in treating gambling disorder is compliance with psychological treatment. Gambling takes many forms and can differ greatly in its features such as speed of play and skill requirements. The type of gambling a pathological gambler opts for may play a key role in treatment compliance. The aim of the present study was to determine whether within treatment seeking sample of gambling disorder clients, gambling activity has any correlation with their resultant treatment outcomes. The study incorporated 524 treatment-seeking individuals who are clients of the National Problem Gambling Clinic in London. All of the clients were assessed prior to treatment and fulfilled the Problem Gambling Severity Index criteria for problem gambling. Data concerning clients' gambling behavior over the previous year was gathered using self-reports. Subsequently, the data was fitted to a multinomial logistic regression model, with the treatment outcome (i.e. pre-treatment dropouts, during treatment dropouts, and completed treatment) as the dependent variable and gambling behavior as the independent variable, whilst controlling for socio-demographic factors. The use of gaming machines was a significant predictor of dropping out pre-treatment (p < 0.05, RRR 1.616), whilst betting on sports events was a significant predictor of dropping out during treatment (p < 0.01, RRR 2.435). Treatment outcomes have been found to significantly differ based on participation in certain gambling activities. Further research into the salient features of these gambling activities may help to further explain pre-treatment and during treatment dropouts within this population.

Impulsivity and Gambling Type Among Treatment-Seeking Disordered Gamblers: An Explorative Study.

Several studies have found that certain traits of impulsivity are associated with gambling disorder, and influence its severity. Furthermore, it has been suggested that some forms of gambling, particularly electronic gambling machines, are particularly widespread among pathological gamblers. In the present, exploratory study, we aim to clarify the role played by impulsivity in influencing the choice of specific gambling activities, by examining the relation between individual dimensions of impulsivity, and the choice of specific gambling activities in a clinical population. 100 consecutively admitted pathological gamblers at the National Problem Gambling Clinic in London (UK) in 2014 were administered the UPPS-P and BIS-11 impulsivity questionnaires, the Problem Gambling Severity Index, and underwent a structured interview concerning their gambling activities in the month and year prior to assessment. The correlation between individual gambling activities and impulsivity dimensions was analyzed both at a bivariate level, and using logistic regression. We found a significant correlation between Negative Urgency, Motor impulsivity and low-stakes machine gambling on multivariate analysis. Negative urgency (i.e. the tendency to act impulsively in response to negative affect), and Motor impulsivity (a tendency to rash action and restlessness) might be mediating factors in the choice of electronic gambling machines, particularly among patients whose gambling is escape-oriented. Structural and situational characteristics of gambling machines, particularly the widespread availability of low-stakes-rather than high-stakes-gaming machines, might concur to the choice of this form of gambling among individuals who present higher negative urgency and restlessness.

Fatal systemic angiomatosis with widespread sclerotic skeletal changes, diagnosed with the aid of a bone marrow biopsy: the lymphatics enter the bone marrow.

A 56-year-old female presented with popliteal venous thrombosis, splenomegaly, and sclerotic bone lesions. Bone marrow biopsy showed fibrosis, proliferation of abnormal blood vessels and lymphatics, bone remodelling, and no significant changes in haematopoietic elements. Following a relatively indolent initial clinical course, one year later she rapidly deteriorated and died of respiratory failure associated with widespread disease. Ingrowth of podoplanin+ lymphatics mixed with CD34+/podoplanin- blood vessels into the bone marrow is a new finding and may be a unique feature of this disease.

Gambling Disorder: Exploring Pre-treatment and In-treatment Dropout Predictors. A UK Study.

The aim of this study was to identify predictors of treatment dropout in a sample of gamblers attending a specialist clinic for gambling disorder. We analysed data on 846 treatment-seeking pathological gamblers. Firstly, we investigated differences in socio-demographic and clinical variables between treatment completers and pre-treatment dropouts, as well as between treatment completers and during-treatment dropouts. Subsequently, variables were entered into a multinomial logistic regression model to identify significant predictors of pre-treatment and in-treatment dropout. Overall, 44.8% of clients did not complete the treatment: 27.4% dropped out before starting it, while 17.4% dropped out during the treatment. Younger age and use of drugs were associated with pre-treatment dropout, while family history of gambling disorder, a lower PGSI score, and being a smoker were related with in-treatment dropout. Our findings suggest that pre-treatment dropouts differ from in-treatment dropouts, and, thus, further research will benefit from considering these groups separately. In addition, this newly gained knowledge will also be helpful in increasing treatment retention in specific subgroups of problem gamblers.