Next generation sequencing reveals novel genetic variants (SRY, DMRT1, NR5A1, DHH, DHX37) in adults with 46,XY DSD

Context: The genetic basis of human sex development is slowly being elucidated and more than 40 different genetic causes of differences (or disorders) of sex development (DSD) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. / Objective: We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSD in individuals with no specific molecular diagnosis. / Partcipants and Design: We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2 and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n=27) and partially-virilised 46,XY DSD (pvDSD) (n=25), a group that included partial gonadal dysgenesis (PGD) and those with a broad ”partial androgen insensitivity syndrome” label. Targetted sequencing of 168 genes was undertaken. / Results: Overall a likely genetic cause was found in 16/52 (30.8%) individuals (22.2% CGD; 40.0% pvDSD). Pathogenic variants were found in SRY (n=3), DMRT1 (n=1), NR5A1/SF-1 (n=1) and DHH (n=1) in the CGD group, and in NR5A1 (n=5), DHH (n=1) and DHX37 (n=4) in the pvDSD group. / Conclusions: Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible

A Standardised Procedure for Evaluating Creative Systems: Computational Creativity Evaluation Based on What it is to be Creative

Computational creativity is a flourishing research area, with a variety of creative systems being produced and developed. Creativity evaluation has not kept pace with system development with an evident lack of systematic evaluation of the creativity of these systems in the literature. This is partially due to difficulties in defining what it means for a computer to be creative; indeed, there is no consensus on this for human creativity, let alone its computational equivalent. This paper proposes a Standardised Procedure for Evaluating Creative Systems (SPECS). SPECS is a three-step process: stating what it means for a particular computational system to be creative, deriving and performing tests based on these statements. To assist this process, the paper offers a collection of key components of creativity, identified empirically from discussions of human and computational creativity. Using this approach, the SPECS methodology is demonstrated through a comparative case study evaluating computational creativity systems that improvise music

Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review

We combined information published worldwide on the seroprevalence of hepatitis B surface antigen (HbsAg) and antibodies against hepatitis C virus (anti-HCV) in 27 881 hepatocellular carcinomas (HCCs) from 90 studies. A predominance of HBsAg was found in HCCs from most Asian, African and Latin American countries, but anti-HCV predominated in Japan, Pakistan, Mongolia and Egypt. Anti-HCV was found more often than HBsAg in Europe and the United States

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

BACKGROUND: 90% of tumors) and established genetic drivers (e.g. SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (e.g. DNA damage-signaling) and specific events (e.g. 3p loss) predicted survival post-relapse. CONCLUSIONS: rMB is defined by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes

Aims: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. Methods: We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies

Can Research Assessments Themselves Cause Bias in Behaviour Change Trials? A Systematic Review of Evidence from Solomon 4-Group Studies

BACKGROUND: The possible effects of research assessments on participant behaviour have attracted research interest, especially in studies with behavioural interventions and/or outcomes. Assessments may introduce bias in randomised controlled trials by altering receptivity to intervention in experimental groups and differentially impacting on the behaviour of control groups. In a Solomon 4-group design, participants are randomly allocated to one of four arms: (1) assessed experimental group; (2) unassessed experimental group (3) assessed control group; or (4) unassessed control group. This design provides a test of the internal validity of effect sizes obtained in conventional two-group trials by controlling for the effects of baseline assessment, and assessing interactions between the intervention and baseline assessment. The aim of this systematic review is to evaluate evidence from Solomon 4-group studies with behavioural outcomes that baseline research assessments themselves can introduce bias into trials. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases were searched, supplemented by citation searching. Studies were eligible if they reported appropriately analysed results in peer-reviewed journals and used Solomon 4-group designs in non-laboratory settings with behavioural outcome measures and sample sizes of 20 per group or greater. Ten studies from a range of applied areas were included. There was inconsistent evidence of main effects of assessment, sparse evidence of interactions with behavioural interventions, and a lack of convincing data in relation to the research question for this review. CONCLUSIONS/SIGNIFICANCE: There were too few high quality completed studies to infer conclusively that biases stemming from baseline research assessments do or do not exist. There is, therefore a need for new rigorous Solomon 4-group studies that are purposively designed to evaluate the potential for research assessments to cause bias in behaviour change trials

Effects Of Inorganic Nitrate And Nitrite Consumption On Cognitive Function And Cerebral Blood Flow: A Systematic Review And Meta-Analysis Of Randomised Clinical Trials.

We conducted a systematic review and meta-analysis of randomized clinical trials examining the effect of inorganic nitrate or nitrite supplementation on cognitive function (CF) and cerebral blood flow (CBF). Two databases (PubMed, Embase) were searched for articles from inception until May 2017. Inclusion criteria were: randomized clinical trials; participants >18 years old; trials comparing a nitrate/nitrite intervention with a control. Thirteen and nine trials were included in the meta-analysis to assess CF and CBF, respectively. Random-effects models were used and the effect size described as standardized mean differences (SMDs). A total of 297 participants (median of 23 per trial) were included for CF; 163 participants (median of 16 per trial) were included for CBF. Nitrate/nitrite supplementation did not influence CF (SMD +0.06, 95% CI: -0.06, 0.18, P = 0.32) or CBF under resting (SMD +0.14, 95% CI: -0.13, 0.41, P = 0.31), or stimulated conditions (SMD +0.23, 95% CI: -0.11, 0.56, P = 0.19). The meta-regression showed an inverse association between duration of the intervention and CBF (P = 0.02) but no influence of age, BMI or dose (P < 0.05). Nitrate and nitrite supplementation did not modify CBF or CF. Further trials employing larger samples sizes and interventions with longer duration are warranted

Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma

Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma. Retrospective follow-up study. Forty-three patients (mean age 56 +/- 14 years), treated by transsphenoidal surgery for non-functioning pituitary macroadenoma, were included in this analysis. Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 +/- 0.37 to 0.75 +/- 0.36 (P <0.01) (right eye), and from 0.60 +/- 0.32 to 0.82 +/- 0.30 (P <0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 +/- 0.36 to 0.82 +/- 0.34 (P <0.05) (right eye), and from 0.82 +/- 0.30 to 0.88 +/- 0.27 (P <0.05) (left eye). Visual acuity improves progressively after surgical treatment for non-functioning pituitary macroadenomas, at least within the first year after transsphenoidal surger

A Randomized Trial Evaluating Prosaptide™ for HIV-Associated Sensory Neuropathies: Use of an Electronic Diary to Record Neuropathic Pain

Objectives: To examine the efficacy and safety of Prosaptide™ (PRO) for the treatment of painful HIV-associated sensory neuropathies (HIV-SN). Design: A randomized, double-blind, placebo-controlled, multicenter study in participants with sensory neuropathy. Pain modulating therapy was discontinued prior to baseline. Participants were stratified by sural sensory nerve action potential (SNAP) amplitude. Participants were trained to use an electronic diary (ED) to record pain. Setting: Peripheral neuropathies are common complications of HIV infection. The pathogenesis is unknown and currently treatments are restricted to symptomatic measures. We examined PRO against placebo (PBO) for treatment of painful HIV-SN and performed a post-hoc evaluation of an electronic diary (ED) to record HIV-associated neuropathic pain. Participants: Eligible participants included adults with neurologist-confirmed painful HIV-SN.Interventions 2, 4, 8, or 16 mg/d PRO or PBO administered via subcutaneous (SC) injection for six weeks. Neurotoxic antiretroviral drug usage was held constant.Outcome Measures Changes from baseline in the weekly average of evaluable daily random prompts measuring pain using the Gracely pain scale and adverse events. Results: 237 participants were randomized. The study was stopped after a planned futility analysis. There were no between-group differences in the frequency of adverse events or laboratory toxicities. The 6-week mean (sd) Gracely pain scale changes were −0.12 (0.23), −0.24 (0.35), −0.15 (0.32), −0.18 (0.34), and −0.18 (0.32) for the 2, 4, 8, 16 mg, and PBO arms respectively. A similar variability of pain changes recorded using the ED were noted compared to previous trials that used paper collection methods.Conclusions 6-week treatment with PRO was safe but not effective at reducing HIV-associated neuropathic pain. Use of an ED to record neuropathic pain is novel in HIV-SN, resulted in reasonable compliance in recording pain data, but did not decrease the variability of pain scores compared to historical paper collection methods. Trial Registration: Current Controlled Trials NCT0028637