Funders and publishers should roll out policies in ways to support their evaluation

We examine how prize announcements in economics influence the attention of insiders and outsiders to the field. Insiders pay greatest attention to consensus papers cited by the Nobel Prize Committee and written by past Clark Medal winners; outsiders focus more on consensus papers not written by Clark Medal awardees. In both cases, the entry of new citing authors accounts for most of the enhanced attention. We also consider the direct impact of the Clark Medal on citations and find effects comparable to those arising with the Nobel Prize. Our results imply that prizes enhance the leadership role of star scientists.

Predicting the impact of coding and noncoding variants on splicing is challenging, particularly in non-canonical splice sites, leading to missed diagnoses in patients. Existing splice prediction tools are complementary but knowing which to use for each splicing context remains difficult. Here, we describe Introme, which uses machine learning to integrate predictions from several splice detection tools, additional splicing rules, and gene architecture features to comprehensively evaluate the likelihood of a variant impacting splicing. Through extensive benchmarking across 21,000 splice-altering variants, Introme outperformed all tools (auPRC: 0.98) for the detection of clinically significant splice variants. Introme is available at https://github.com/CCICB/introme .

Abstract Prognostic biomarkers for esophageal adenocarcinoma (EAC) remain elusive but may be helpful in treatment planning, as TNM staging often fails to accurately predict survival. Advanced stage patients are treated by peri-operative chemo/radiotherapy; biomarkers associated with survival are thus likely to represent both true prognostic markers as well as markers of response to chemo/radiotherapy. Here we present first-pass genomic findings for a cohort of optimally staged EAC patients treated by surgery alone. DNA was extracted from fresh frozen EAC and matching normal squamous esophageal tissues obtained at esophagectomy from 65 consenting patients who did not receive any neo- or adjuvant chemo- or radiotherapy due to institutional preference at the time of tissue collection. Library preparation and sequencing for a targeted 600 cancer-associated gene panel designed using the Roche/NimbleGen EZ Choice Library NimbleDesign platform were conducted on Illumina-based platforms followed by analysis with an accredited bioinformatics pipeline. The panel design incorporated the entire coding region plus 10 bp of flanking intron of each gene. Mean age 70 yrs; 88% male. All patients underwent an en bloc esophagectomy (mean 35 lymph nodes). TNM (7th ed.) stages were 61% Stage 3, 18% stage 2, 14% stage 1, 6% stage 4. At median 9.5 years follow-up, 20 (31%) patients remained alive. Copy number changes were common, reflecting chromosomal instability. Less than 8% of patients had high tumour mutational burden (>10mut/MB), associated with mutations in DNA repair genes. Commonest somatic mutations included TP53 (HR: 0.43) and LRP1B (HR: 1.7). Pathways implicated included RTK signalling (PIK3CA, EGFR, KRAS), DNA damage (BRCA1, PALB2, MGMT) and histone remodelling (ARID1A, ARID2, KMT2D). Peri-operative treatment means linking genomic changes independent of stage to clinical outcomes is difficult. Neoadjuvant and/or adjuvant treatment is now standard for T2–4 or node positive EAC. This cohort of 65 patients, most of whom had stage 3 disease and all of whom underwent optimal staging with en bloc esophagectomy, represents a unique opportunity to analyze characteristics of EAC without confounding by peri-operative treatment. An EAC-specific DNA sequencing panel approach offers potential for personalized therapy.

Objective The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development. Design We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

We model open access as facilitating full-text acquisition, which, while often increasing cites, can reduce cites from readers who refrain from citing superficially after realizing the article is not worth citing. We test the theory with data on over 200,000 science articles binned by cites in the pre-study period. Consistent with theory, we find that opening access to an article on the journal's website has a "Matthew effect" on citations: negative for the least-cited articles, positive for the most cited, and monotonic for quality levels in between. Estimates for broader open-access platforms and for cites coming from insiders versus outsiders also follow patterns consistent with theory.

Background: Papillary thyroid carcinoma (PTC) accounts for 80% of all thyroid carcinomas.PTC is associated with a BRAF gene mutation that results in a valine to glutamate substitution at position 600 (V600E), constitutively activating the MAP-kinase pathway.The incidence of the BRAF V600E mutation in PTCs is reportedly variable (43-90%) and has been associated with aggressive tumor behavior.Treatment with targeted BRAF-inhibitors may be considered in some patients.Thus, the presence of this mutation may have implications for prognosis and treatment.Initially, polymerase chain reaction (PCR) and/or direct Sanger sequencing were the ubiquitous molecular techniques used for BRAF V600E detection, albeit expensive and time-consuming.However, multiple authors have recently shown the high specificity and sensitivity of immunohistochemistry (IHC) staining via mouse monoclonal antibody (Clone VE1) for BRAF V600E detection in PTC.While most research efforts on the latter have originated from the fields of surgery, oncology and endocrinology, the feasibility of using IHC to test for BRAF V600E in PTC specimens deserves scrutiny in the pathology literature.Design: BRAF V600E IHC (VE1 clone) was performed on all non-incidental papillary carcinomas, all incidental papillary microcarcinomas 0.6 cm or larger, and any incidental papillary microcarcinomas with adverse features.We retrospectively analyzed 66 consecutive PTCs that underwent BRAF VE1 IHC at our institution from October 2018 to September 2019.Ancillary validation was performed using nextgeneration genomic sequencing (NGS) on 6 historic cases, 3 with diffuse weak and 3 with diffuse moderate cytoplasmic BRAF expression.Results: Of 66 consecutive PTC cases stained by BRAF V600E-specific antibody IHC, 56 (85%) were positive.All 6 validation cases (weak or moderate by IHC) were positive for the BRAF V600E mutation by NGS. Conclusions:The 85% incidence in this study is high, and is in agreement with recent studies evaluating classic PTCs.Lower reported incidences may have reflected potential dilution with other follicular neoplasms including NIFTP and the follicular variant of PTC.Molecular techniques, especially NGS, are not universally accessible.Using IHC to detect BRAF mutation is more cost and time-efficient.Due to the potential treatment and prognostic implications of BRAF V600E, accurate and efficient detection is critical.

Abstract The transcription factor OTX2 is implicated in pituitary, ocular and craniofacial development. Mutations have been described in patients with variable congenital hypopituitarism (CH) ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD) with/without an ectopic posterior pituitary (EPP).We aimed (i) to establish the contribution of OTX2 mutations in the etiology of CH in a sub-cohort of patients and to study their functional consequences and (ii) establish a detailed human OTX2 expression profile in a hypothalamo-pituitary (HP) context. We screened 127 patients from national (n=103) and international centers (n=24) on the septo-optic dysplasia (SOD) spectrum with variable eye abnormalities. Eye abnormalities included micro/anophthalmia, retinal dystrophy and/or coloboma in 29 of these patients, with the rest having optic nerve hypoplasia (ONH). An EPP was reported on MRI in 35 patients. The cohort previously tested negative for mutations in HESX1, SOX2, SOX3, PROKR2 and GH1. Transactivation assays involved a dual-luciferase reporter in murine hypothalamic GT1-7 neurons transiently transfected with OTX2 constructs. In situ hybridization was performed to analyze human brain OTX2 expression during embryogenesis. Seven heterozygous OTX2 changes were identified: two chromosomal deletions spanning OTX2 in patients with micro/anophthalmia, GHD and an EPP, with one patient having cerebellar hypoplasia. Three missense substitutions resulting in truncated proteins: (i) the previously reported p.S138* and (ii) p.C170*, in two patients with retinal dystrophy, EPP and IGHD respectively, and (iii) the novel p.E79* in a patient with micro/anophthalmia, EPP and CPHD. A novel insertion-deletion resulting in a truncated protein p.S167* in a patient with microphthalmia, GHD, ONH, EPP and an enlarged abnormal pituitary, and a novel deletion resulting in a frameshift p.Val139Aspfs*39 in a patient with microcephaly, microphthalmia, ONH and an EPP were also identified. The human OTX2 variants caused a significant reduction in transactivation compared to wild type. Our gene expression data identified human OTX2 transcripts in the posterior pituitary, retina, ear, thalamus, choroid plexus, and in the hypothalamus during embryogenesis, but not in RP. To conclude, we identified OTX2 variants in 7 unrelated CH patients with eye abnormalities including 3 with retinal dystrophy and one with a cerebellar abnormality. As OTX2 is involved at multiple levels during HP development, these patients should be monitored for evolving endocrinopathies. Human OTX2 is expressed in the posterior pituitary, the retina and the ear at CS19 and 20 (between 6-7 weeks gestation), and in areas of the hindbrain at CS23, but not in RP at any stage analyzed in this study. The endocrine phenotypes in patients with OTX2 mutations are most likely of hypothalamic origin.

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a syndrome of unknown etiology characterized by profound fatigue exacerbated by physical activity, also known as post-exertional malaise (PEM). Previously, we did not detect evidence of immune dysregulation or virus reactivation outside of PEM periods. Here we sought to determine whether cardiopulmonary exercise stress testing of ME/CFS patients could trigger such changes. ME/CFS patients (n = 14) and matched sedentary controls (n = 11) were subjected to cardiopulmonary exercise on 2 consecutive days and followed up to 7 days post-exercise, and longitudinal whole blood samples analyzed by RNA-seq. Although ME/CFS patients showed significant worsening of symptoms following exercise versus controls, with 8 of 14 ME/CFS patients showing reduced oxygen consumption ([Formula: see text]) on day 2, transcriptome analysis yielded only 6 differentially expressed gene (DEG) candidates when comparing ME/CFS patients to controls across all time points. None of the DEGs were related to immune signaling, and no DEGs were found in ME/CFS patients before and after exercise. Virome composition (P = 0.746 by chi-square test) and number of viral reads (P = 0.098 by paired t-test) were not significantly associated with PEM. These observations do not support transcriptionally-mediated immune cell dysregulation or viral reactivation in ME/CFS patients during symptomatic PEM episodes.

Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

Does data disclosure have an impact on citations? Four leading economics journals introduced a data disclosure policy between 2004 and 2006. We use panel data consisting of 17,135 article citing-year observations from 1996 to 2015 for articles published in these journals. Empirical articles that did not disclose data (46% of the sample) serve as a control group. Evidence for a positive open data citation effect is weak (6% and not statistically significant). On the other hand, the citation impacts of publication are substantial and precisely estimated. Pure theory, hybrid and purely empirical articles enjoy citations benefits of 22%, 32% and 44%, respectively. Our pre- and post-publication citation data allow us to identify the citation effects of data disclosure and publication, while controlling for intrinsic article quality.

Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3 -related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/ PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

In 2005, the Do Bugs Need Drugs (DBND) program was imported to British Columbia (BC) from Alberta with the goal of reducing unnecessary antibiotic use in the community. The objective of this study was to estimate the impact of the program on antibiotic-associated costs and cost-benefit. We used data on antibiotic prescription and costs from BC PharmaNet for the period of 1996 to 2014. We conducted interrupted time series regression to formally interpret the impact of the DBND program. The average monthly prescription rate fell by 14.5%, from 54.3 to 46.4 per 1000 population between 2005 and 2014. The proportionate contribution of macrolide prescription decreased from 19.2% in 2005 to 13.2% in 2014 and for quinolones decreased from 13.1% in 2005 to 12% in 2014. The proportion of prescriptions for both penicillins and tetracyclines increased by > 35.5%. Before the program, the average monthly cost of antibiotics was increasing by CAD $8.12 per 1000 population (p < 0.001). After program introduction, average monthly cost decreased by CAD $18.19 per 1000 population (p < 0.001), creating an annual savings for BC in 2014 of CAD $83.6 million. In 2014, one Canadian dollar spent on the DBND program was associated with conservative savings of CAD $76.20. Significant cost savings have been observed in association with a community antimicrobial stewardship program focused on both public and prescribers. Such programs are an effective strategy in cost-benefit terms and should therefore be considered for universal adoption in Canadian healthcare systems.

We analyze a model in which journals cannot commit to subscription fees when authors (who prefer low subscription fees because this boosts readership) make submission decisions. A hold‐up problem arises, manifested as excessive subscription fees. Open access is a crude attempt to avoid hold up by eliminating subscription fees. We assess the profitability and efficiency of traditional relative to open‐access journals in a monopoly model (with extensions to nonprofit, bundled, hybrid, and competing journals). We apply the theory to understand the evolving market for academic journals in the Internet age and policies currently being debated such as an open‐access mandate.

Blood samples for studies of circulating DNA in disease are often collected in clinical settings where prompt processing of samples is not possible. In order to avoid problems associated with leukocyte lysis after prolonged blood storage, stabilised blood tubes have been developed containing preservatives that prevent cell lysis. We evaluated Streck BCT tubes and PAXgene ccfDNA tubes, as well as standard EDTA blood collection tubes, in terms of DNA yield and fragment size.