The next-generation Open Targets Platform: reimagined, redesigned, rebuilt.

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

A report of a retained bullet in the bladder which migrated from an extraperitoneal injury.

Genitourinary trauma secondary to a gunshot wound is uncommon as it only occurs in about 10% of cases. We present a case of a gentleman who suffered a gunshot wound to the pelvis. The bullet was originally extraluminal to the bladder; however, upon repeat CT scan eight days later, the bullet had migrated intra-luminally. We hope to show through this case that uncomplicated extraperitoneal injuries with an adjacent missile might benefit from early surgical exploration.

Effect of combination NSAID and NBUVB treatment in non-photoadapters-A pilot study.

BACKGROUND: Vitiligo is a disorder of dyspigmentation that can impact quality of life. While narrow-band ultraviolet B (NBUVB) is an effective treatment for vitiligo, a subset of patients are unable to respond to phototherapy as they cannot photoadapt. However, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to increase the minimal erythema dose. PURPOSE: To determine whether ibuprofen allows non-photoadapters to respond to therapeutic doses of NBUVB and maintain photoadaptation. METHOD: Four patients unable to tolerate NBUVB or excimer past a dose of 1000 mJ/cm2 were enrolled in the study and given ibuprofen 400 mg prior to phototherapy, which was performed 2-3 times a week. Patients were followed up to 72 treatments to demonstrate photoadaptation and maintenance of response to phototherapy. Patients were clinically monitored by serial photographs approximately every 12 treatments. Response to phototherapy was monitored by tracking the dose of NBUVB received at each session. Maintenance of response was monitored for six treatments after discontinuing the ibuprofen. Percent change in pigmentation was also recorded. RESULTS: Three out of four subjects enrolled in the study were able to increase their doses of phototherapy to a therapeutic range, and subjects continued to photoadapt for six treatments after discontinuing ibuprofen. Two subjects achieved repigmentation during their course of phototherapy. CONCLUSION: Ibuprofen may be a safe alternative to corticosteroids for select patients with vitiligo that are unable to photoadapt. It appears that the ability to photoadapt continues once ibuprofen is discontinued, negating the need for chronic use. Enabling photoadaptation allows patients to achieve therapeutic doses of NBUVB phototherapy, leading to repigmentation and improved outcomes. TRIAL REGISTRATION: The trial was registered through Henry Ford Hospital IRB-No. 9744.

Concomitant Left Atrial Reduction in Rheumatic Mitral Valve Disease With Giant Left Atrium: Our Technique With Midterm Results.

OBJECTIVE: The giant left atrium is a frequent finding with rheumatic heart disease. The enlarged left atrium was found to be a risk factor for early mortality and postoperative higher thromboembolic events, but its management remains controversial. Most of the surgeons just do the mitral valve procedure without any intervention for enlarged left atrium. We present our center's experience of patients with giant left atrium who underwent a newer technique of left atrium reduction concomitant with mitral valve procedure. METHODS: Between January 2012 and February 2015, 25 patients, who underwent surgery for concomitant left atrium reduction with mitral valve disease, were included in the study after institute's ethics committee clearance. Patients having combined aortic and mitral valve disease were excluded. Preoperative, intraoperative, and postoperative data were collected. All the patients were also followed up clinically and echocardiographically in postoperative period. RESULTS: There were 15 (60%) females. The mean ± SD age of the patients was 36.92 ± 5.4 years. Preoperatively, all patients were in long-standing persistent atrial fibrillation. The mean ± SD bypass and aortic cross-clamp time were 74.56 ± 3.85 and 51.72 ± 4.32 minutes, respectively. There was a significant reduction of left atrium diameter and volume from 94.48 ± 11.0 mm to 40.08 ± 1.35 mm and 348.3 ± 121.1 to 26.57 ± 2.9 mL/m, respectively. There was no early or late mortality. At a mean ± SD follow-up of 42.28 ± 12.1 months, all patients were in New York Heart Association I or II class and 24 (96%) patients were in normal sinus rhythm. CONCLUSIONS: Concurrent left atrium reduction with mitral valve procedure is a feasible and effective technique for event-free survival of the patients having giant left atrium with mitral disease.

Worldwide distribution of the DCDC2 READ1 regulatory element and its relationship with phoneme variation across languages.

DCDC2 is a gene strongly associated with components of the phonological processing system in animal models and in multiple independent studies of populations and languages. We propose that it may also influence population-level variation in language component usage. To test this hypothesis, we investigated the evolution and worldwide distribution of the READ1 regulatory element within DCDC2, and compared its distribution with variation in different language properties. The mutational history of READ1 was estimated by examining primate and archaic hominin sequences. This identified duplication and expansion events, which created a large number of polymorphic alleles based on internal repeat units (RU1 and RU2). Association of READ1 alleles was studied with respect to the numbers of consonants and vowels for languages in 43 human populations distributed across five continents. Using population-based approaches with multivariate ANCOVA and linear mixed effects analyses, we found that the RU1-1 allele group of READ1 is significantly associated with the number of consonants within languages independent of genetic relatedness, geographic proximity, and language family. We propose that allelic variation in READ1 helped create a subtle cognitive bias that was amplified by cultural transmission, and ultimately shaped consonant use by different populations over time.

Whole genome association study of brain-wide imaging phenotypes: A study of the ping cohort.

Neuropsychological disorders have a biological basis rooted in brain function, and neuroimaging data are expected to better illuminate the complex genetic basis of neuropsychological disorders. Because they are biological measures, neuroimaging data avoid biases arising from clinical diagnostic criteria that are subject to human understanding and interpretation. A challenge with analyzing neuroimaging data is their high dimensionality and complex spatial relationships. To tackle this challenge, we introduced a novel distance covariance tests that can assess the association between genetic markers and multivariate diffusion tensor imaging measurements, and analyzed a genome-wide association study (GWAS) dataset collected by the Pediatric Imaging, Neurocognition, and Genetics (PING) study. We also considered existing approaches as comparisons. Our results showed that, after correcting for multiplicity, distance covariance tests of the multivariate phenotype yield significantly greater power at detecting genetic markers affecting brain structure than standard mass univariate GWAS of individual neuroimaging biomarkers. Our results underscore the usefulness of utilizing the distance covariance to incorporate neuroimaging data in GWAS.

A molecular-genetic and imaging-genetic approach to specific comprehension difficulties in children.

Children with poor reading comprehension despite typical word reading skills were examined using neuropsychological, genetic, and neuroimaging data collected from the Genes, Reading and Dyslexia Study of 1432 Hispanic American and African American children. This unexpected poor comprehension was associated with profound deficits in vocabulary, when compared to children with comprehension skills consistent with their word reading. Those with specific comprehension difficulties were also more likely to have RU2Short alleles of READ1 regulatory variants of DCDC2, strongly associated with reading and language difficulties. Subjects with RU2Short alleles showed stronger resting state functional connectivity between the right insula/inferior frontal gyrus and the right supramarginal gyrus, even after controlling for potentially confounding variables including genetic ancestry and socioeconomic status. This multi-disciplinary approach advances the current understanding of specific reading comprehension difficulties, and suggests the need for interventions that are more appropriately tailored to the specific comprehension deficits of this group of children.

A method for integrating neuroimaging into genetic models of learning performance.

Specific learning disorders (SLD) are an archetypal example of how clinical neuropsychological (NP) traits can differ from underlying genetic and neurobiological risk factors. Disparate environmental influences and pathologies impact learning performance assessed through cognitive examinations and clinical evaluations, the primary diagnostic tools for SLD. We propose a neurobiological risk for SLD with neuroimaging biomarkers, which is integrated into a genome-wide association study (GWAS) of learning performance in a cohort of 479 European individuals between 8 and 21 years of age. We first identified six regions of interest (ROIs) in temporal and anterior cingulate regions where the group diagnosed with learning disability has the least overall variation, relative to the other group, in thickness, area, and volume measurements. Although we used the three imaging measures, the thickness was the leading contributor. Hence, we calculated the Euclidean distances between any two individuals based on their thickness measures in the six ROIs. Then, we defined the relative similarity of one individual according to the averaged ranking of pairwise distances from the individuals to those in the SLD group. The inverse of this relative similarity is called the neurobiological risk for the individual. Single nucleotide polymorphisms in the AGBL1 gene on chromosome 15 had a significant association with learning performance at a genome-wide level. This finding was supported in an independent cohort of 2,327 individuals of the same demographic profile. Our statistical approach for integrating genetic and neuroimaging biomarkers can be extended into studying the biological basis of other NP traits.