Spatially Uniform ReliefF (SURF) for computationally-efficient filtering of gene-gene interactions

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies are becoming the de facto standard in the genetic analysis of common human diseases. Given the complexity and robustness of biological networks such diseases are unlikely to be the result of single points of failure but instead likely arise from the joint failure of two or more interacting components. The hope in genome-wide screens is that these points of failure can be linked to single nucleotide polymorphisms (SNPs) which confer disease susceptibility. Detecting interacting variants that lead to disease in the absence of single-gene effects is difficult however, and methods to exhaustively analyze sets of these variants for interactions are combinatorial in nature thus making them computationally infeasible. Efficient algorithms which can detect interacting SNPs are needed. ReliefF is one such promising algorithm, although it has low success rate for noisy datasets when the interaction effect is small. ReliefF has been paired with an iterative approach, Tuned ReliefF (TuRF), which improves the estimation of weights in noisy data but does not fundamentally change the underlying ReliefF algorithm. To improve the sensitivity of studies using these methods to detect small effects we introduce Spatially Uniform ReliefF (SURF).</p> <p>Results</p> <p>SURF's ability to detect interactions in this domain is significantly greater than that of ReliefF. Similarly SURF, in combination with the TuRF strategy significantly outperforms TuRF alone for SNP selection under an epistasis model. It is important to note that this success rate increase does not require an increase in algorithmic complexity and allows for increased success rate, even with the removal of a nuisance parameter from the algorithm.</p> <p>Conclusion</p> <p>Researchers performing genetic association studies and aiming to discover gene-gene interactions associated with increased disease susceptibility should use SURF in place of ReliefF. For instance, SURF should be used instead of ReliefF to filter a dataset before an exhaustive MDR analysis. This change increases the ability of a study to detect gene-gene interactions. The SURF algorithm is implemented in the open source Multifactor Dimensionality Reduction (MDR) software package available from <url>http://www.epistasis.org</url>.</p

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Background: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. Methods: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Findings: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21–24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of –1·7 (95% CI –2·0 to –1·3) for odevixibat and –0·8 (–1·3 to –0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline –0·9 [95% CI –1·4 to –0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change –90 μmol/L [95% CI –133 to –48] with odevixibat vs 22 μmol/L [–35 to 80] with placebo; difference in LS mean change –113 μmol/L [95% CI –179 to –47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Interpretation: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Funding: Albireo Pharma, an Ipsen company

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Defining the role of autographa californica multiple nucleopolyhedrovirus immediate early-0 and immediate early-1 proteins in viral genome replication and early gene transactivation

The immediate early-0 (IE0) and IE1 proteins of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) are key transregulators in the viral replication cycle. If both proteins are absent, the virus is inactive. Either protein can support viral replication but both are required to achieve wildtype infection. Both IE0 and IE1 are involved in viral DNA replication and transcriptional transactivation of early genes. In this study, to analyze IE0 and IE1’s function, ie0, ie0MtoA or ie1 were placed under the control of identical promoters (ie1 or gp64) to achieve comparable levels of protein expression. The ie1 promoter produced higher levels of IE0, IE0MtoA and IE1 compared to the gp64 promoter. Time course assays of infected Spodoptera frugiperda 9 (Sf9) cells allowed examination of viral DNA replication and budded virus (BV) production. The results showed that when IE0 and IE1 protein levels were high, either IE0, IE1 or IE0 and IE1 together maintained DNA replication and BV production similar to wildtype levels. However, when IE0 and IE1 protein levels were low, only when IE0 and IE1 were present together was DNA replication and BV production similar to wildtype. These results suggest that during the virus replication cycle when cellular levels of IE0 or IE1 are low, for example at the beginning of infection, the presence of both proteins results in more efficient DNA replication. Transient transactivation studies were also performed to examine IE0 and IE1’s ability to activate nineteen viral early gene promoters. At low levels of IE0 and IE1 expression, a group of viral early gene promoters were found to be differentially transactivated by IE0 alone or when both IE0 and small amounts of IE1 were together. These results suggest that during early times post-infection, when cellular levels of viral proteins are low, IE0 in the presence of a small amount of IE1 results in rapid onset of viral DNA replication and efficient transactivation of a specific set of viral early gene promoters. In context of virus infection, rapid viral replication by IE0 and IE1 and transactivation of early genes by IE0 may counter the insect’s defense mechanisms like sloughing and apoptosis.Arts and Sciences, Irving K. Barber School of (Okanagan)Biology, Department of (Okanagan)Graduat

INDIVIDUAL PRURITUS AND BILE ACID RESPONSES OVER TIME WITH ODEVIXIBAT TREATMENT: POOLED DATA FROM THE PHASE 3 ASSERT AND ASSERT-EXT STUDIES IN PATIENTS WITH ALAGILLE SYNDROME

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FAT-SOLUBLE VITAMIN LEVELS IN PATIENTS WITH ALAGILLE SYNDROME TREATED WITH ODEVIXIBAT IN THE PHASE 3 ASSERT STUDY

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OUTCOMES WITH ODEVIXIBAT TREATMENT IN PATIENTS WITH ALAGILLE SYNDROME: ANALYSIS OF PRURITUS RESPONDERS FROM THE PHASE 3 ASSERT STUDY

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The application of 3D printing in neurosurgery: present and future

Background: For about 20 years we have been observing the development of three-dimensional (3D) printing. The aim of this study was to systematize the current knowledge on the use of 3D printing technology in neurosurgery and to aetmpt an outline the future paths of its development. Material and methods: The analysis was based on English-language literature from 2017-2021 indexed in the Mendeley and Scopus databases. Results: The application of 3D printing in neurosurgery concerns: 1) teaching students, 2) training of residents neurosurgeons, 3) individualized surgery planning, 4) dedicated cranial and spinal implants, 5) the future of 3D printing in neurosurgical implantology. There were 5 main neurosurgery subtopics in which 3D printing was used: “vascular neurosurgery” (31%), “skull, cranial neurosurgery” (22.4%), “neuro-oncology” (19.3%), “spine” (14.3%) and “others” (13%). The number of published articles has been steadily increasing by 11-33% annually. Conclusion: 3D printing has an enormous potential for clinical use and in the we will continue to observe its dynamic development. In neurosurgery 3D prints are currently most commonly used for didactic purposes as detailed anatomical models, for training residents and young surgeons and by specialists for the simulation of complex or innovative surgeries. The future of the use of additive 3D printing in neurosurgery lies in the biological 3D printing, the creation of artifcial organs and the development of biological implants in tissue engineering. Dzierżanowska N, Krakowiak M, Sokal P. The application of 3D printing in neurosurgery: present and future. Eur J Transl Clin Med. 2023;6(1):70-78

Postharvest short cold temperature treatment to preserve fruit quality after Drosophila suzukii damage

Blueberry (Vaccinium corymbosum) and strawberry (Fragaria ananassa) are fruits heavily colonised by Drosophila suzukii in the field while damage increases considerably during the postharvest period. In order to reduce the damage, a short exposure to low temperature can be used to limit the survival of D. suzukii eggs and to prevent the decline in quality of infested fruits. Berries were artificially infested and kept at 0.5 and 5.0 degrees C for 10 and 24 hours. Damage was visually assessed at 3, 6, and 9 days and emergence of flies considered. Berries treated with 0.5 degrees C for 24 h had a higher reduction in emergence of adults in both blueberry (83%) and strawberry (59%) and lower fruit damage. The treatment prolonged the shelf life of infested fruits up to 6 days in blueberry and 3 days in strawberry, compared to untreated control. A direct relation was found between the number of emerging adults and the decay index. It is concluded that short cold temperature exposures would be helpful in order to constrain pest development and sustain berry marketability