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Aberrant splicing is a major cause of rare diseases.  However, its prediction from genome sequence alone remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we develop FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1 causing mucolipidosis. FRASER automatically controls for latent confounders, which are widespread and affect sensitivity substantially. Moreover, FRASER is based on a count distribution and multiple testing correction, thus reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor loss of sensitivity. Applying FRASER to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available. Aberrant splicing is a major contributor to rare disease, but detection accuracy using current methods is limited. Here, the authors develop an algorithm that detects aberrant splicing and intron retention events from RNA-seq data and apply it to diagnosis in mitochondrial disease.

Aberrant splicing is a major cause of genetic disorders but its direct detection in transcriptomes is limited to clinically accessible tissues such as skin or body fluids. While DNA-based machine learning models can prioritize rare variants for affecting splicing, their performance in predicting tissue-specific aberrant splicing remains unassessed. Here we generated an aberrant splicing benchmark dataset, spanning over 8.8 million rare variants in 49 human tissues from the Genotype-Tissue Expression (GTEx) dataset. At 20% recall, state-of-the-art DNA-based models achieve maximum 12% precision. By mapping and quantifying tissue-specific splice site usage transcriptome-wide and modeling isoform competition, we increased precision by threefold at the same recall. Integrating RNA-sequencing data of clinically accessible tissues into our model, AbSplice, brought precision to 60%. These results, replicated in two independent cohorts, substantially contribute to noncoding loss-of-function variant identification and to genetic diagnostics design and analytics. AbSplice predicts aberrant splicing for 50 human tissues by integrating sequence-based deep learning models, DNA variation and RNA-seq obtained from accessible tissues.

Aberrant splicing is a major cause of rare diseases, yet its prediction from genome sequence remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we developed FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1. FRASER automatically controls for latent confounders, which are widespread and substantially affect sensitivity. Moreover, FRASER is based on a count distribution and multiple testing correction, reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor sensitivity loss. The application to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available. Footnotes * https://github.com/gagneurlab/FRASER

Aberrant splicing is a major cause of genetic disorders but its direct detection in transcriptomes is limited to clinically accessible tissues such as skin or body fluids. While DNA-based machine learning models allow prioritizing rare variants for affecting splicing, their performance on predicting tissue-specific aberrant splicing remains unassessed. Here, we generated the first aberrant splicing benchmark dataset, spanning over 8.8 million rare variants in 49 human tissues. At 20% recall, state-of-the-art DNA-based models cap at 10% precision. By mapping and quantifying tissue-specific splice site usage transcriptome-wide and modeling isoform competition, we increased precision by three-fold at the same recall. Integrating RNA-sequencing data of clinically accessible tissues brought precision to 60%. These results, replicated in two independent cohorts, substantially contribute to non-coding loss-of-function variant identification and to genetic diagnostics design and analytics.

Open surgery for developmental dysplasia of the hip (DDH) may cause severe pain due to tenotomies and pelvic–femoral osteotomies. This study aims to evaluate the analgesic effect of ultrasound-guided Lumbar Erector Spina Plane (L-ESP) Block in pediatric patients undergoing DDH surgery. Sixty children scheduled for DDH surgery were randomly assigned into two groups. Group I ( n  = 30) received L-ESP with 0.5 mL/kg of 0.25% bupivacaine before surgery. In contrast, Group II ( n  = 30), as the control group, received the same volume of saline injection. Identical postoperative analgesia protocol was adjusted for both groups. Parental satisfaction, pain levels, ibuprofen, and opioid consumption were recorded. Pain levels were evaluated with the FLACC (Face, Legs, Activity, Crying, Consolability) scale. FLACC scores at the first 24th hours were lower in the L-ESP group than the control group ( p  < 0.001). Rescue opioid utilization was higher in the control group (15/26) than in the L-ESP group (2/29) ( p  < 0.001). The consumption of ibuprofen was higher in the control group than in the L-ESP group in the ward (24/26 vs. 3/29, p  < 0.001, respectively). Parental satisfaction was superior in the L-ESP group ( p  = 0.024). To provide postoperative analgesia for DDH surgery, ultrasound-guided L-ESP may be an effective and alternative regional anesthetic technique.

PurposeBreast surgery is an exceedingly common procedure and associated with an increased incidence of acute and chronic pain. Preemptive regional anesthesia techniques may improve postoperative analgesia for patients undergoing breast surgery. The aim of this study was to evaluate the effect of preoperative bilateral serratus plane block on postoperative opioid consumption in patients undergoing breast reduction surgery.MethodsAfter ethical board approval, 40 patients undergoing breast reduction surgery were randomized into 2 groups: control group (Group C, n = 20) and serratus plane block group (Group SPB, n = 20). Group C received bilateral ultrasound-guided 2 ml 0.9% saline subcutaneously each block side, Group SPB received ultrasound-guided bilateral SPB with 0.25% bupivacaine 30 ml each side. The groups were administered the routine general anesthesia protocol. All operations were performed with the mediocentral pedicled reduction mammaplasty technique by the same surgeon. Postoperative analgesia was performed intravenously in the 2 groups twice a day with dexketoprofen trometamol 50 mg and patient-controlled analgesia with fentanyl. Postoperative analgesia was evaluated using the visual analog scale (VAS). Fentanyl consumption, additional analgesia requirement and opioid-related side effects were recorded during the first 24 h after surgery.ResultsCompared with control, the VAS score was statistically lower in the SPB group during all measurement times (p < 0.05). The 24-h opioid consumption was significantly higher in the control group compared with the SPB group (372.50 ± 39.65 vs. 296.25 ± 58.08 μq, respectively; p < 0.001). In addition, the analgesia requirement was statistically lower in the SPB group (8/20 vs. 2/20, respectively, p < 0.028). Nausea or vomiting was observed more often in the control group than in SPB block (9/20 vs. 2/20, respectively, p = 0.013), whereas other side effects were similar for the two groups.ConclusionsSPB can be used safely bilaterally in the management of pain for breast reduction surgery as it is easy to perform, provides excellent analgesia, and reduces opioid consumption and opioid sparing effect.Level of Evidence IIThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Background Varicocele occurs as a result of dilatation of the pampiniform plexus in the spermatic veins. In this study, our primary aim was to evaluate the effect of Transversalis Fascia Plane Block (TFPB) on pain scores in the postoperative period in patients undergoing varicocelectomy surgery, and our secondary aim was to evaluate the effect of TFPB on analgesic consumption. Methods The study was initiated following local ethics committee approval, and sixty ASA I-II patients > 18y scheduled to undergo varicocelectomy and who consented to participation were enrolled. Before the procedure, the patients were randomly assigned two groups: Transversalis Fascia Plan block group (Group TFPB) or surgical incision site infiltration group (Group I).All surgeries were carried out under general anesthesia, and microsurgery using the subinguinal approach. After surgical suturing, TFPB and local infiltration blocks were applied prior to termination of anesthesia.For each block, 20 mL of 0.25% bupivacaine was utilized. Patients' demographic information, passive and active VAS ratings after surgery, usage of non steroidal anti-inflammatory medications and rescue analgesia, and the requirement for rescue analgesia, were recorded. Results A total of 60 patients were included in the study. In terms of demographic data, there was no difference between the groups. At all hours, there was a statistically significant decrease in favor of Group TFPB in terms of active and passive VAS scores ( p  < 0.001), non steroidal anti-inflammatory analgesic use ( p  < 0.05), and tramadol requirement ( p  < 0.001). Conclusion This study has shown that TFPB can provide a more effective analgesia when compared to surgical site infiltration.

This guide provides background and examples for the use of practical aggregate grading tools to improve aggregate performance in concrete and allow the paste content of a concrete mixture to be reduced while achieving satisfactory workability and physical properties. The aggregate grading of a concrete mixture impacts the workability, durability, strength, and sustainability of concrete. These grading tools can also be used to proportion concrete mixtures as well as troubleshoot issues associated with mixtures from high to low workability. This guide docs not make recommendations, but it does describe and give examples on how to use these tools.