Background:
While various techniques have been described to augment the anterolateral side of the knee, such as lateral extra-articular tenodesis and anterolateral ligament (ALL) reconstruction ...(ALLR), it is unclear how they affect clinical outcomes. The aim of this study was to compare the results of 2 ALLR techniques for combined anterior cruciate ligament (ACL)/ALL reconstruction.
Hypothesis:
The graft rupture rate, complications, and patient-reported outcomes are similar between a reconstruction technique using a continuous gracilis graft (CG) and single femoral tunnel for ACL/ALL reconstruction, and one using a separate gracilis graft (SG) and independent femoral tunnels.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
A retrospective analysis of data collected prospectively at 2 hospitals was conducted: one in which a CG is preferred when performing combined ACL/ALL reconstruction and the other in which an SG is preferred. The medical records at these 2 hospitals were searched to identify ACL-deficient patients who had undergone ACL/ALL reconstruction between 2015 and 2020. Eligible patients were between 18 and 60 years of age, had the reconstruction surgery done within 24 months of the injury, and had ≥2 years of follow-up. The eligible patients were contacted to gather outcomes, or their outcomes were collected in person during their last follow-up visit. Outcomes evaluated included graft rupture rate, complication rate, and Lysholm and International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) scores. Preoperative and intraoperative data were also evaluated.
Results:
A total of 237 patients were available for analysis in the GC group and 178 in the SG group with a mean follow-up of 3 years (CG: SD, 9.6 months; SG: SD, 8.1 months). The authors found a low rate of graft rupture (CG: 3.4%; SG: 2.8%; P = .785) and no difference between techniques. The complication rate was 6% in the CG group, while it was 10% in the SG group (P = .112). The mean value of the IKDC-SKF was similar between techniques (CG: 88.1; SG: 87.9; P = .267), and the mean Lysholm score was excellent in both sets of patients (CG: 90.0; SG: 92.4; P < .001).
Conclusion:
This study found little to no difference in the graft rupture rate, complication rate, and functional knee scores when using a CG or SG for ALLR during combined ACL/ALL reconstruction. Both techniques are equivalent and can be used for an anterolateral augmentation procedure in combination with ACL reconstruction.
Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in ...epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5'UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient's fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.
Highly identical segmental duplications (SDs) account for over 5% of the human genome and are enriched in the short arm of the chromosome 16. These SDs are susceptibility factors for recurrent ...chromosomal rearrangements mediated by non-allelic homologous recombination (NAHR). Chromosomal microarray analysis (CMA) has been widely used as the first-tier test for individuals with developmental disabilities and/or congenital anomalies and several genomic disorders involving the 16p-arm have been identified with this technique. However, the resolution of CMA and the limitations of short-reads whole genome sequencing (WGS) technology do not allow the full characterization of the most complex chromosomal rearrangements. Herein, we report on two unrelated patients with a de novo 16p13.11p11.2 triplication associated with a 16p11.2 duplication, detected by CMA. These patients share a similar phenotype including hypotonia, severe neurodevelopmental delay with profound speech impairment, hyperkinetic behavior, conductive hearing loss, and distinctive facial features. Short-reads WGS could not map precisely any of the rearrangement's breakpoints that lie within SDs. We used optical genome mapping (OGM) to determine the relative orientation of the triplicated and duplicated segments as well as the genomic positions of the breakpoints, allowing us to propose a mechanism involving recombination between allelic SDs and a NAHR event. In conclusion, we report a new clinically recognizable genomic disorder. In addition, the mechanism of these complex chromosomal rearrangements involving SDs could be unraveled by OGM.
Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different ...mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.
Deletions of the long arm of chromosome 20 (20q) are rare, with only 16 reported patients displaying a proximal interstitial 20q deletion. A 1.62 Mb minimal critical region at 20q11.2, encompassing ...three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome. The leading clinical features include growth retardation, intractable feeding difficulties with gastroesophageal reflux, hypotonia and psychomotor developmental delay. Common facial dysmorphisms including triangular face, hypertelorism, and hypoplastic alae nasi were additionally reported. Here, we present the clinical and molecular findings of five new patients with proximal interstitial 20q deletions. We analyzed the phenotype and molecular data of all previously reported patients with 20q11.2q12 microdeletions, along with our five new cases. Copy number variation analysis of patients in our cohort has enabled us to identify the second critical region in the 20q11.2q12 region and redefine the first region that is initially identified. The first critical region spans 359 kb at 20q11.2, containing six MIM genes, including two disease‐causing genes, GDF5 and CEP250. The second critical region spans 706 kb at 20q12, encompassing four MIM genes, including two disease‐causing genes, MAFB and TOP1. We propose GDF5 to be the primary candidate gene generating the phenotype of patients with 20q11.2 deletions. Moreover, we hypothesize TOP1 as a potential candidate gene for the second critical region at 20q12. Of note, we cannot exclude the possibility of a synergistic role of other genes involved in the deletion, including a contiguous gene deletion syndrome or position effect affecting both critical regions. Further studies focusing on patients with proximal 20q deletions are required to support our hypothesis.
First reports of fetal SMARCC1 related hydrocephalus Rive Le Gouard, Nicolas; Nicolle, Romain; Lefebvre, Mathilde ...
European journal of medical genetics,
August 2023, 2023-Aug, 2023-08-00, 20230801, Volume:
66, Issue:
8
Journal Article
Peer reviewed
The SMARCC1 gene has been involved in congenital ventriculomegaly with aqueduct stenosis but only a few patients have been reported so far, with no antenatal cases, and it is currently not annotated ...as a morbid gene in OMIM nor in the Human Phenotype Ontology. Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents. SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes. Here, we report the two first antenatal cases of SMARCC1 LoF variants detected by Whole Genome Sequencing (WGS). Ventriculomegaly is the common feature in those fetuses. Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene. This makes the identification of this condition in WGS as well as the genetic counseling challenging.
Despite considerable achievements of combustion kinetics, the chemical kinetic impacts of trace promoting species on practical fuel combustion has been hitherto handled seperately either as ignition ...or extinction-related effects, overlooking the impact of the extinction process on re-ignition kinetics. We herein demonstrate the applicability of oscillatory stirred reactor configuration to quantify the combined impacts of the methyl radical on ignition/extinction of primary reference fuels (PRF) in stoichiometric and ultra-lean conditions, thereby complementing steady-state configurations for kinetic mechanism validation. A new convenient reactivity metric is proposed based on the matching of temperature Fourier spectrum of additivated fuels with corresponding PRF. Using a new skeletal mechanism obtained from calibration on a variety of ignition experiments, we characterize ignition regimes by CEMA analysis and highlight the key reactions of the C1-C3 reaction subsets that should be included in minimal skeletal mechanisms used in reactive CFD modeling to properly describe re-ignition phenomena over a variety of new combustion applications involving methyl radical injection.
Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in ...patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI.
CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG).
At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval CI, 63.9%–95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%–85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%–96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%–96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%–79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%–100%; specificity, 100%).
In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.
Devic’s neuromyelitis optica is an inflammatory demyelinating disorder normally restricted to the optic nerves and spinal cord. Since the identification of a specific autoantibody directed against ...aquaporin 4, neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody, neuromyelitis optica has been considered an entity distinct from multiple sclerosis. Recent findings indicate that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody has a pathogenic role through complement-dependent astrocyte toxicity. However, the link with demyelination remains elusive. Autoantibodies can act as receptor agonists/antagonists or alter antigen density in their target cells. We hypothesized that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody impairs astrocytic function and secondarily leads to demyelination. Rat astrocytes and oligodendrocytes from primary cultures and rat optic nerves were exposed long-term (24 h) to immunoglobulin G in the absence of complement. Immunoglobulin G was purified from the serum of patients with neuromyelitis optica who were either neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive or negative, as well as from healthy controls. Flow cytometry analysis showed a reduction of membrane aquaporin 4 and glutamate transporter type 1 on astrocytes following contact with immunoglobulin G purified from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive serum only. The activity of glutamine synthetase, an astrocyte enzyme converting glutamate into glutamine, decreased in parallel, indicating astrocyte dysfunction. Treatment also reduced oligodendrocytic cell processes and approximately 30% oligodendrocytes died. This deleterious effect was confirmed ex vivo; exposed optic nerves showed reduction of myelin basic protein. Immunoglobulin G from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody seronegative patients and from healthy controls had no similar effect. Neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody did not directly injure oligodendrocytes cultured without astrocytes. A toxic bystander effect of astrocytes damaged by neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on oligodendrocytes was identified. Progressive accumulation of glutamate in the culture medium of neuromyelitis optica-immunoglobulin G/aquaporin 4-antibody-treated glial cells supported the hypothesis of a glutamate-mediated excitotoxic death of oligodendrocytes in our models. Moreover, co-treatment of glial cultures with neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody and d+2-amino-5-phosphonopentanoic acid, a competitive antagonist at the N-methyl-d-aspartate/glutamate receptor, partially protected oligodendrocytes. Co-immunolabelling of oligodendrocyte markers and neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody showed that astrocytic positive processes were in close contact with oligodendrocytes and myelin in rat optic nerves and spinal cord, but far less so in other parts of the central nervous system. This suggests a bystander effect of neuromyelitis optica-immunoglobulin G-damaged astrocytes on oligodendrocytes in the nervous tissues affected by neuromyelitis optica. In conclusion, in these cell culture models we found a direct, complement-independent effect of neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on astrocytes, with secondary damage to oligodendrocytes possibly resulting from glutamate-mediated excitotoxicity. These mechanisms could add to the complement-induced damage, particularly the demyelination, seen in vivo.
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