Local bone metabolism during the consolidation process of spinal interbody fusion

INTRODUCTION: Although computed tomography (CT) can identify the presence of eventual bony bridges following lumbar interbody fusion (LIF) surgery, it does not provide information on the ongoing formation process of new bony structures. 18F sodium fluoride (18F-NaF) positron emission tomography (PET) could be used as complementary modality to add information on the bone metabolism at the fusion site. However, it remains unknown how bone metabolism in the operated segment changes early after surgery in uncompromised situations. This study aimed to quantify the changes in local bone metabolism during consolidation of LIF. MATERIALS AND METHODS: Six skeletally mature sheep underwent LIF surgery. 18F-NaF PET/CT scanning was performed 6 and 12 weeks postoperatively to quantify the bone volume and metabolism in the operated segment. Bone metabolism was expressed as a function of bone volume. RESULTS: Early in the fusion process, bone metabolism was increased at the endplates of the operated vertebrae. In a next phase, bone metabolism increased in the center of the interbody region, peaked, and declined to an equilibrium state. During the entire postoperative time period of 12 weeks, bone metabolism in the interbody region was higher than that of a reference site in the spinal column. CONCLUSION: Following LIF surgery, there is a rapid increase in bone metabolism at the vertebral endplates that develops towards the center of the interbody region. Knowing the local bone metabolism during uncompromised consolidation of spinal interbody fusion might enable identification of impaired bone formation early after LIF surgery using 18F-NaF PET/CT scanning

Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

From Springer Nature via Jisc Publications RouterHistory: received 2021-03-09, accepted 2021-09-13, registration 2021-10-01, online 2021-10-18, pub-electronic 2021-10-18, collection 2021-12Publication status: PublishedFunder: Wellcome Trust; Grant(s): RP-2016-07-011, 200990/Z/16/ZFunder: Health Education EnglandAbstract: The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being ‘pathogenic’ or ‘benign’ is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as ‘pathogenic’ or ‘likely pathogenic’; one in five of these cases could lead to new or refined diagnoses

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Early bone ingrowth and segmental stability of a trussed titanium cage versus a polyether ether ketone cage in an ovine lumbar interbody fusion model

BACKGROUND CONTEXT: Lumbar interbody fusion is an effective treatment for unstable spinal segments. However, the time needed to establish a solid bony interbody fusion between the two vertebrae may be longer than twelve months after surgery. During this time window, the instrumented spinal segment is assumed to be at increased risk for instability related complications such as cage migration or subsidence. It is hypothesized that the design of new interbody cages that enable direct osseointegration of the cage at the vertebral endplates, without requiring full bony fusion between the two vertebral endplates, might shorten the time window that the instrumented spinal segment is susceptible to failure. PURPOSE: To quantify the bone ingrowth and resulting segmental stability during consolidation of lumbar interbody fusion using two different cage types. STUDY DESIGN: Preclinical ovine model. METHODS: Seven skeletally mature sheep underwent bi-segmental lumbar interbody fusion surgery with one conventional polyether ether ketone (PEEK) cage, and one newly developed trussed titanium (TT) cage. After a postoperative time period of 13 weeks, non-destructive range of motion testing and histological analysis were performed. Additionally, sample specific finite element (FE) analysis was performed to predict the stability of the interbody fusion region alone. RESULTS: Physiological movement of complete spinal motion segments did not reveal significant differences between the segments operated with PEEK and TT cages. The onset of creeping substitution within the cage seemed to be sooner for PEEK cages, which led to significantly higher bone volume over total volume (BV/TV) compared to the TT cages. TT cages showed significantly more direct bone to implant contact (BIC). Although the mean stability of the interbody fusion region alone was not statistically different between the PEEK and TT cages, the variation within the cage types illustrated an all-or-nothing response for the PEEK cages while a more gradual increase in stability was found for the TT cages. CONCLUSIONS: Spinal segments operated with conventional PEEK cages were not different from those operated with newly developed TT cages in terms of segmental stability but did show a different mechanism of bone ingrowth and attachment. Based on the differences in development of bony fusion, we hypothesize that TT cages might facilitate increased early segmental stability by direct osseointegration of the cage at the vertebral endplates without requiring complete bony bridging through the cage. CLINICAL SIGNIFICANCE: Interbody cage type affects the consolidation process of spinal interbody fusion. Whether different consolidation processes of spinal interbody fusion result in clinically significant differences requires further investigation

Early bone ingrowth and segmental stability of a trussed titanium cage versus a polyether ether ketone cage in an ovine lumbar interbody fusion model

BACKGROUND CONTEXT: Lumbar interbody fusion is an effective treatment for unstable spinal segments. However, the time needed to establish a solid bony interbody fusion between the two vertebrae may be longer than twelve months after surgery. During this time window, the instrumented spinal segment is assumed to be at increased risk for instability related complications such as cage migration or subsidence. It is hypothesized that the design of new interbody cages that enable direct osseointegration of the cage at the vertebral endplates, without requiring full bony fusion between the two vertebral endplates, might shorten the time window that the instrumented spinal segment is susceptible to failure. PURPOSE: To quantify the bone ingrowth and resulting segmental stability during consolidation of lumbar interbody fusion using two different cage types. STUDY DESIGN: Preclinical ovine model. METHODS: Seven skeletally mature sheep underwent bi-segmental lumbar interbody fusion surgery with one conventional polyether ether ketone (PEEK) cage, and one newly developed trussed titanium (TT) cage. After a postoperative time period of 13 weeks, non-destructive range of motion testing and histological analysis were performed. Additionally, sample specific finite element (FE) analysis was performed to predict the stability of the interbody fusion region alone. RESULTS: Physiological movement of complete spinal motion segments did not reveal significant differences between the segments operated with PEEK and TT cages. The onset of creeping substitution within the cage seemed to be sooner for PEEK cages, which led to significantly higher bone volume over total volume (BV/TV) compared to the TT cages. TT cages showed significantly more direct bone to implant contact (BIC). Although the mean stability of the interbody fusion region alone was not statistically different between the PEEK and TT cages, the variation within the cage types illustrated an all-or-nothing response for the PEEK cages while a more gradual increase in stability was found for the TT cages. CONCLUSIONS: Spinal segments operated with conventional PEEK cages were not different from those operated with newly developed TT cages in terms of segmental stability but did show a different mechanism of bone ingrowth and attachment. Based on the differences in development of bony fusion, we hypothesize that TT cages might facilitate increased early segmental stability by direct osseointegration of the cage at the vertebral endplates without requiring complete bony bridging through the cage. CLINICAL SIGNIFICANCE: Interbody cage type affects the consolidation process of spinal interbody fusion. Whether different consolidation processes of spinal interbody fusion result in clinically significant differences requires further investigation

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD