Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Activation of the cGAS-STING innate immune response in cells with deficient mitochondrial topoisomerase TOP1MT.

The recognition that cytosolic mitochondrial DNA (mtDNA) activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect TOP1MT function, P193L, was discovered in a family with multiple early onset autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Although there was no previous genetic association between TOP1MT and autoimmune disease, the role of TOP1MT as a regulator of mtDNA led us to investigate whether TOP1MT could mediate the release of mtDNA to the cytosol, where it could then activate the cGAS-STING innate immune pathway known to be activated in SLE and other autoimmune diseases. Through analysis of cells with reduced TOP1MT expression, we show that loss of TOP1MT results in release of mtDNA to the cytosol, which activates the cGAS-STING pathway. We also characterized the P193L variant for its ability to rescue several TOP1MT functions when expressed in TOP1MT knockout cells. We show that the P193L variant is not fully functional, as its re-expression at high levels was unable to rescue mitochondrial respiration deficits, and only showed partial rescue for other functions, including repletion of mtDNA replication following depletion, nucleoid size, steady state mtDNA transcripts levels and mitochondrial morphology. Additionally, expression of P193L at endogenous levels was unable to rescue mtDNA release-mediated cGAS-STING signaling. Overall, we report a link between TOP1MT and mtDNA release leading to cGAS-STING activation. Moreover, we show that the P193L variant has partial loss of function that may contribute to autoimmune disease susceptibility via cGAS-STING mediated activation of the innate immune system.

Cholangiocytes Modulate CD100 Expression in the Liver and Facilitate Pathogenic T-Helper 17 Cell Differentiation.

BACKGROUND & AIMS: Chronic inflammation surrounding bile ducts contributes to the disease pathogenesis of most cholangiopathies. Poor efficacy of immunosuppression in these conditions suggests biliary-specific pathologic principles. Here we performed biliary niche specific functional interpretation of a causal mutation (CD100 K849T) of primary sclerosing cholangitis (PSC) to understand related pathogenic mechanisms. METHODS: Biopsy specimens of explanted livers and endoscopy-guided sampling were used to assess the CD100 expression by spatial transcriptomics, immune imaging, and high-dimensional flow cytometry. To model pathogenic cholangiocyte-immune cell interaction, splenocytes from mutation-specific mice were cocultured with cholangiocytes. Pathogenic pathways were pinpointed by RNA sequencing analysis of cocultured cells and cross-validated in patient materials. RESULTS: CD100 is mainly expressed by immune cells in the liver and shows a unique pattern around PSC bile ducts with RNA-level colocalization but poor detection at the protein level. This appears to be due to CD100 cleavage as soluble CD100 is increased. Immunophenotyping suggests biliary-infiltrating T cells as the major source of soluble CD100, which is further supported by reduced surface CD100 on T cells and increased metalloproteinases in cholangiocytes after coculturing. Pathogenic T cells that adhered to cholangiocytes up-regulated genes in the T-helper 17 cell differentiation pathway, and the CD100 mutation boosted this process. Consistently, T-helper 17 cells dominate biliary-resident CD4 T cells in patients. CONCLUSIONS: CD100 exerts its functional impact through cholangiocyte-immune cell cross talk and underscores an active, proinflammatory role of cholangiocytes that can be relevant to novel treatment approaches.

Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.

INTRODUCTION: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. METHODS: Good manufacturing practice [2-13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner. RESULTS: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13 C]lactate, TCA-associated metabolite [5-13 C]glutamate, and [1-13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). CONCLUSIONS: HP [2-13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Revealing parental mosaicism: the hidden answer to the recurrence of apparent de novo variants.

Mosaicism refers to the presence of two or more populations of genetically distinct cells within an individual, all of which originate from a single zygote. Previous literature estimated the percentage of parental mosaicism ranged from 0.33 to 25.9%. In this study, parents whose children had previously been diagnosed with developmental disorders with an apparent de novo variant were recruited. Peripheral blood, buccal and semen samples were collected from these parents if available for the detection of potential parental mosaicism using droplet digital PCR, complemented with the method of blocker displacement amplification. Among the 20 families being analyzed, we report four families with parental mosaicism (4/20, 20%). Two families have maternal gonosomal mosaicism (EYA1 and EBF3) and one family has paternal gonadal mosaicism (CHD7) with a pathogenic/ likely pathogenic variant. One family has a paternal gonosomal mosaicism with a variant of uncertain significance (FLNC) with high clinical relevance. The detectable variant allele frequency in our cohort ranged from 8.7-35.9%, limit of detection 0.08-0.16% based on our in-house EBF3 assay. Detecting parental mosaicism not only informs family with a more accurate recurrence risk, but also facilitates medical teams to create appropriate plans for pregnancy and delivery, offering the most suitable care.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population.

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

Prioritize Variant Reclassification in Pediatric Long QT Syndrome-Time to Revisit.

Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome associated with sudden cardiac death. Accurate interpretation and classification of genetic variants in LQTS patients are crucial for effective management. All patients with LQTS with a positive genetic test over the past 18 years (2002-2020) in our single tertiary pediatric cardiac center were identified. Reevaluation of the reported variants in LQTS genes was conducted using the American College of Genetics and Genomics (ACMG) guideline after refinement by the US ClinGen SVI working group and guideline by Walsh et al. on genetic variant reclassification, under multidisciplinary input. Among the 59 variants identified. 18 variants (30.5%) were reclassified. A significant larger portion of variants of unknown significance (VUS) were reclassified compared to likely pathogenic (LP)/pathogenic (P) variants (57.7% vs 9.1%, p < 0.001). The rate of reclassification was significantly higher in the limited/disputed evidence group compared to the definite/moderate evidence group (p = 0.0006). All LP/P variants were downgraded in the limited/disputed evidence group (p = 0.0057). VUS upgrades are associated with VUS located in genes within the definite/moderate evidence group (p = 0.0403) and with VUS present in patients exhibiting higher corrected QT intervals (QTc) (p = 0.0445). A significant number of pediatric LQTS variants were reclassified, particularly for VUS. The strength of the gene-disease association of the genes influences the reclassification performance. The study provides important insights and guidance for pediatricians to seek for reclassification of "outdated variants" in order to facilitate contemporary precision medicine.

Super-Obesity is Associated With an Increased Risk of Complications Following Primary Total Knee Arthroplasty.

BACKGROUND: Obesity, defined as a body mass index (BMI) ≥ 30, is an ever-growing epidemic, with > 35% of adults in the United States currently classified as obese. Super-obese individuals, defined as those who have a BMI ≥ 50, are the fastest-growing portion of this group. This study sought to quantify the infection risk as well as the incidence of surgical, medical, and thromboembolic complications among super-obese patients undergoing total knee arthroplasty (TKA). METHODS: An all-payer claims database was used to identify patients who underwent elective, primary TKA between 2016 and 2021. Patients who had a BMI ≥ 50 were compared to those who had a normal BMI of 18 to 25. Demographics and the incidence of 90-days postoperative complications were compared between the 2 groups. Univariate analysis and multivariable regression were used to assess differences between groups. RESULTS: In total, 3,376 super-obese TKA patients were identified and compared to 17,659 patients who had a normal BMI. Multivariable analysis indicated that the super-obese cohort was at an increased postoperative risk of periprosthetic joint infection (adjusted odds ratio [aOR] 3.7, 95% confidence interval [CI]: 2.1 to 6.4, P < .001), pulmonary embolism (aOR 2.2, 95%-CI: 1.0 to 5.0, P = .047), acute respiratory failure (aOR 4.1, 95%-CI: 2.7 to 6.1, P < .001), myocardial infarction (aOR 2.5, 95%-CI: 1.1 to 5.8, P = .026), wound dehiscence (aOR 2.3, 95%-CI: 1.4 to 3.8, P = .001), and acute renal failure (aOR 3.2, 95%-CI: 2.4 to 4.2, P < .001) relative to patients who have normal BMI. CONCLUSIONS: Super-obese TKA patients are at an elevated risk of postoperative infectious, surgical, medical, and thromboembolic complications. As such, risk stratification, as well as appropriate medical management and optimization, is of utmost importance for this high-risk group.

Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.

Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and/or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging.

Hyperpolarized [2-13C]pyruvate MR molecular imaging with whole brain coverage.

Hyperpolarized (HP) 13C Magnetic Resonance Imaging (MRI) was applied for the first time to image and quantify the uptake and metabolism of [2-13C]pyruvate in the human brain to provide new metabolic information on cerebral energy metabolism. HP [2-13C]pyruvate was injected intravenously and imaged in 5 healthy human volunteer exams with whole brain coverage in a 1-minute acquisition using a specialized spectral-spatial multi-slice echoplanar imaging (EPI) pulse sequence to acquire 13C-labeled volumetric and dynamic images of [2-13C]pyruvate and downstream metabolites [5-13C]glutamate and [2-13C]lactate. Metabolic ratios and apparent conversion rates of pyruvate-to-lactate (kPL) and pyruvate-to-glutamate (kPG) were quantified to investigate simultaneously glycolytic and oxidative metabolism in a single injection.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations.

PURPOSE: This meta-analysis aims to compare the diagnostic and clinical utility of exome sequencing (ES) vs genome sequencing (GS) in pediatric and adult patients with rare diseases across diverse populations. METHODS: A meta-analysis was conducted to identify studies from 2011 to 2021. RESULTS: One hundred sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of ES (0.38, 95% CI 0.36-0.40) and GS (0.34, 95% CI 0.30-0.38) were similar (P = .1). Within-cohort comparison illustrated 1.2-times odds of diagnosis by GS over ES (95% CI 0.79-1.83, P = .38). GS studies discovered a higher range of novel genes than ES studies; yet, the rate of variant of unknown significance did not differ (P = .78). Among high-quality studies, clinical utility of GS (0.77, 95% CI 0.64-0.90) was higher than that of ES (0.44, 95% CI 0.30-0.58) (P < .01). CONCLUSION: This meta-analysis provides an important update to demonstrate the similar diagnostic rates between ES and GS and the higher clinical utility of GS over ES. With the newly published recommendations for clinical interpretation of variants found in noncoding regions of the genome and the trend of decreasing variant of unknown significance and GS cost, it is expected that GS will be more widely used in clinical settings.

Prenatal diagnosis of Myhre syndrome with a heterozygous pathogenic variant in SMAD4 gene presented with thick nuchal translucency and cardiac abnormalities.

Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability.

PURPOSE: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gßγ units. Human diseases have been reported for all five Gß proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort. METHODS: We discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants. RESULTS: We identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction. CONCLUSION: Missense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum.

BACKGROUND: O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility. METHODS: Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible. RESULTS: We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances. CONCLUSION: Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

The Utility of Routine Postoperative Radiographs in the Asymptomatic Total Hip Arthroplasty Patient.

BACKGROUND: Total hip arthroplasty (THA) patients often receive routine radiographs in the year following their index surgery. This study sought to investigate the clinical and economic value of obtaining routine postoperative hip radiographs for asymptomatic patients following primary elective THA. METHODS: A retrospective cohort study of consecutive patients who underwent primary elective THA from 2016 to 2019 was conducted. Patients undergoing nonelective or revision THA, radiographic follow-up <10 months, and patients aged <18 years were excluded. All radiographs were reviewed for abnormalities in the first postoperative year by an arthroplasty fellowship-trained orthopaedic surgeon, blinded to the symptoms of the patient. RESULTS: Of the 327 patients (351 hips) included, 57.2% were women and 68.2% were White, with an average age of 65 years (range, 22-97 years) and average body mass index of 29.1 kg/m2 (range, 16.2-49.8 kg/m2). Only four (0.4%) radiographic series revealed abnormalities with the potential to alter postoperative management. One patient experienced a change in management directly related to their abnormal finding (closed reduction for dislocation at 10.2 months postoperatively). The remaining three abnormal radiographic findings included femoral stem subsidence, progressive radiolucencies around an acetabular component, and cement mantle fracture. The average cost for each radiographic series was $155.27, resulting in total direct charges of $167,691.60. CONCLUSION: Routine postoperative radiographs may be of limited utility in the asymptomatic patient in the first year following elective primary THA. Consideration should be given to limit postoperative radiographs following standard elective THA, while reserving postoperative radiographic evaluation for patients who are symptomatic. LEVEL OF EVIDENCE: Level III.

Ceramic Femoral Heads Exhibit Lower Wear Rates Compared to Cobalt Chrome: A Meta-Analysis.

BACKGROUND: Wear between the femoral head and acetabular liners continues to limit the longevity of total hip arthroplasty implants despite advances in implant materials. The purpose of this meta-analysis was to compare linear wear rates of cobalt-chromium (CoCr) and fourth-generation ceramic femoral heads on highly cross-linked polyethylene (XLPE) liners. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted to identify all studies between 2003 and 2020 that examined in vivo wear rates of either fourth-generation ceramics or CoCr femoral heads on XLPE liners. Studies were analyzed in a weighted means analysis of wear rates and a random effects meta-analysis. RESULTS: A total of 36 studies met inclusion criteria (1,657 CoCr and 659 ceramic patients). The pooled, weighted mean wear rate was 0.063 mm/year (standard deviation [SD]: 0.061, confidence interval [CI]: 0.049-0.077) for CoCr and 0.047 mm/year (SD: 0.057, CI: 0.033-0.062; P < .01) for ceramic (P < .01). A meta-analysis of 4 studies directly comparing ceramic and CoCr found that CoCr heads demonstrated 0.029 mm/year more wear than ceramic heads (95% CI: 0.026-0.059, P = .306). Mean wear for 32-mm heads was significantly higher for ceramic (P < .01), while mean wear for 36-mm heads was significantly higher for CoCr (P < .01). CONCLUSION: Fourth-generation ceramic femoral heads were found to have significantly lower wear rates than CoCr heads. Unlike previous studies, this meta-analysis included only in vivo studies and those with the same generation of highly XLPE liners.