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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
BMC Biol ; 19(1): 142, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294116

RESUMO

BACKGROUND: The opportunistic pathogen Naegleria fowleri establishes infection in the human brain, killing almost invariably within 2 weeks. The amoeba performs piece-meal ingestion, or trogocytosis, of brain material causing direct tissue damage and massive inflammation. The cellular basis distinguishing N. fowleri from other Naegleria species, which are all non-pathogenic, is not known. Yet, with the geographic range of N. fowleri advancing, potentially due to climate change, understanding how this pathogen invades and kills is both important and timely. RESULTS: Here, we report an -omics approach to understanding N. fowleri biology and infection at the system level. We sequenced two new strains of N. fowleri and performed a transcriptomic analysis of low- versus high-pathogenicity N. fowleri cultured in a mouse infection model. Comparative analysis provides an in-depth assessment of encoded protein complement between strains, finding high conservation. Molecular evolutionary analyses of multiple diverse cellular systems demonstrate that the N. fowleri genome encodes a similarly complete cellular repertoire to that found in free-living N. gruberi. From transcriptomics, neither stress responses nor traits conferred from lateral gene transfer are suggested as critical for pathogenicity. By contrast, cellular systems such as proteases, lysosomal machinery, and motility, together with metabolic reprogramming and novel N. fowleri proteins, are all implicated in facilitating pathogenicity within the host. Upregulation in mouse-passaged N. fowleri of genes associated with glutamate metabolism and ammonia transport suggests adaptation to available carbon sources in the central nervous system. CONCLUSIONS: In-depth analysis of Naegleria genomes and transcriptomes provides a model of cellular systems involved in opportunistic pathogenicity, uncovering new angles to understanding the biology of a rare but highly fatal pathogen.

3.
J Med Genet ; 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321325

RESUMO

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

4.
J Burn Care Res ; 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34329478

RESUMO

To better understand trends in burn treatment patterns related to definitive closure, this study sought benchmark real-world survey data with national data contained within the National Burn Repository version 8.0 (NBR v8.0) across key burn center practice patterns, resource utilization, and clinical outcomes. A survey, administered to a representative sample of US burn surgeons, collected information across several domains: burn center characteristics; patient characteristics including number of patients and burn size and depth; aggregate number of procedures; resource use such as autograft procedure time, and dressing changes; and costs. Survey findings were aggregated by key outcomes (number of procedures, costs) nationally and regionally. Aggregated burn center data were also compared to the NBR to identify trends relative to current treatment patterns. Benchmarking survey results against the NBR v8.0 demonstrated shifts in burn center patient mix, with more severe cases being seen in the inpatient setting and less severe burns moving to the outpatient setting. An overall reduction in the number of autograft procedures was observed compared to NBR v8.0, and time efficiencies improved as the intervention time per TBSA decreases as TBSA increases. Both nationally and regionally, an increase in costs were observed.The results suggest resource use estimates from NBR v8.0 may be higher than current practices, thus highlighting the importance of improved and timely NBR reporting and further research on burn center standard of care practices. This study demonstrates significant variations in burn center characteristics, practice patterns, and resource utilization thus increasing our understanding of burn center operations and behavior.

5.
Injury ; 52(8): 2475-2478, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34059323

RESUMO

INTRODUCTION: The calcaneus is the most commonly fractured hindfoot bone, accounting for over 60% of all tarsal fractures. The aim of this study was to compare the mechanism of injury and psychological health status in patients presenting with calcaneal fractures to an age- and sex-matched control group with ankle fractures. PATIENTS AND METHODS: This retrospective study was undertaken within an orthopaedic unit at a tertiary hospital. An electronic medical record chart review was performed to identify eligible patients. Descriptive statistics were used to summarise the demographic and clinical characteristics of the patients. Between-group differences were analysed with the Mann-Whitney U test and Fisher's exact test for continuous and categorical variables, respectively. Multivariable binary logistic regression was used to determine the relationship between fracture type and underlying psychopathology, adjusting for mechanism of injury. RESULTS: Two-hundred and fifteen patients met the eligibility criteria for calcaneal fractures and these patients were subsequently matched to 215 ankle fracture patients. Men accounted for 154 (71.6%) of the patients in each group. Over half (51.2%) of all calcaneal fractures were due to an uncontrolled fall above one-metre, as opposed to 26.0% of ankle fractures, p < 0.001. Falling from a standing height was more common in the ankle fracture group, 37 (17.2%) versus 10 (4.7%), p < 0.001. Patients with calcaneal fractures were more likely to have a diagnosed psychological health complaint, 63 (29.3%) versus 32 (14.9%), p < 0.001. Suicidal ideation was significantly more common in the calcaneal fracture group 14 (6.5%) versus 3 (1.4%), p = 0.011. The presence of premorbid psychopathology was associated with calcaneal fracture, after adjusting for mechanism of injury (odds ratio 2.20, 95% confidence interval 1.32 to 3.65, p = 0.003). CONCLUSION: Calcaneal and ankle fractures display differences in both the mechanism of injury and the history of psychological health conditions. However, after adjusting for the mechanism of injury, diagnosed premorbid psychopathology remains twice as likely in someone with a calcaneal fracture as opposed to an ankle fracture. It may be prudent for orthopaedic surgeons to consider further investigations of psychological health when managing patients with a calcaneal fracture.


Assuntos
Fraturas do Tornozelo , Calcâneo , Fraturas Ósseas , Transtornos Mentais , Fixação Interna de Fraturas , Fraturas Ósseas/complicações , Fraturas Ósseas/epidemiologia , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
6.
Otol Neurotol ; 42(8): e1143-e1151, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34049328

RESUMO

OBJECTIVES: To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD. BACKGROUND: Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown. METHODS: Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis. RESULTS: Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis. CONCLUSION: The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.


Assuntos
Deformidades Congênitas do Pé , Deformidades Congênitas da Mão , Sinostose , Ossos do Carpo/anormalidades , Heterogeneidade Genética , Humanos , Estribo/anormalidades , Sinostose/genética , Ossos do Tarso/anormalidades
7.
J Invertebr Pathol ; 183: 107598, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33957131

RESUMO

Genetically engineered crops expressing insecticidal toxins from Bacillus thuringiensis (Bt) have improved the management of targeted lepidopteran pests and reduced the use of insecticide sprays. These benefits explain an increasing adoption of Bt crops worldwide, intensifying the selection pressure on target species and the risk of resistance. Nucleopolyhedroviruses (NPVs) are effective bioinsecticides against numerous important lepidopteran pests. If Bt-resistant insects are shown to be susceptible to NPVs then these bioinsecticides could be a valuable component of Insecticide Resistance Management (IRM) strategies for Bt crops. We assessed the effectiveness of a Helicoverpa nucleopolyhedrovirus (HearNPV) against several different Bt-resistant strains. Utilising a droplet feeding bioassay we confirmed susceptibility to HearNPV in Helicoverpa punctigera and Helicoverpa armigera larvae resistant to the Bt toxins Cry1Ac, Cry2Ab, and Vip3A. Dual resistant H. punctigera, (Cry1Ac/Cry2Ab, and Cry2Ab/Vip3A) and dual resistant H. armigera (Cry2Ab/Vip3A) were also susceptible to HearNPV. Regardless of their specific resistance profile, Bt-resistant larvae displayed statistically similar lethal concentration (LC50) and lethal time (LT50) responses to HearNPV when compared to Bt-sensitive control insects. These results indicate that Bt-resistant H. armigera and H. punctigera are not cross-resistant to HearNPV. Consequently, the use of HearNPV against these pests may be a valuable tool to an IRM strategy for controlling Bt-resistant populations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33864888

RESUMO

BACKGROUND: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. OBJECTIVE: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management. METHODS: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. RESULTS: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. CONCLUSIONS: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.

9.
J Foot Ankle Surg ; 60(4): 692-696, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33546992

RESUMO

Research publication is a central to the scientific process and comprehensive bibliometric analysis is a leading way to better understand trends within research. Currently, there are limited bibliometric analyses of literature pertaining to foot and ankle surgery. This study aims to quantify the volume of research and investigate what may affect publication and citation. Journals associated with the 3 major orthopedic foot and ankle societies (Foot & Ankle International[FAI], Foot and Ankle Surgery, and The Foot) and one podiatric college (Journal of Foot and Ankle Surgery®) were evaluated from January 2009 to December 2018 using Scopus (Elsevier, Amsterdam, the Netherlands). Descriptive statistics were used to summarize article characteristics and regression modeling was used to determine factors associated with a country's current and future productivity and an article's citation rate. A total of 4994 articles were published over the 10-year period, with the largest contributor of publications being the United States of America (USA), who produced 2096 (41.8%) publications. Regression analysis found no association between a country's productivity and gross domestic product or population. There was no significant relationship between a country's baseline publication rate and future publication rate. The variables significantly associated with an increased citation count were; the number of years since publication, the number of authors, publication in FAI and if the article was a review. To our knowledge this is the largest bibliometric analysis of foot and ankle publications. The majority of research is being produced by the USA, but there are numerous complex factors associated with citation and publication rates. Further research is required to fully assess these factors and characterize the state of foot and ankle surgery research.


Assuntos
Ortopedia , Publicações Periódicas como Assunto , Tornozelo , Bibliometria , Humanos , Países Baixos , Estados Unidos
10.
Transbound Emerg Dis ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33560563

RESUMO

The European rabbit (Oryctolagus cuniculus) is one of the most devastating invasive species in Australia. Since the 1950s, myxoma virus (MYXV) and rabbit haemorrhagic disease virus (RHDV) have been used to manage overabundant rabbit populations. Resistance to MYXV was observed within a few years of the release. More recently, resistance to lethal RHDV infection has also been reported, undermining the efficiency of landscape-scale rabbit control. Previous studies suggest that genetic resistance to lethal RHDV infection may differ locally between populations, yet the mechanisms of genetic resistance remain poorly understood. Here, we used genotyping by sequencing (GBS) data representing a reduced representation of the genome, to investigate Australian rabbit populations. Our aims were to understand the relationship between populations and identify possible genomic signatures of selection for RHDV resistance. One population we investigated had previously been reported to show levels of resistance to lethal RHDV infection. This population was compared to three other populations with lower or no previously reported RHDV resistance. We identified a set of novel candidate genes that could be involved in host-pathogen interactions such as virus binding and infection processes. These genes did not overlap with previous studies on RHDV resistance carried out in different rabbit populations, suggesting that multiple mechanisms are feasible. These findings provide useful insights into the different potential mechanisms of genetic resistance to RHDV virus which will inform future functional studies in this area.

11.
Ann Surg Oncol ; 28(8): 4553-4560, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33423175

RESUMO

BACKGROUND: Surgical resection remains the cornerstone of ovarian cancer management. In 2017, the authors implemented a multi-disciplinary surgical team comprising gynecologic oncologists as well as colorectal, hepatobiliary, and upper gastrointestinal (GI) surgeons to increase gross macroscopic resection rates. This report aims to describe changes in complete cytoreduction rates and morbidity after the implementation of a multi-disciplinary surgical team comprising gynecologic oncologists as well as colorectal, hepatobiliary, and upper GI surgeons in a tertiary gynecologic oncology unit. METHODS: The study used two cohorts. Cohort A was a retrospectively collated cohort from 2006 to 2015. Cohort B was a prospectively collated cohort of patients initiated in 2017. A multidisciplinary approach to preoperative medical optimization, intraoperative management, and postoperative care was implemented in 2017. The patients in cohort B with upper abdominal disease were offered primary cytoreduction with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Before 2017, the patients with upper abdominal disease received neoadjuvant chemotherapy (cohort A). RESULTS: This study included 146 patients in cohort A (2006-2015) and 93 patients in cohort B (2017-2019) with stages 3 or 4 ovarian cancer. The overall complete macroscopic resection rate (CC0) increased from 58.9 in cohort A to 67.7% in cohort B. The rate of primary cytoreductive surgery (CRS) increased from 38 (55/146) in cohort A to 42% (39/93) in cohort B. The CC0 rate for the patients who underwent primary CRS increased from 49 in cohort A to 77% in cohort B. Major morbidity remained stable throughout both study periods (2006-2019). CONCLUSIONS: The study data demonstrate that implementation of a multidisciplinary team intraoperative approach and a meticulous approach to preoperative optimization resulted in significantly improved complete resection rates, particularly for women offered primary CRS.


Assuntos
Neoplasias dos Genitais Femininos , Hipertermia Induzida , Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Feminino , Neoplasias dos Genitais Femininos/cirurgia , Humanos , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
13.
Insect Sci ; 28(3): 627-638, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32558234

RESUMO

The fall armyworm (FAW), Spodoptera frugiperda, is a major pest native to the Americas that has recently invaded the Old World. Point mutations in the target-site proteins acetylcholinesterase-1 (ace-1), voltage-gated sodium channel (VGSC) and ryanodine receptor (RyR) have been identified in S. frugiperda as major resistance mechanisms to organophosphate, pyrethroid and diamide insecticides respectively. Mutations in the adenosine triphosphate-binding cassette transporter C2 gene (ABCC2) have also been identified to confer resistance to Cry1F protein. In this study, we applied a whole-genome sequencing (WGS) approach to identify point mutations in the target-site genes in 150 FAW individuals collected from China, Malawi, Uganda and Brazil. This approach revealed three amino acid substitutions (A201S, G227A and F290V) of S. frugiperda ace-1, which are known to be associated with organophosphate resistance. The Brazilian population had all three ace-1 point mutations and the 227A allele (mean frequency = 0.54) was the most common. Populations from China, Malawi and Uganda harbored two of the three ace-1 point mutations (A201S and F290V) with the 290V allele (0.47-0.58) as the dominant allele. Point mutations in VGSC (T929I, L932F and L1014F) and RyR (I4790M and G4946E) were not detected in any of the 150 individuals. A novel 12-bp insertion mutation in exon 15 of the ABCC2 gene was identified in some of the Brazilian individuals but absent in the invasive populations. Our results not only demonstrate robustness of the WGS-based genomic approach for detection of resistance mutations, but also provide insights for improvement of resistance management tactics in S. frugiperda.


Assuntos
Toxinas de Bacillus thuringiensis/farmacologia , Endotoxinas/farmacologia , Proteínas Hemolisinas/farmacologia , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Spodoptera , Acetilcolinesterase/genética , Animais , Diamida/farmacologia , Genes de Insetos , Genoma de Inseto , Organofosfatos/farmacologia , Mutação Puntual/genética , Mutação Puntual/fisiologia , Piretrinas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Spodoptera/efeitos dos fármacos , Spodoptera/genética , Canais de Sódio Disparados por Voltagem/genética , Sequenciamento Completo do Genoma
14.
Artigo em Inglês | MEDLINE | ID: mdl-33202113

RESUMO

OBJECTIVE: Musculoskeletal conditions of the foot and ankle are common, yet the cost-effectiveness of the variety of treatments available is not well defined. The aim of this systematic review was therefore to identify, appraise and synthesise the literature pertaining to the cost-effectiveness of interventions for musculoskeletal foot and ankle conditions. METHODS: Electronic databases were searched for studies presenting economic evaluations of non-surgical and surgical treatments for acute or chronic musculoskeletal conditions of the foot and ankle. Data on cost, incremental cost-effectiveness and quality-adjusted life years for each intervention and comparison were extracted. Risk of bias was assessed using the Drummond checklist for economic studies (range 0-35). RESULTS: Thirty-six studies were identified reporting non-surgical interventions (n=10), non-surgical versus surgical interventions (n=14) and surgical interventions (n=12). The most common conditions were osteoarthritis, ankle fracture and Achilles tendon rupture. The strongest economic evaluations were for interventions managing end-stage ankle osteoarthritis, ankle sprain, ankle fracture, calcaneal fracture, and Achilles tendon rupture. Total ankle replacement and ankle arthrodesis for end-stage ankle osteoarthritis, in particular, have been demonstrated through high-quality studies to be cost-effective compared to the non-surgical alternative. CONCLUSION: Selected interventions for musculoskeletal foot and ankle conditions dominate comparators, whereas others require thoughtful consideration as they provide better clinical improvements, but at an increased cost. Researchers should consider measuring and reporting costs alongside clinical outcome to provide context when determining the appropriateness of interventions for other foot and ankle complaints to best inform future clinical practice guidelines.

15.
Foot Ankle Surg ; 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-33189547

RESUMO

BACKGROUND: The aim of this study was to determine if a single or separate construct with interfragmentary screw was associated with higher rates non-union following first metatarsophalangeal joint (MTPJ) arthrodesis. METHODS: A retrospective analysis of patients undergoing first MTPJ arthrodesis between April 2010 and June 2017 was performed. Patients who received either a single (Stryker Anchorage 1 MTP Cross Plate) or separate (Stryker Anchorage 1 MTP locking plate with one Asnis partially threaded compression screw) construct locking plate and interfragmentary compression screw were reviewed. Descriptive statistics were generated for sample demographics and between-group differences were calculated. Multivariable regressions explored internal fixation type and association with non-union. RESULTS: A total of 280 first MTPJ arthrodesis met the inclusion criteria and were reviewed. The incidence of non-union was 7.9% of procedures (22 joints). Following multivariable binary logistic regression, the single construct locking plate with interfragmentary compression screw was associated with an increased risk of non-union (OR 3.43, 95% CI 1.26-9.33), adjusting for age, gender and comorbidity. CONCLUSIONS: A single construct interfragmentary screw and locking plate (Stryker Anchorage 1 MTP Cross Plate) was associated with an increased incidence of non-union following first MTPJ arthrodesis.

16.
ANZ J Surg ; 90(12): 2549-2552, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33021023

RESUMO

BACKGROUND: The aim of this study was to conduct a readability analysis on both patient take-home information and consent forms for common foot and ankle procedures. Our hypothesis was that the objective reading skills required to read and comprehend the documentation currently in use would exceed the recommendations in place by both national and international bodies. METHODS: The current Queensland Health consent forms are divided into specific subsections. The readability of consent form subsections C and G (sections containing detailed information on risks of the procedure and pertaining to informed patient consent specifically) and patient take-home information (provided as take-home leaflet from the consent form which is procedure specific) was assessed by an online readability software program using five validated methods calculated by application of the algorithms for (i) Flesch-Kincaid grade level, (ii) the SMOG (Simple Measure of Gobbledygook), (iii) Coleman-Liau index, (iv) automated readability index and the (v) Linsear Wriste formula. RESULTS: The mean ± standard deviation reading grade level of risk (section C), grade level of patient consent (section G) and grade level for procedure-specific take-home patient information were 8.7 ± 0.9, 11.6 ± 1.2 and 7.5 ± 0.2, respectively. CONCLUSION: The readability of sections C and G of the Queensland Health consent form exceeds the recommendations by national and international bodies, but the patient take-home information appears suitable. Consideration should be given to lower the reading grade level of patient consent forms to better reflect the reading grade of the Australian population.


Assuntos
Compreensão , Termos de Consentimento , Tornozelo , Austrália , Humanos , Internet , Queensland
17.
Clin Genet ; 98(4): 353-364, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33111345

RESUMO

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

18.
Blood Adv ; 4(19): 4873-4886, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33035329

RESUMO

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.


Assuntos
Hematologia , Telomerase , Biologia , Hibridização in Situ Fluorescente , Mutação , Fenótipo , Prevalência , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo
19.
J Med Genet ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060287

RESUMO

Current clinical approaches for mutation discovery are based on short sequence reads (100-300 bp) of exons and flanking splice sites targeted by multigene panels or whole exomes. Short-read sequencing is highly accurate for detection of single nucleotide variants, small indels and simple copy number differences but is of limited use for identifying complex insertions and deletions and other structural rearrangements. We used CRISPR-Cas9 to excise complete BRCA1 and BRCA2 genomic regions from lymphoblast cells of patients with breast cancer, then sequenced these regions with long reads (>10 000 bp) to fully characterise all non-coding regions for structural variation. In a family severely affected with early-onset bilateral breast cancer and with negative (normal) results by gene panel and exome sequencing, we identified an intronic SINE-VNTR-Alu retrotransposon insertion that led to the creation of a pseudoexon in the BRCA1 message and introduced a premature truncation. This combination of CRISPR-Cas9 excision and long-read sequencing reveals a class of complex, damaging and otherwise cryptic mutations that may be particularly frequent in tumour suppressor genes replete with intronic repeats.

20.
PLoS One ; 15(9): e0239197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997669

RESUMO

Mutations in BRCA1 and BRCA2 cause deficiencies in homologous recombination repair (HR), resulting in repair of DNA double-strand breaks by the alternative non-homologous end-joining pathway, which is more error prone. HR deficiency of breast tumors is important because it is associated with better responses to platinum salt therapies and PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and gene-expression patterns. The term "BRCA-like" (or "BRCAness") describes tumors that harbor an HR defect but have no detectable germline mutation in BRCA1 or BRCA2. A better understanding of the genes and molecular events associated with tumors being BRCA-like could provide mechanistic insights and guide development of targeted treatments. Using data from The Cancer Genome Atlas (TCGA) for 1101 breast-cancer patients, we identified individuals with a germline mutation, somatic mutation, homozygous deletion, and/or hypermethylation event in BRCA1, BRCA2, and 59 other cancer-predisposition genes. Based on the assumption that BRCA-like events would have similar downstream effects on tumor biology as BRCA1/BRCA2 germline mutations, we quantified these effects based on somatic-mutation signatures and gene-expression profiles. We reduced the dimensionality of the somatic-mutation signatures and expression data and used a statistical resampling approach to quantify similarities among patients who had a BRCA1/BRCA2 germline mutation, another type of aberration in BRCA1 or BRCA2, or any type of aberration in one of the other genes. Somatic-mutation signatures of tumors having a non-germline aberration in BRCA1/BRCA2 (n = 80) were generally similar to each other and to tumors from BRCA1/BRCA2 germline carriers (n = 44). Additionally, somatic-mutation signatures of tumors with germline or somatic events in ATR (n = 16) and BARD1 (n = 8) showed high similarity to tumors from BRCA1/BRCA2 carriers. Other genes (CDKN2A, CTNNA1, PALB2, PALLD, PRSS1, SDHC) also showed high similarity but only for a small number of events or for a single event type. Tumors with germline mutations or hypermethylation of BRCA1 had relatively similar gene-expression profiles and overlapped considerably with the Basal-like subtype; but the transcriptional effects of the other events lacked consistency. Our findings confirm previously known relationships between molecular signatures and germline or somatic events in BRCA1/BRCA2. Our methodology represents an objective way to identify genes that have similar downstream effects on molecular signatures when mutated, deleted, or hypermethylated.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Genes Neoplásicos , Mutação em Linhagem Germinativa , Metilação de DNA , Bases de Dados Genéticas , Feminino , Humanos
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