RESUMO
PURPOSE: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts. CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
Assuntos
Perda Auditiva , Lisina-tRNA Ligase/genética , Transtornos do Neurodesenvolvimento , Alelos , Animais , Modelos Animais de Doenças , Perda Auditiva/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Intraoperative ultrasound (IUS) localization for breast cancer is a noninvasive localization technique. In 2015, an IUS program for breast-conserving surgery (BCS) was initiated in a large, integrated health care system. This study evaluated the clinical results of IUS implementation. METHODS: The study identified breast cancer patients with BCS from 1 January to 31 October 2015 and from 1 January to 31 October 2019. Clinicopathologic characteristics were collected, and localization types were categorized. Clinical outcomes were analyzed, including localization use, surgeon adoption of IUS, day-of-surgery intervals, and re-excision rates. Multivariate logistic regression analysis was performed to evaluate predictors of re-excision. RESULTS: The number of BCS procedures increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019. The IUS rate increased from 4% of lumpectomies (n = 79) in 2015 to 28% of lumpectomies (n = 632) in 2019 (p < 0.001). Surgeons using IUS increased from 6% (5 of 88 surgeons) in 2015 to 70% (42 of 60 surgeons) in 2019. In 2019, 76% of IUS surgeons performed at least 25% of lumpectomies with IUS. The mean time from admission to incision was shorter with IUS or seed localization than with wire localization (202 min with IUS, 201 with seed localization, 262 with wire localization in 2019; p < 0.001). The IUS re-excision rates were lower than for other localization techniques (13.6%, vs 19.6% for seed localization and 24.7% for wire localization in 2019; p = 0.006), and IUS predicted lower re-excision rates in a multivariable model (odds ratio [OR], 0.59). CONCLUSIONS: In a high-volume integrated health system, IUS was adopted for BCS by a majority of surgeons. The use of IUS decreased the time from admission to incision compared with wire localization, and decreased re-excision rates compared with other localization techniques.
Assuntos
Neoplasias da Mama , Prestação Integrada de Cuidados de Saúde , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia Segmentar , Reoperação , Estudos RetrospectivosRESUMO
OBJECTIVE: The purpose of this study was to evaluate the effectiveness of corticosteroid injections into the greater trochanteric bursa as opposed to the subgluteus medius bursa in patients with greater trochanteric pain syndrome. MATERIALS AND METHODS: We retrospectively reviewed 183 injections (149 performed in women, 34 performed in men; age range 23-90 years; median, 53 years) performed for treatment of greater trochanteric pain syndrome. A 10-cm visual analog scale survey was used to assess pain level before the procedure and 14 days after the procedure. A 3-mL corticosteroid solution was injected into either the greater trochanteric bursa or the subgluteus medius bursa under direct ultrasound guidance. Procedure images were retrospectively reviewed to determine the site of injection. Diagnostic images obtained at the time of the procedure were also reviewed for findings of tendinopathy, bursitis, and enthesopathy. Statistical analysis of differences in pain reduction was performed, as was analysis for association between pain relief and demographic variables of age, sex, previous injections, and ultrasound findings. RESULTS: Sixty-five injections met the inclusion criteria; 56 performed in women and nine performed in men (age range, 30-82 years; median, 53 years). Forty-one injections were into the greater trochanteric bursa and 24 into the subgluteus medius bursa. There was a statistically significant difference in pain reduction between greater trochanteric bursa and subgluteus medius bursa injections with a median pain reduction of 3 as opposed to 0 (p < 0.01). There was no statistically significant association between pain relief and demographic variables or ultrasound findings. CONCLUSION: Corticosteroid injections into the greater trochanteric bursa may be more effective than injections into the subgluteus medius bursa for treatment of greater trochanteric pain syndrome.
Assuntos
Corticosteroides/administração & dosagem , Artralgia/diagnóstico por imagem , Artralgia/tratamento farmacológico , Fêmur/diagnóstico por imagem , Ultrassonografia de Intervenção , Adulto , Idoso , Idoso de 80 Anos ou mais , Bolsa Sinovial , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
BACKGROUND/AIMS: A major goal of intracranial surgery is to maximize resection while minimizing neurological morbidity, particularly motor dysfunction. Direct cortical stimulation (DCS) is a common intraoperative adjunct used to identify functional motor cortex. In this study, we report on the safety/efficacy of short pulse train DCS (direct cortical stimulation motor-evoked potential, dcMEP) for motor mapping and monitoring during intracranial surgery. METHODS: A retrospective analysis of 29 patients undergoing elective craniotomy for lesions near the motor cortex was performed. dcMEP mapping (40-120 V, 500-1,000 Hz, 5-9 pulses/s, 1- to 3-ms interstimulus interval, monopolar, 50-µs pulse width) was performed either alone (n = 29) or in addition to standard DCS (n = 6). Outcome measures were positive MEPs and the presence of seizures during stimulation. dcMEP-based continuous corticospinal tract (CST) monitoring was also performed. Changes in stimulation threshold and new postoperative neurological deficits were recorded. RESULTS: dcMEP mapping success was 96% and was not affected by preoperative motor status. Intraoperative seizure rates for dcMEP were 3% and were not related to preoperative seizure status. CST monitoring success rate was 96%, and changes in stimulation threshold were predictive of new permanent motor deficits. CONCLUSIONS: dcMEP is an effective method for mapping motor function and may prove useful for continuous CST monitoring.