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Protein lysine acetylation is a critical post-translational modification involved in a wide range of biological processes. To date, about 20,000 acetylation sites of Homo sapiens were identified through mass spectrometry-based proteomic technology, but more than 95% of them have unclear functional annotations because of the lack of existing prioritization strategy to assess the functional importance of the acetylation sites on large scale. Hence, we established a lysine acetylation functional evaluating model (LAFEM) by considering eight critical features surrounding lysine acetylation site to high-throughput estimate the functional importance of given acetylation sites. This was achieved by selecting one of the random forest models with the best performance in 10-fold cross-validation on undersampled training dataset. The global analysis demonstrated that the molecular environment of acetylation sites with high acetylation functional scores (AFSs) mainly had the features of larger solvent-accessible surface area, stronger hydrogen bonding-donating abilities, near motif and domain, higher homology, and disordered degree. Importantly, LAFEM performed well in validation dataset and acetylome, showing good accuracy to screen out fitness directly relevant acetylation sites and assisting to explain the core reason for the difference between biological models from the perspective of acetylome. We further used cellular experiments to confirm that, in nuclear casein kinase and cyclin-dependent kinase substrate 1, acetyl-K35 with higher AFS was more important than acetyl-K9 with lower AFS in the proliferation of A549 cells. LAFEM provides a prioritization strategy to large scale discover the fitness directly relevant acetylation sites, which constitutes an unprecedented resource for better understanding of functional acetylome.
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Lisina , Proteómica , Humanos , Lisina/metabolismo , Acetilación , Espectrometría de Masas , Procesamiento Proteico-Postraduccional , Proteoma/metabolismoRESUMEN
PURPOSE: A lateral ankle sprain is the most common musculoskeletal injury in the physically active population. However, it is unclear how the clinical condition evolves during the period after the injury and what proportion of patients develops chronic symptoms. Therefore, the purpose of this study is to assess the evolution of patient-reported outcome measures after a first time lateral ankle sprain. METHODS: A prospective clinical study assessed the patient-reported outcome measures (PROMs) of a consecutive group of 100 patients during 1 year after a first lateral ankle sprain. The Karlsson score and Foot and Ankle Outcome Score (FAOS) were assessed at 6 weeks, 3 months, 6 months, 9 months and 1 year. The Cumberland Ankle Instability Tool (CAIT)-score was assessed at 6 months, 9 months and 1 year. The difference between the time points of all scores was analysed using the positive change over time (binomial test versus 50%) and the difference in score (signed rank test). The time to sustained excellent level was also assessed overall and in several subgroups: age, gender, degree of injury (2 or 3), avulsion fracture, use of crutches, use of cast. Differences between subgroups were assessed by a generalized log-rank test. RESULTS: All clinical scores demonstrated an improvement up to 12 months after the sprain. The median Karlsson score (interquartile range) improved from 62 (50-80) at 6 weeks to 90 (72-100) at 3 months, to 97 (82-100) at 6 months to 100 (90-100) at 9 months, to 100 (100-100) at 1 year. The analysis of positive change over time demonstrated a significant positive change (P-value <.0005) between all time points except between 6 weeks and 12 weeks when using the FAOS quality score. The difference in score demonstrated a significant change (P-value <.01) between all time points except between 36 weeks and 48 weeks when using the FAOS pain and FAOS sports score. Age and presence of an avulsion fracture were correlated with a slower recovery and worse results. At 1 year, in total 13 patients (13%) had a worse outcome corresponding to a Karlsson score < 81 or CAIT score < 24. CONCLUSION: The clinical condition after a first ankle sprain demonstrated a significant improvement in PROMs between the different time points in the first year. Twelve months after a first lateral ankle sprain 13% had a fair or poor outcome. Higher age and presence of an avulsion fracture were correlated with a slower recovery and worse results. This information is useful in clinical practice to predict further progression and inform patients. Moreover, it is valuable to improve treatment strategies. LEVEL OF EVIDENCE: Level II (prospective cohort study).
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Understanding the functional consequence of noncoding variants is of great interest. Though genome-wide association studies or quantitative trait locus analyses have identified variants associated with traits or molecular phenotypes, most of them are located in the noncoding regions, making the identification of causal variants a particular challenge. Existing computational approaches developed for prioritizing noncoding variants produce inconsistent and even conflicting results. To address these challenges, we propose a novel statistical learning framework, which directly integrates the precomputed functional scores from representative scoring methods. It will maximize the usage of integrated methods by automatically learning the relative contribution of each method and produce an ensemble score as the final prediction. The framework consists of two modes. The first 'context-free' mode is trained using curated causal regulatory variants from a wide range of context and is applicable to predict regulatory variants of unknown and diverse context. The second 'context-dependent' mode further improves the prediction when the training and testing variants are from the same context. By evaluating the framework via both simulation and empirical studies, we demonstrate that it outperforms integrated scoring methods and the ensemble score successfully prioritizes experimentally validated regulatory variants in multiple risk loci.
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Biología Computacional/métodos , Aprendizaje Profundo , Variación Genética , Modelos Estadísticos , ARN no Traducido/genética , Secuencias Reguladoras de Ácido Ribonucleico , Programas Informáticos , Algoritmos , Bases de Datos Genéticas , Regulación de la Expresión Génica , HumanosRESUMEN
The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing-remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every -0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Degeneración Retiniana , Humanos , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Estudios Retrospectivos , Retina/diagnóstico por imagen , Caminata , Degeneración Retiniana/diagnóstico por imagen , AtrofiaRESUMEN
BACKGROUND: This study compared the clinical and functional outcomes of patients initially treated with observation or medical treatment with those of patients treated with local treatment (surgery alone or surgery with adjuvant radiotherapy) to confirm whether observation or medical treatment is an appropriate first-line management approach for patients with desmoid tumors. METHODS: We retrospectively reviewed the medical records of 99 patients with histologically confirmed primary desmoid tumors treated between 1978 and 2018. The median follow-up period was 57 months. We evaluated event-free survival, defined as the time interval from the date of initial diagnosis to the date of specific change in treatment strategy or recurrence or the last follow-up. RESULTS: An event (specific change in treatment strategy or recurrence) occurred in 28 patients (28.3%). No significant difference in event-free survival was found between the first-line observation/medical treatment and local treatment groups (p = 0.509). The median Musculoskeletal Tumor Society score of the patients treated with first-line local treatment was 29 (interquartile range [IQR], 23-30), whereas that of the patients managed with first-line observation or medical treatment was 21 (IQR, 19-29.5). First-line observation or medical treatment was more frequently chosen for larger tumors (p = 0.045). In the patients treated with local treatment, local recurrence was not related to the surgical margin (p = 0.976). CONCLUSION: Upfront surgery is not advantageous compared to more conservative treatments such as observation or medical treatment for patients with desmoid tumors.
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Fibromatosis Agresiva , Tratamiento Conservador , Fibromatosis Agresiva/cirugía , Humanos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/terapia , Radioterapia Adyuvante , Estudios RetrospectivosRESUMEN
OBJECTIVES: The CentPillar stem (Stryker Orthopaedics), an anatomical short stem, was designed to match the proximal femoral canal shape in both patients with normal hips and those with developmental dysplasia of the hip (DDH). The long-term outcomes of the CentPillar stem was examined herein. METHODS: In total, 222 hips that underwent total hip arthroplasty using the CentPillar stem were analyzed. DDH was the main reason for surgery (79.3%). Implant survivorship was assessed using Kaplan-Meier analysis. For radiographic evaluation, stress shielding was assessed using the Engh classification. For functional evaluation, patients' ability to perform deep hip bending activities (sit on the floor, squat, and sit straight) was assessed. RESULTS: During a median follow-up of 13.1 years, 2 stem revisions were performed (aseptic loosening and late hematogenous periprosthetic infection), and the overall cumulative implant survival rate was 99.0% at 15 years. In the radiographic evaluation, grade >3 stress shielding was found in only one hip. More than 80% of the patients were able to perform each of the three deep hip bending activities. CONCLUSIONS: Good fixation at the proximal part of the femur was obtained, and the implant survival rate of the CentPillar stem was excellent during a long-term follow-up.
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Artroplastia de Reemplazo de Cadera , Durapatita/provisión & distribución , Fémur/diagnóstico por imagen , Fémur/cirugía , Estudios de Seguimiento , Prótesis de Cadera , Humanos , Diseño de Prótesis , Falla de Prótesis , Reoperación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that may lead to severe joint pain. There are several scores to evaluate the disease activity of RA. This study aimed to evaluate if clinical factors which representing activity scores and health assessment score. MATERIAL AND METHODS: This study was conducted prospectively by including adult patients with RA. Clinical factors and 5 RA disease activity and health assessment scores were evaluated. Each activity score was executed for clinical predictors by using multivariate linear regression analysis. RESULTS: There were 33 female adult patients in the study. The average (SD) age was 52.33 (11.11) years, while the duration of RA was 7.65 years. The DAS28 ESR had 1 predictor: RA duration with a coefficient of -0.04. For DAS28 CRP, CDAI, and SDAI scores, body mass index (BMI) and RA duration were independent factors for the scores with negative coefficient values. For the HAQ score, both age and rheumatoid duration were positively associated with the score. The coefficients of both factors were 0.02 and 0.03, respectively. CONCLUSIONS: Age, RA duration, and BMI were associated with RA activity and functional score. Body mass index is a potential modifiable factor that may be associated with RA activities.
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The aim of this study was to investigate changes in balance control for stance and gait tasks in patients 2 years before and after vestibular neurectomy (VN) performed to alleviate intractable Meniere's disease. Amplitudes of trunk sway in roll and pitch directions were measured for stance and gait tasks in 19 patients using gyroscopes mounted at the lower-back. Measurements before VN and 2 years later were compared to those of healthy age-matched controls (HC). We also examined if changes in trunk sway amplitudes were correlated with patients' subjective assessment of disability using the AAO-HNS scale. For patients with low AAO-HNS scores 0-2 (n = 14), trunk roll and pitch sway velocities, standing eyes closed on foam, increased 2 years post VN compared to HC values (p < 0.01). Trunk sway amplitudes remained at levels of HC for simple gait tasks, but task durations were longer and therefore gait slower. For complex gait tasks (stairs), balance control remained impaired at 2 years. In patients with AAO-HNS high scores level 6 (n = 5), balance control remained abnormal, compared to HC, 2 years postoperatively for all stance, several simple and all complex gait tasks. Trunk sway in the pitch and roll directions for stance tasks was correlated with clinical (AAO-HNS) scores (p ≤ 0.05). These results indicate that VN leads to chronic balance problems for stance and complex gait tasks. The problems are greater for patients with high compared to low AAO-HNS scores, thereby explaining the different symptoms reported by these patients. The lack of balance recovery in VN patients to levels of HCs after 2 years contrasts with the 3 months average recovery period for acute vestibular neuritis patients and is indicative of the effects of neurectomy on central compensation processes.
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Desnervación , Marcha/fisiología , Enfermedad de Meniere/cirugía , Equilibrio Postural/fisiología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Enfermedad de Meniere/fisiopatología , Persona de Mediana EdadRESUMEN
PURPOSE: The correlation between tendon bone healing and clinical functional scores after anterior cruciate ligament reconstruction (ACLR) using four-stranded hamstring tendon autograft has rarely being reported. The purpose of this study was to determine the correlation between magnetic resonance imaging (MRI)-based tendon bone healing and clinical functional scores after ACLR using hamstring tendon. METHODS: Thirty-eight patients with ACLR using four-stranded hamstring tendon autograft were included in this prospective study in the authors' hospital from 2013 to 2014. All patients were performed Tegner, Lysholm, International Knee Documentation Committee (IKDC) subjective scores, KT-1000 and MRI examinations in 3, 6, 12 months after the operation, respectively. According to MRI, the healing degree of tendon bone was divided into five grades, and the healing degree of the tendon at different time points was evaluated. Moreover, the correlations between the clinical scores and tendon bone healing level at 12 months after the operation were determined. RESULTS: The Tegner, Lysholm, and IKDC scores of all patients were gradually improved over time after ACLR, and the degree of tendon bone healing was gradually increased. Moreover, there were significantly positive correlations between the level of tendon bone healing and the clinical functional scores at 12 months after the operation. CONCLUSION: The clinical functional scores and the degree of tendon bone healing were gradually improved over time after ACLR. Moreover, there were significant positive correlations between the level of tendon bone healing and clinical functional scores of knee joint at the first year after the operation. LEVEL OF EVIDENCE: III.
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Reconstrucción del Ligamento Cruzado Anterior , Autoinjertos/trasplante , Tendones Isquiotibiales/trasplante , Imagen por Resonancia Magnética , Cicatrización de Heridas , Adolescente , Adulto , Lesiones del Ligamento Cruzado Anterior/cirugía , Femenino , Humanos , Traumatismos de la Rodilla/cirugía , Articulación de la Rodilla/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trasplante Autólogo , Adulto JovenRESUMEN
PURPOSE: The purpose of this study was to assess post-operative patient subjective satisfaction and to analyze associated peri-operative factors following biplanar medial open wedge high tibial osteotomy (OWHTO). METHODS: The study cohort consisted of 88 patients with a minimum of two years of follow-up. Patient satisfaction was evaluated with a questionnaire that assessed (1) overall satisfaction, (2) pain relief, (3) daily living functions, and (4) cosmesis. Patients were categorized into two groups (satisfied or unsatisfied) based on overall satisfaction questionnaire. Pre- and post-operative objective clinical statuses were assessed with a knee scoring system based on the American Knee Society (AKS), the Western Ontario McMaster University Osteoarthritis Index (WOMAC), and range of motion. RESULTS: Of the 88 patients, 85.2% were graded as satisfied according to the overall satisfaction estimation. The percentage of patients satisfied with pain relief, daily living functions, and cosmesis were 85.2%, 86.4%, and 86.4%, respectively. Multivariable logistic regression analysis demonstrated that pre-operative Hip-Knee-Ankle angle (HKAA) (odds ratio (OR) = 1.812), post-operative AKS knee score (OR = 1.156), and post-operative HKAA (OR = 0.717) were significantly associated with overall satisfaction. Pre-operative HKAA (OR = 1.436), post-operative WOMAC activity score (OR = 0.865), and post-operative HKAA (OR = 0.505) were significant predictors for satisfaction with pain reduction, daily living functions, and cosmesis, respectively. CONCLUSIONS: Biplanar medial OWHTO is an effective treatment for osteoarthritis with varus deformity in terms of subjective satisfactory outcome. Several factors, including pre- and post-operative HKAA, post-operative AKS and WOMAC score, were significant predictors for subjective satisfaction. LEVEL OF EVIDENCE: Level III.
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Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugía , Osteotomía/métodos , Satisfacción del Paciente/estadística & datos numéricos , Tibia/cirugía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Rango del Movimiento Articular , Resultado del TratamientoRESUMEN
BACKGROUND: obesity and osteoarthritis have strong inter-relationship with multi-factorial mechanism that caused pain and leads to decreased quality of life. Exercise has been identified as prevention and management against obesity and joint pain. This systematic review aims to assess the effect between exercises compared to diet group for chronic pain management, physical and mental function in obese patients with chronic musculoskeletal problem. METHODS: we performed a systematic search of Randomized Control Trial studies from Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EBSCO; SCIENCEDIRECT (Elsevier); SCOPUS, grey literature, trial registry, ongoing study for published studies, and from the ClinicalTrial.gov, thesis of rehabilitation medicine in RSCM, and proceeding books for unpublished studies that was last updated on November 2016. Risk of bias was assessed using Cochrane risk-of-bias tool and data were analyzed using Review Manager 2014. RESULTS: one study showed no difference in pain reduction (assessed using VAS) between two groups. Two studies showed improvement in physical function measured using 6MWT in exercise group at 6 and 18 months with mean difference 28.12 [11.20, 45.04] and 26.21 [9.01, 43.41]. There was no significant effects observed for Mental and Physical Function based on SF-36 after 6 months (1 study) and 18 months (2 studies) observation, with mean difference 1.10 [-0.79, 2.99] and 0.08 [-1.53, 1.70] respectively for Mental Function score and -0.30 [-2.54, 1.94] and -0.36 [-2.30, 1.57] respectively for Physical Function score. CONCLUSION: exercise can improve physical function objectively, but could not reduce pain in obese patients with chronic musculoskeletal problem subjectively.
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Terapia por Ejercicio , Dolor Musculoesquelético/rehabilitación , Obesidad/complicaciones , Enfermedad Crónica , Humanos , Manejo del Dolor , Rendimiento Físico Funcional , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: Despite cognitive tests have been validated in multiple sclerosis (MS), a neuropsychological evaluation is not implemented in the Expanded Disability Status Scale (EDSS) scoring. METHODS: We used the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and orientation tests (OTs) to measure the cerebral functional system (CFS) score and to evaluate its impact on the EDSS. We compared EDSS calculated as usual (Native-EDSS) and after the use of the BICAMS and OT (NPS-EDSS). RESULTS: We tested 604 MS patients with BICAMS, OTs, and EDSS. In all, 384 patients (63.6%) had at least one altered test at the BICAMS. Older age, lower education, higher Native-EDSS, and male gender were independently associated with at least one impaired BICAMS test. Native-EDSS was different from NPS-EDSS (-0.112; p < 0.001) in 99 patients (16%). When considering patients with a Native-EDSS ⩽ 4.0, the proportion of miscalculated EDSS was 25%. CONCLUSION: The use of brief neuropsychological tests leads to a more accurate CFS assessment in two-thirds of MS patients, and a more accurate EDSS calculation in 25% of patients with a score ⩽4.0. This may help clinicians to better recognize cognitive impairment in everyday clinical practice, especially in the case of isolated cognitive worsening.
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Disfunción Cognitiva/diagnóstico , Esclerosis Múltiple/diagnóstico , Examen Neurológico/métodos , Pruebas Neuropsicológicas , Orientación/fisiología , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Disfunción Cognitiva/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Examen Neurológico/normas , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Despite the overall success of total knee arthroplasty (TKA), a relatively large proportion of patients remain dissatisfied with the outcome. We hypothesized that patients with a lower threshold for pain were more likely to have worse outcomes after TKA. METHODS: Forty-eight consecutive patients with primary knee osteoarthritis graded a standardized painful stimulus caused by inflating a sphygmomanometer placed on the forearm, on a visual analog scale (VAS) scale before their TKA. We compared the VAS scores to patients' Knee Society scores and Knee Society function scores 2 years after TKA. RESULTS: Patients with a severe VAS score (>74 mm) had significantly worse Knee Society scores compared to patients with mild (0-44 mm) and moderate (45-74 mm) VAS scores (55 ± 20.5 vs 81.5 ± 11.1 and 84.8 ± 13, respectively, P = .04) and worse Knee Society Function scores (34 ± 20.7 vs 75.2 ± 17.3 and 77 ± 17.4, respectively, P = .027) at 2 years after TKA. CONCLUSIONS: Patients with a lower threshold for pain, as determined by a standardized painful stimulus, are more likely to have lower Knee Society pain and function scores after TKA.
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Artroplastia de Reemplazo de Rodilla/efectos adversos , Dimensión del Dolor/métodos , Dolor Postoperatorio/etiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Articulación de la Rodilla/cirugía , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/cirugía , Dolor/etiología , Dimensión del Dolor/instrumentación , Estudios Prospectivos , Esfigmomanometros , Resultado del TratamientoRESUMEN
This randomized controlled study was conducted to assess the effects of platelet-rich plasma (PRP) on outcomes of total knee arthroplasty (TKA). Forty patients who underwent unilateral TKA were evaluated prospectively; 20 received intraoperative PRP and 20 served as control subjects. The results showed no significant differences in reduction of bleeding, range of motion, swelling around the knee joint, muscle power recovery, pain, Knee Society Scores, and Knee Injury and Osteoarthritis Outcome Score between the 2 groups. Additionally, no distinct clinical characteristics were found in patients who received intraoperative PRP. Therefore, we conclude that intraoperative PRP does not improve outcomes of TKA.
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Artroplastia de Reemplazo de Rodilla/métodos , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugía , Plasma Rico en Plaquetas , Administración Tópica , Anciano , Anciano de 80 o más Años , Artralgia/prevención & control , Femenino , Hemostasis Quirúrgica/métodos , Hemostáticos/administración & dosificación , Humanos , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Masculino , Osteoartritis de la Rodilla/terapia , Dolor Postoperatorio/prevención & control , Rango del Movimiento Articular , Resultado del TratamientoRESUMEN
The appearance and spread of mutations that cause drug resistance in rapidly evolving diseases, including infections by the SARS-CoV-2 virus, are major concerns for human health. Many drugs target enzymes, and resistance-conferring mutations impact inhibitor binding or enzyme activity. Nirmatrelvir, the most widely used inhibitor currently used to treat SARS-CoV-2 infections, targets the main protease (Mpro) preventing it from processing the viral polyprotein into active subunits. Our previous work systematically analyzed resistance mutations in Mpro that reduce binding to inhibitors; here, we investigate mutations that affect enzyme function. Hyperactive mutations that increase Mpro activity can contribute to drug resistance but have not been thoroughly studied. To explore how hyperactive mutations contribute to resistance, we comprehensively assessed how all possible individual mutations in Mpro affect enzyme function using a mutational scanning approach with a fluorescence resonance energy transfer (FRET)-based yeast readout. We identified hundreds of mutations that significantly increased the Mpro activity. Hyperactive mutations occurred both proximal and distal to the active site, consistent with protein stability and/or dynamics impacting activity. Hyperactive mutations were observed 3 times more than mutations which reduced apparent binding to nirmatrelvir in recent studies of laboratory-grown viruses selected for drug resistance. Hyperactive mutations were also about three times more prevalent than nirmatrelvir binding mutations in sequenced isolates from circulating SARS-CoV-2. Our findings indicate that hyperactive mutations are likely to contribute to the natural evolution of drug resistance in Mpro and provide a comprehensive list for future surveillance efforts.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Mutación , Lactamas , Leucina , Nitrilos , Saccharomyces cerevisiae , Resistencia a MedicamentosRESUMEN
[Purpose] The purpose of this study was to examine the effect of closed kinetic chain exercises performed by an unstable exercise group (UEG) and a stable exercise group (SEG) on the knee joint, proprioception, and functional scores of patients who underwent anterior cruciate ligament (ACL) reconstruction. [Subjects] Twenty-eight patients participated in this study. The exclusion criteria were fracture or neurological disease. [Methods] The subjects were randomly assigned to one of two groups, each with 14 people. Each group took part in a 60-minute exercise program, three times a week for six weeks. [Results] The results of the clinical evaluation at 45°proprioception showed statistically significant differences between the two groups. The results of the clinical evaluation at 15°proprioception showed no statistically significant differences between the two groups. [Conclusion] The proprioception and functional scores of the patients in the UEG who underwent ACL reconstruction were superior to those in the SEG group.
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Background: An increased femoral anteversion angle (FAA) is a predisposing factor for recurrent patellar dislocations (RPDs), and combined procedures including derotational distal femoral osteotomy (DDFO) have been shown to be good options. Purpose: To investigate the safety and effectiveness of combined DDFO on clinical and radiological outcomes to treat RPDs with an increased FAA. Study Design: Systematic review; Level of evidence, 4. Methods: This review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. We searched 7 databases for articles from inception to March 10, 2023, that reported outcomes after combined DDFO in patients with an RPD and increased FAA. Two reviewers independently extracted data and assessed study quality. Outcomes evaluated were functional scores, redislocation rates, complications, satisfaction, and radiological parameters. A meta-analysis was performed to pool functional scores, with data reported as mean differences (MDs) and 95% confidence intervals (CIs). Results: Included were 8 studies of 189 knees from 183 patients, with a mean patient age of 22.4 years and a mean follow-up of 33.4 months. The mean preoperative FAA ranged from 31° to 42.70°, and the mean postoperative FAA ranged from 10° to 19.08°. Significant improvements were found in the Kujala score (MD, 26.96 [95% CI, 23.54 to 30.37]), Lysholm score (MD, 26.17 [95% CI, 22.13 to 30.22]), visual analog scale score for pain (MD, -2.61 [95% CI, -3.12 to -2.10]), and Tegner activity score (MD, 1.33 [95% CI, 0.86 to 1.79]). No subluxation or redislocation occurred. The overall complication rate was 10.6%, and most of the complications were pain (60%) and limited knee activity (20%). The overall satisfaction rate was 83.3%. The patellar tilt angle significantly decreased from 40.7° ± 11.9° to 20.5° ± 8.7° and from 26.35° ± 6.86° to 11.65° ± 2.85° in 2 studies. Conclusion: Combined DDFO was found to be safe and effective for the treatment of RPDs and an increased FAA by addressing both patellar dislocations and torsional malalignment. However, because of the lack of comparisons, it remains to be investigated when DDFO should be combined in such patients.
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Background: There are few sports-specific knee functional scales in the Arabic language. The Knee Outcome Survey-Sports Activities Scale (KOS-SAS) is a validated sports-specific patient-reported outcome measure that assesses knee function in an athletic population. Purpose: To provide a validated Arabic version of the KOS-SAS (KOS-SAS-Ar) while achieving cross-cultural adaptation for use in an Arabic-speaking population with sports-related knee disorders. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: There were 2 independent translators who conducted a forward translation of the KOS-SAS, followed by a backward translation by different translators. Subsequently, researchers and expert invitees judged the conceptual content and cultural adaptations of the final translation. A total of 276 patients completed the KOS-SAS-Ar as well as the International Knee Documentation Committee (IKDC) subjective assessment of knee function and a visual analog scale (VAS) for pain. Statistical analysis was performed for test-retest reliability, convergent validity, construct validity, and factor analysis. Results: The test-retest reliability of the KOS-SAS-Ar was high (r = 0.9). The items of the KOS-SAS-Ar had statistically significant internal consistency, with a Cronbach alpha of .924 (P < .0001). The KOS-SAS-Ar Symptoms subscore correlated with the VAS pain score (P < .0001), and the KOS-SAS-Ar Functional Limitations subscore correlated with the IKDC subjective score (P < .0001). The construct validity of the KOS-SAS-Ar was satisfactory (Kaiser-Meyer-Olkin value = 0.868; Bartlett test: P < .0001). Factor analysis showed a statistical correlation among the 11 items of the KOS-SAS-Ar. Conclusion: The KOS-SAS-Ar demonstrated favorable reliability and validity, and it appears to be a suitable tool for Arabic-speaking patients with sports-related knee conditions.
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OBJECTIVES: To present one of the first descriptive case series of pediatric and adolescent lower extremity stress injuries, their management, and outcomes in athletes and non-athletes. METHODS: The IRB-approved retrospective study included patients under 18 years at a tertiary children's hospital who were diagnosed with a lower extremity stress fracture/reaction. Demographic data, mechanism of injury, physical exam, radiographic findings, treatment, & outcomes were collected. Descriptive statistical analysis was conducted. RESULTS: Ninety-seven patients with stress injuries on clinical exams and on radiographs or MRI were included. The average age when diagnosed was 11.7 years (range 1.1-18 years) and the most common injuries were to the tibia (n = 33, 28.4%) and the least common involved were the cuneiforms (n = 4, 3.4%). Patients under the age of 14 were more likely to experience cuboid and calcaneal stress injuries (mean age 5.5 and 8.3 years respectively). Nineteen patients (19.6%) had high-risk stress fractures, with the average age of 14.9 years versus 11.6 for those with low risk (p-value = 0.01) and return to activity time being 15 weeks compared to 10.5 (p-value = 0.027). The most common forms of treatment were controlled ankle motion (CAM), walker boots (58.6%), and physical therapy (PT) (38.1%). The mean Lower Extremity Function Score of the patient population was 73.8, indicating no clinically important difference from full functionality. CONCLUSION: Lower extremity stress injuries in this cohort were most seen in the tibia, although patients younger than 14 had a high number of cuboid and calcaneal stress injuries. Those with high-risk stress fractures were older and took longer to recover from when compared to low-risk injuries. Treatment is commonly conservative, with CAM boots and PT being the most frequently utilized interventions and serving as a successful approach to treatment, with patients returning to activity at an average of 11.4 weeks, which is comparable to similar studies.
Asunto(s)
Fracturas por Estrés , Traumatismos de la Pierna , Huesos Tarsianos , Humanos , Niño , Adolescente , Lactante , Preescolar , Fracturas por Estrés/diagnóstico por imagen , Fracturas por Estrés/terapia , Estudios Retrospectivos , Traumatismos de la Pierna/diagnóstico por imagen , Traumatismos de la Pierna/terapia , Extremidad Inferior , Huesos Tarsianos/lesionesRESUMEN
Objective: To investigate the effectiveness of hip continuous passive motion (hCPM) on hip development at skeletal maturity and gross motor function for spastic cerebral palsy children with hip dysplasia. Methods: Prospective case-control research of hCPM with goal-directed training versus merely goal-directed training. On the basis of goal-directed training, the hCPM group used the hip joint CPM instrument (the external fixator was connected to the power device to make the hip joint carry out continuous passive movement) for 40-60â min, twice a day, and five times a week, and received continuous training for 8 weeks simultaneously. The control group received only goal-directed training for 8 weeks. Functional outcomes pertaining to the affected hip joints were assessed via gross motor function measure (GMFM), migration percentage (MP), acetabular index (AI), and Harris hip functional score (HHS) at the time of enrollment and the end of the intervention. Results: The case-control research included 65 participants (mean age = 46.20â months, SD = 17.09â months; Gross Motor Function Grading System level: III = 41, IV = 24) who were randomly selected to either the hCPM (n = 45) or the control group (n = 20). No differences were found in baseline (acquisition phase) GMFM, MP, AI, or HHS (t = -1.720, P = 0.090; t* = 1.836, P* = 0.071; t# = -1.517, P# = 0.139; t* = -1.310, P* = 0.195; t# = -1.084, P# = 0.097; t = -1.041, P = 0.301). At the 8-week follow-up, GMFM, MP, AI, and HHS significantly improved over baseline in the hCPM group (hCPM group: t = 18.59, 20.172*, 40.291#, 16.820*, 32.900#, 28.081; P < 0.001). Between-group differences at 8-week follow-up times points favored the hCPM group for GMFM (t = -2.637, P = 0.011), MP (t* = 2.615, P* = 0.014; t# = 3.000, P# = 0.006), AI (t* = 2.055, P* = 0.044; t# = 2.223, P# = 0.030), HHS (t = -4.685, P < 0.001) (*: left side; #: right side). Conclusion: Spastic cerebral palsy children with hip dysplasia achieved meaningful functional improvement after 8 weeks of goal-directed training with hCPM therapy.