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In the United States, rates of Mycobacterium tuberculosis infection have been declining for decades. Osteoarticular tuberculosis of the ankle is rarely observed. We present the case of a 65-year-old man who immigrated to the United States from India 24 years before the onset of symptoms. The patient initially reported atraumatic swelling and pain of the left ankle and foot and was treated for venous insufficiency. Later, the patient was referred to a nonsurgical orthopaedic clinic for additional workup and was found to have elevated inflammatory markers. MRI showed septic arthritis and osteomyelitis of the talus, distal tibia, and calcaneus. Joint aspiration revealed elevated white blood cell counts with predominately PMNs. The patient was then referred to an orthopaedic foot and ankle surgeon and underwent extensive irrigation and débridement. The patient was discharged on empiric antibiotics. Culture results from the original joint aspirate returned 14 days after surgery as positive for acid-fast bacillus, later identified as M tuberculosis by sequencing. Empiric antibiotics were discontinued, and the patient was started on appropriate antituberculotic therapy. This case report illustrates the challenge in the diagnosis of skeletal tuberculosis and the importance of including this condition on the differential for patients with atypical foot and ankle presentations.
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Artritis Infecciosa , Mycobacterium tuberculosis , Articulación Talocalcánea , Tuberculosis Osteoarticular , Masculino , Humanos , Anciano , Tobillo , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/cirugía , Artritis Infecciosa/diagnóstico , Tuberculosis Osteoarticular/diagnóstico por imagen , Tuberculosis Osteoarticular/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
Background: Increasing attention is being paid to the costs associated with various orthopaedic surgeries. Here, we studied the factors that influence costs associated with surgically treated acute Achilles tendon tears. Methods: We retrospectively identified patients with surgically repaired acute Achilles tendon tears, excluding insertional ruptures or chronic tendon issues. Using the Value Driven Outcome (VDO) tool from our institution, we assessed total direct costs as well as facility costs. Briefly, the VDO tool includes an item-level database that can capture detailed cost data-costs are then reported as relative mean data. Cost variables were adjusted to 2022 US dollars, and total direct cost was compared with patient characteristics using gamma regressions to report cost ratios with 95% CIs. Results: Our cohort consisted of 224 patients with Achilles tendon tears surgically repaired by one of 4 fellowship-trained orthopaedic foot and ankle surgeons. There were no differences in demographics, total direct costs, or facility costs based on surgical positioning (prone n = 156, supine n = 68). Open repairs (n = 215), compared with percutaneous techniques (n = 9) that used commercially available instrumentation, had 37% less total direct costs (P < .001, 95% CI 0.55-0.72). Compared with surgery at a main academic hospital (n = 15), procedures at an ambulatory care center (n = 207) had 19% lower total direct costs (P = .040, 95% CI 0.66-0.99) and 41% lower facility costs (P < .001, 95% CI 0.5-0.7). Conclusion: Improving cost-effective orthopaedic care remains an increasingly important goal. Patient positioning for Achilles tendon repair does not appear to have meaningful impacts on cost. When clinically appropriate, considering surgery location at an ambulatory center appears to reduce surgical costs. Level of Evidence: Level III, retrospective comparative study.
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Ankle tendon pathology is an important cause of pain, instability, and disability. Surgical treatment is often employed when conservative management fails. The quantity and variety of ankle tendon repair/reconstruction surgeries have increased over time. As surgical techniques for ankle tendon surgery evolve and increase in prevalence, postoperative imaging of these tendons rises. Therefore, it is exceedingly important for radiologists to be familiar with these procedures, their expected postoperative appearance, imaging pitfalls, and potential complications. This article reviews the key imaging findings of a variety of common ankle tendon surgical procedures.
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Tobillo , Procedimientos de Cirugía Plástica , Humanos , Diagnóstico por Imagen , Dolor , Tendones/diagnóstico por imagen , Tendones/cirugíaRESUMEN
OBJECTIVES: To examine the effectiveness and complication rates in age- and size-appropriate patients with either stable or unstable fracture patterns treated with elastic stable intramedullary nailing (ESIN). DESIGN: Retrospective case series. SETTING: Academic tertiary care children's hospital. PATIENTS/PARTICIPANTS: This was a consecutive series of 106 preadolescent children with femoral shaft fractures. The mean age of the patients was 8.0 years (range, 4.0-16.0 years). INTERVENTION: All children were treated by retrograde ESIN. MAIN OUTCOME MEASURES: Fractures were categorized as either length stable or unstable. Length stability and complications were assessed. A subset of patients with final full-length, standing x-rays was also evaluated. RESULTS: We analyzed 63 stable and 43 length unstable fractures. The mean age and weight of the patients with stable and unstable fractures were similar. There was no difference in complication rates between groups (χ2(1) = 0.00, P = 0.99). There was no difference (t(96.93) = 0.53, P = 0.59) in femoral shaft length change. Leg length discrepancies as assessed by full-length standing radiographs at follow-up were similar (χ2(2) = 1.52, P = 0.47). CONCLUSIONS: Preadolescent children younger than 10 years do not experience increased complications after ESIN of length unstable femur fractures [odds ratio (OR) = 1.68 (0.18-16.87), P = 0.65]. Length unstable femur fractures are not at increased risk of more complications [OR = 0.90 (0.26-2.92), P = 0.87], early femoral shortening [OR = (0.42-2.02), P = 0.85], or leg length discrepancy [OR = (0.13-1.56), P = 0.21] when treated with ESIN. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for complete description of levels of evidence.
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Fracturas del Fémur , Fijación Intramedular de Fracturas , Humanos , Niño , Preescolar , Adolescente , Fijación Intramedular de Fracturas/efectos adversos , Estudios Retrospectivos , Diáfisis/cirugía , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/cirugía , Fémur/cirugía , Diferencia de Longitud de las Piernas/etiologíaRESUMEN
BACKGROUND: Patient satisfaction has garnered interest as a tool to measure health care quality. However, orthopedic studies in total joint arthroplasty, spine, and hand patients have offered conflicting relationships between Press Ganey (PG) satisfaction metrics and patient-reported outcome (PRO) measures. No prior study has assessed the relationship between PG and PROs in foot and ankle patients. Whether satisfaction and outcomes instruments, though, measure similar or differing aspects of the patient experience is unclear. Here, we tested if there was an association between Patient-Reported Outcomes Measurement Information System (PROMIS) outcomes and PG satisfaction scores. METHODS: PG and PROMIS outcomes data for new patient visits to an orthopedic foot and ankle clinic between 2015 and 2017 were retrospectively analyzed. Patients that completed PG satisfaction surveys were included for study. All patients who completed PG surveys and completed one or both PROMIS physical function (PF) or pain interference (PI) metrics administered by computerized adaptive testing were included. Negative binomial regressions were used to compare PRO scores to PG overall satisfaction and PG satisfaction with care provider, adjusting for patient characteristics. Results were reported as dissatisfaction score ratios, which represented the amount of PG dissatisfaction associated with a 10-point increase in PROMIS PF or PI. Of the 3984 new patient visits, only 441 completed the PG survey (11.3% response rate). RESULTS: Ceiling effects were seen with PG data: 64% of patients reported perfect satisfaction with care provider and 27% had perfect overall satisfaction. Higher function on the PROMIS PF was weakly associated with increased overall satisfaction (ratio = 0.82, 95% CI: 0.68-0.99, P = .039) and increased satisfaction with care provider (ratio = 0.60, 95% CI: 0.40-0.92, P = .019). However, pain (PROMIS PI) was not associated with overall satisfaction or with satisfaction with care provider. CONCLUSIONS: Based on our data here, patient satisfaction was weakly related to patient-reported function but not pain interference among this subset of new patients presenting to a foot and ankle clinic. Given our essentially negative findings, further study is needed to determine which aspects of the PG satisfaction and PROMIS scores track similarly. Further, our findings add to the growing literature showcasing limitations of the PG tool, including low response rates and notable ceiling effects. If satisfaction metrics and patient-reported outcomes capture differing aspects of the patient experience, we need to better understand how that influences the measurement of health care quality and value. LEVEL OF EVIDENCE: Level III, comparative study.
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Articulación del Tobillo/fisiopatología , Dolor/fisiopatología , Tobillo , Humanos , Ortopedia , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Satisfacción Personal , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Preoperative emotional distress has been shown to negatively influence joint arthroplasty and spine surgery, but limited data exist for foot and ankle outcomes. Emotional distress can be captured through modern tools like the Patient-Reported Outcomes Instrument Measurement System (PROMIS) anxiety domain. We hypothesized that patients with greater preoperative PROMIS anxiety scores would report greater pain and less function after foot and ankle surgery than patients with lower preoperative anxiety levels. METHODS: Elective foot and ankle surgeries from May 2016 to December 2017 were retrospectively identified. PROMIS anxiety, pain interference (PI), and physical function (PF) scores were collected before and after surgery. Patients were grouped based on preoperative PROMIS scores greater or less than 59.4. A cutoff of PROMIS anxiety above 59.4 was selected as the threshold that corresponds to traditional measures of anxiety. RESULTS: Compared to patients with less preoperative anxiety (average: 47.2, n=146), patients with higher preoperative anxiety (average: 63.9, n=59) had greater preoperative pain (PROMIS PI: 63.5 vs 59.1, P < .001) and lower physical function (PROMIS PF: 37.9 vs 42.0, P = .001). Postoperatively, patients with higher preoperative anxiety had more residual pain and greater functional disability as compared to patients with less preoperative emotional distress (PROMIS PI: 58.6 vs 52.9, P < .001; PROMIS PF: 39.8 vs 44.4, P < .001; respectively). CONCLUSION: Our evidence showed that preoperative emotional anxiety predicted worse pain and function at early operative follow-up. Measures of preoperative anxiety could be useful in identifying patients at risk for poorer operative outcomes, but continued study is necessary. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
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Tobillo/cirugía , Ansiedad , Pie/cirugía , Procedimientos Ortopédicos/psicología , Dolor Postoperatorio/psicología , Medición de Resultados Informados por el Paciente , Periodo Preoperatorio , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) is being used to assess outcomes in many patient populations despite limited validation. The purpose of this study was to investigate the relationship between American Shoulder and Elbow Surgeons (ASES) and Simple Shoulder Test (SST) scores and PROMIS Physical Function (PF) and Upper Extremity (UE) function scores collected preoperatively in patients undergoing rotator cuff repair. METHODS: This cross-sectional study analyzed 164 consecutive patients undergoing arthroscopic rotator cuff repair. Study inclusion required preoperative completion of the ASES and SST evaluations, as well as the PROMIS PF, UE, and Pain Interference computerized adaptive tests. Descriptive statistics were produced, and Pearson correlation coefficients were calculated between each of the outcome measures. RESULTS: Average PROMIS UE scores indicated greater impairment than PROMIS PF scores (34 vs 44). Three percent of patients reached the PROMIS UE ceiling score of 56. PROMIS PF scores demonstrated a weak correlation with ASES scores (r = 0.43, P < .001) and a moderate correlation with SST scores (r = 0.51, P < .001). PROMIS UE scores demonstrated a moderate correlation with both ASES scores (r = 0.59, P < .001) and SST scores (r = 0.62, P < .001). PROMIS Pain Interference scores demonstrated weak negative correlations with both ASES scores (r = -0.43, P < .001) and SST scores (r = -0.41, P < .001). Patients answered fewer questions on average using the PROMIS PF and UE instruments as compared with the ASES and SST instruments. CONCLUSION: PROMIS UE scores indicate greater impairment and demonstrate a stronger correlation with the legacy shoulder scores than PROMIS PF scores in patients with symptomatic rotator cuff tears. PROMIS computerized adaptive tests allow for more efficient patient-reported outcome data collection compared with traditional outcome scores.
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Medición de Resultados Informados por el Paciente , Lesiones del Manguito de los Rotadores/fisiopatología , Lesiones del Manguito de los Rotadores/cirugía , Extremidad Superior/fisiopatología , Adolescente , Adulto , Anciano , Artroplastia , Artroscopía , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Identifying preoperative risk factors that may portend poorer operative outcomes remains a topic of current interest. In hip and knee arthroplasty patients, the presence of patient-reported allergies (PRAs) has been associated with worse pain and function after joint replacement. However, these results have not been replicated across studies, including in shoulder arthroplasty cases. The impact of PRAs on foot and ankle outcomes has yet to be studied. The purpose of our study was to evaluate whether PRAs influence patient-reported outcome in foot and ankle surgery. METHODS: To determine if PRAs are linked to poorer operative outcomes, we retrospectively identified 159 patients who underwent elective foot and ankle surgery. PRA data were obtained via chart review, and patient-reported outcomes were assessed preoperatively and postoperatively via multiple domains, including Patient Reported Outcome Measurement Information System (PROMIS) physical function, pain interference, and depression measures. Consistent with prior methodology, we compared outcome measures (preoperative, postoperative, and the change in outcome scores) between patients without self-reported allergies to patients with at least 1 PRA. RESULTS: There were 159 patients studied; 79 patients had no allergies listed, and 80 patients had at least 1 PRA. Of the 80 patients with at least 1 PRA, there were a total of 170 possible allergies. There were no differences in preoperative, postoperative, or the change in outcome scores for all PROMIS measures (physical function, pain interference, and depression; P > .05) between patients with at least 1 PRA and those patients without any listed PRAs. CONCLUSIONS: We were unable to prove our hypothesis that PRAs were linked to poorer patient-reported outcomes following foot and ankle surgery. Closer review of the published reports linking PRAs to worse total joint arthroplasty outcomes revealed data that, while statistically significant, are likely not clinically relevant. Our negative findings, then, may in fact parallel prior studies on hip, knee, and shoulder arthroplasty patients. The presence of PRAs does not appear to be a risk factor for suboptimal outcomes in foot and ankle surgery. LEVEL OF EVIDENCE: Level III, comparative series.
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Depresión/etiología , Pie/cirugía , Hipersensibilidad , Medición de Resultados Informados por el Paciente , Complicaciones Posoperatorias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Ortopédicos/efectos adversos , Dolor Postoperatorio/etiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/psicología , Periodo Posoperatorio , Estudios Retrospectivos , Factores de Riesgo , AutoinformeRESUMEN
INTRODUCTION: Classification systems for hallux rigidus imply that, as radiographic changes progress, symptoms will concurrently increase in severity. However, symptom intensity and radiographic severity can be discordant for many patients. We studied the correlation between hallux rigidus grades and the Foot and Ankle Ability Measure (FAAM) scores to better understand this relationship. METHODS: We retrospectively reviewed weight-bearing radiographs of the foot and FAAM Activities of Daily Living (ADL) questionnaires for 84 patients with hallux rigidus. The Spearman rank coefficient was used to correlate clinical-radiographic hallux rigidus grade with FAAM ADL scores. RESULTS: In 84 patients, the clinical-radiographic grade for hallux rigidus showed no relationship with FAAM ADL score (r = -0.10; P = 0.36) but did show moderate correlation with patient age (r = 0.63; P < 0.001). DISCUSSION: Advancing radiographic changes in hallux rigidus did not correspond with patient symptoms as measured via FAAM ADL scores. CONCLUSION: The reliability and validity of current grading criteria for hallux rigidus may require further exploration. LEVEL OF EVIDENCE: Level III.
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Hallux Rigidus/complicaciones , Actividades Cotidianas , Articulación del Tobillo/diagnóstico por imagen , Articulación del Tobillo/fisiopatología , Femenino , Pie/diagnóstico por imagen , Pie/fisiopatología , Hallux Rigidus/diagnóstico por imagen , Hallux Rigidus/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Reproducibilidad de los Resultados , Estudios Retrospectivos , Encuestas y Cuestionarios , Soporte de PesoRESUMEN
BACKGROUND: Traditional patient-reported outcome instruments like the Foot and Ankle Ability Measure (FAAM) quantify patient disability but often are limited by responder burden and incomplete questionnaires. The Patient-Reported Outcome Measurement Information System (PROMIS) overcomes such obstacles through computer-adaptive technology and can capture outcome data from various domains including physical and psychosocial function. Prior work has compared the FAAM with PROMIS physical function; however, there is little evidence comparing the association between foot and ankle-specific tools like the FAAM with more general outcomes measures of PROMIS pain interference and depression in foot and ankle conditions. QUESTIONS/PURPOSES: (1) We asked whether there was a relationship between FAAM Activities of Daily Living (ADL) scores with PROMIS physical function, pain interference, and depression in patients with hallux valgus. (2) Additionally, we asked if we could identify specific factors that are associated with variance in FAAM and PROMIS physical function scores in patients with hallux valgus. METHODS: Eighty-five new patients with either a primary or secondary diagnosis of hallux valgus based on clinic billing codes from July 2015 to February 2016 were retrospectively identified. Patients completed FAAM ADL paper-based surveys and electronic PROMIS questionnaires for physical function, pain interference, and depression from new patient visits at a single time. Spearman rho correlations were performed between FAAM ADL and PROMIS scores. Analyses then were used to identify differences in FAAM ADL and PROMIS physical function measures based on demographic variables. Stepwise linear regressions then determined which demographic and/or outcome variable(s) accounted for the variance in FAAM ADL and PROMIS physical function scores. RESULTS: FAAM scores correlated strongly with PROMIS physical function (r = 0.70, p < 0.001), moderately with PROMIS pain interference (r = -0.65, p < 0.001), and weakly with PROMIS depression (r = -0.35, p < 0.001) scores. Regression analyses showed that PROMIS pain interference scores alone were associated with sizeable portions of the variance in FAAM ADL (R2 = 0.44, p < 0.001) and PROMIS physical function (R2 = 0.57, p < 0.001) measures. CONCLUSIONS: PROMIS function and pain measures correlated with FAAM ADL scores, highlighting the interrelationship of pain and function when assessing outcomes in patients with hallux valgus. PROMIS tools allow for more-efficient data collection across multiple domains and, moving forward, may be better poised to monitor changes in pain and function with time compared with traditional outcome measures like the FAAM. CLINICAL RELEVANCE: The relationships shown here between PROMIS and FAAM scores further support the use of PROMIS tools in outcomes-based research. In patients with hallux valgus, pain-related disability appears to be a central feature of the patient-experience. Future studies should assess the association of various outcome domains on other common foot and ankle diagnoses.
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Articulación del Tobillo/fisiopatología , Artralgia/diagnóstico , Evaluación de la Discapacidad , Hallux Valgus/diagnóstico , Dimensión del Dolor , Medición de Resultados Informados por el Paciente , Actividades Cotidianas , Adulto , Anciano , Artralgia/fisiopatología , Artralgia/psicología , Fenómenos Biomecánicos , Depresión/diagnóstico , Depresión/psicología , Femenino , Hallux Valgus/fisiopatología , Hallux Valgus/psicología , Estado de Salud , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Rango del Movimiento Articular , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Recurrent pain and deformity following forefoot surgery can cause significant patient disability. In patients with rheumatoid arthritis, first metatarsophalangeal (MTP) joint arthrodesis with lesser metatarsal head resections-termed the rheumatoid forefoot reconstruction-has been shown to be a reliable operation for pain relief and deformity correction. Limited data, however, have been published on outcomes of the same forefoot reconstruction operation in the nonrheumatoid patient. Here, we describe our experience with this procedure in patients without rheumatoid disease, hypothesizing improved clinical and radiographic outcomes following surgery. METHODS: Following chart review and reviewing billing codes, we retrospectively identified patients without a diagnosis of rheumatoid arthritis who underwent first MTP arthrodesis with lesser metatarsal head resections. Phone surveys were conducted to assess clinical outcomes including pain and patient satisfaction. Preoperative and postoperative radiographs were reviewed for 1, 2 intermetatarsal angle (IMA), hallux valgus angle (HVA), second MTP angle (MTP-2), and lesser MTP alignment (in both sagittal and axial planes). Postoperative radiographs were assessed for radiographic union. We identified 14 nonrheumatoid patients (16 feet) who underwent forefoot reconstruction. Of those, 13 patients (15 feet) were successfully contacted via follow-up phone survey at an average of 44.3 months postoperatively (range: 20-76 months). RESULTS: Mean postoperative satisfaction scores were 9.0 (out of 10). No patients required reoperation at final phone follow-up. Pain scores significantly decreased from 6.2 preoperatively to 1.9 postoperatively ( P <.001). Radiographic parameters (1,2 IMA, HVA, MTP-2, and lesser MTP alignment in the sagittal plane) improved with surgery ( P <.05), and all 16 feet achieved union of the first MTP arthrodesis. CONCLUSION: With decreased pain, high satisfaction rates, and improved radiographic parameters, first MTP arthrodesis coupled with lesser metatarsal head resection was a viable option for nonrheumatoid patients who failed prior attempts at forefoot reconstruction or have chronic forefoot pain with deformity. LEVEL OF EVIDENCE: Level IV, retrospective case series.
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Artritis Reumatoide/cirugía , Artroplastia/métodos , Antepié Humano/cirugía , Hallux Valgus/cirugía , Articulación Metatarsofalángica/cirugía , Articulación Metatarsofalángica/fisiología , Satisfacción del Paciente , Radiografía , Reoperación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹58Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹58Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹58Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors. METHODS: With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back). RESULTS: As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC. CONCLUSIONS: The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation.
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Proteínas Portadoras/genética , Catecol O-Metiltransferasa/genética , Memoria a Corto Plazo/fisiología , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/fisiología , Adulto , Análisis de Varianza , Femenino , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética/métodos , Masculino , Metionina/genética , Pruebas Neuropsicológicas , Oxígeno/sangre , Corteza Prefrontal/irrigación sanguínea , Tiempo de Reacción/genética , Valina/genética , Adulto JovenRESUMEN
The etiology of schizophrenia likely involves genetic interactions. DISC1, a promising candidate susceptibility gene, encodes a protein which interacts with many other proteins, including CIT, NDEL1, NDE1, FEZ1 and PAFAH1B1, some of which also have been associated with psychosis. We tested for epistasis between these genes in a schizophrenia case-control study using machine learning algorithms (MLAs: random forest, generalized boosted regression andMonteCarlo logic regression). Convergence of MLAs revealed a subset of seven SNPs that were subjected to 2-SNP interaction modeling using likelihood ratio tests for nested unconditional logistic regression models. Of the 7C2 = 21 interactions, four were significant at the α = 0.05 level: DISC1 rs1411771-CIT rs10744743 OR = 3.07 (1.37, 6.98) p = 0.007; CIT rs3847960-CIT rs203332 OR = 2.90 (1.45, 5.79) p = 0.003; CIT rs3847960-CIT rs440299 OR = 2.16 (1.04, 4.46) p = 0.038; one survived Bonferroni correction (NDEL1 rs4791707-CIT rs10744743 OR = 4.44 (2.22, 8.88) p = 0.00013). Three of four interactions were validated via functional magnetic resonance imaging (fMRI) in an independent sample of healthy controls; risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during the N-back task, a schizophrenia-linked intermediate biological phenotype: rs3847960-rs440299; rs1411771-rs10744743, rs4791707-rs10744743 (SPM5 p < 0.05, corrected), although we were unable to statistically replicate the interactions in other clinical samples. Interestingly, the CIT SNPs are proximal to exons that encode theDISC1 interaction domain. In addition, the 3' UTR DISC1 rs1411771 is predicted to be an exonic splicing enhancer and the NDEL1 SNP is ~3,000 bp from the exon encoding the region of NDEL1 that interacts with the DISC1 protein, giving a plausible biological basis for epistasis signals validated by fMRI.