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BACKGROUND: Real-world evidence is limited regarding the relationship between race and use of durvalumab, an immunotherapy approved for use in adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This study aimed to evaluate if durvalumab treatment patterns differed by race in patients with unresectable stage III NSCLC in a Veterans Health Administration (VHA) population. MATERIALS AND METHODS: This was a retrospective analysis of White and Black adults with unresectable stage III NSCLC treated with durvalumab presenting to any VHA facility in the US from January 1, 2017, to June 30, 2020. Data captured included baseline characteristics and durvalumab treatment patterns, including treatment initiation delay (TID), interruption (TI), and discontinuation (TD); defined as CRT completion to durvalumab initiation greater than 42 days, greater than 28 days between durvalumab infusions, and more than 28 days from the last durvalumab dose with no new durvalumab restarts, respectively. The number of doses, duration of therapy, and adverse events were also collected. RESULTS: A total of 924 patients were included in this study (White = 726; Black = 198). Race was not a significant factor in a multivariate logistic regression model for TID (OR, 1.39; 95% CI, 0.81-2.37), TI (OR, 1.58; 95% CI, 0.90-2.76), or TD (OR, 0.84; 95% CI, 0.50-1.38). There were also no significant differences in median (interquartile range [IQR]) number of doses (White: 15 [7-24], Black: 18 [7-25]; P = .25) or median (IQR) duration of therapy (White: 8.7 months [2.9-11.8], Black: 9.8 months [3.6-12.0]; P = .08), although Black patients were less likely to experience an immune-related adverse event (28% vs. 36%, P = .03) and less likely to experience pneumonitis (7% vs. 14%, P < .01). CONCLUSION: Race was not found to be linked with TID, TI, or TD in this real-world study of patients with unresectable stage III NSCLC treated with durvalumab at the VHA.
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Carcinoma de Pulmón de Células no Pequeñas , Equidad en Salud , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Estudios Retrospectivos , Salud de los Veteranos , QuimioradioterapiaRESUMEN
BACKGROUND & AIMS: Large prospective studies to establish the prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are lacking. We prospectively assessed the prevalence and severity of NAFLD/NASH in a cohort of asymptomatic middle-aged Americans attending a colonoscopy class at a gastroenterology clinic. METHODS: Screening for NAFLD was performed using magnetic resonance (MR)-based LiverMultiScan® proton density fat fraction (LMS-PDFF). MR exams also included corrected T1 and elastography for liver stiffness measurement (LSM). FibroScan® was also used to measure LSM. Participants with predetermined abnormal imaging parameters were offered a liver biopsy. Biopsies were read in a blinded fashion with results based on the consensus by 2 expert pathologists. The prevalence of NAFLD was determined by PDFF ≥5% or by histological diagnosis of NAFLD (if biopsy data were available). The prevalence of NASH was defined by biopsy. RESULTS: Of 835 participants, 664 met the inclusion and exclusion criteria. The mean age was 56 ± 6.4 years, 50% were male, the mean BMI was 30.48 ± 5.46 kg/m2, and 52% were obese. The prevalence of NAFLD was 38% (95% CI 34-41%) and the prevalence of NASH was 14% (95% CI 12-17%). While no patient had cirrhosis on biopsy, significant fibrosis (F ≥2) was present in 5.9% (95% CI 4-8%) and bridging fibrosis in 1.6% (95% CI 1-3%). In a multivariable analysis, factors associated with the presence of NASH were race, obesity, and diabetes. CONCLUSION: Using state-of-the-art liver imaging modalities and reference biopsy, this study establishes an overall prevalence of NAFLD of 38% and NASH by biopsy of 14% in this cohort of asymptomatic middle-aged US adults. LAY SUMMARY: There are no prospective studies to determine how common is nonalcoholic steatohepatitis (NASH), the severe form of non-alcoholic fatty liver disease (NAFLD). In a large number of asymptomatic middle-aged Americans, we used a combination of state-of-the-art liver imaging methods and liver biopsy to prospectively determine the prevalence of NAFLD and NASH. NAFLD was diagnosed in 38%, NASH in 14%, and significant liver fibrosis in 6% of asymptomatic middle-aged Americans.
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Hígado Graso/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Estudios de Cohortes , Hígado Graso/epidemiología , Femenino , Humanos , Modelos Logísticos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevalencia , Estudios Prospectivos , Estadísticas no Paramétricas , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Stair ascent can be difficult for individuals with transfemoral amputation because of the loss of knee function. Most individuals with transfemoral amputation use either a step-to-step (nonreciprocal, advancing one stair at a time) or skip-step strategy (nonreciprocal, advancing two stairs at a time), rather than a step-over-step (reciprocal) strategy, because step-to-step and skip-step allow the leading intact limb to do the majority of work. A new microprocessor-controlled knee (Ottobock X2(®)) uses flexion/extension resistance to allow step-over-step stair ascent. QUESTIONS/PURPOSES: We compared self-selected stair ascent strategies between conventional and X2(®) prosthetic knees, examined between-limb differences, and differentiated stair ascent mechanics between X2(®) users and individuals without amputation. We also determined which factors are associated with differences in knee position during initial contact and swing within X2(®) users. METHODS: Fourteen individuals with transfemoral amputation participated in stair ascent sessions while using conventional and X2(®) knees. Ten individuals without amputation also completed a stair ascent session. Lower-extremity stair ascent joint angles, moment, and powers and ground reaction forces were calculated using inverse dynamics during self-selected strategy and cadence and controlled cadence using a step-over-step strategy. RESULTS: One individual with amputation self-selected a step-over-step strategy while using a conventional knee, while 10 individuals self-selected a step-over-step strategy while using X2(®) knees. Individuals with amputation used greater prosthetic knee flexion during initial contact (32.5°, p = 0.003) and swing (68.2°, p = 0.001) with higher intersubject variability while using X2(®) knees compared to conventional knees (initial contact: 1.6°, swing: 6.2°). The increased prosthetic knee flexion while using X2(®) knees normalized knee kinematics to individuals without amputation during swing (88.4°, p = 0.179) but not during initial contact (65.7°, p = 0.002). Prosthetic knee flexion during initial contact and swing were positively correlated with prosthetic limb hip power during pull-up (r = 0.641, p = 0.046) and push-up/early swing (r = 0.993, p < 0.001), respectively. CONCLUSIONS: Participants with transfemoral amputation were more likely to self-select a step-over-step strategy similar to individuals without amputation while using X2(®) knees than conventional prostheses. Additionally, the increased prosthetic knee flexion used with X2(®) knees placed large power demands on the hip during pull-up and push-up/early swing. A modified strategy that uses less knee flexion can be used to allow step-over-step ascent in individuals with less hip strength.
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Amputación Quirúrgica/instrumentación , Amputados/rehabilitación , Miembros Artificiales , Articulación de la Rodilla/cirugía , Traumatismos de la Pierna/cirugía , Microcomputadores , Tibia/cirugía , Adulto , Amputación Quirúrgica/efectos adversos , Fenómenos Biomecánicos , Ergonomía , Humanos , Articulación de la Rodilla/fisiopatología , Traumatismos de la Pierna/diagnóstico , Traumatismos de la Pierna/fisiopatología , Masculino , Diseño de Prótesis , Rango del Movimiento Articular , Recuperación de la Función , Tibia/lesiones , Tibia/fisiopatología , Resultado del Tratamiento , Grabación en VideoRESUMEN
BACKGROUND: Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. METHODS: This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. RESULTS: A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). CONCLUSIONS: These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.
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BACKGROUND: Given the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers. MATERIALS AND METHODS: Thirty subjects (13 females, 46-71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates. RESULTS: There was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively. CONCLUSIONS: 8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH.
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Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/tratamiento farmacológico , Imagen por Resonancia Magnética , Pectinas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Ultrasonografía , Anciano , Método Doble Ciego , Elasticidad , Femenino , Humanos , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Cirrosis Hepática/fisiopatología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Resultado del Tratamiento , Ultrasonografía/métodosRESUMEN
BACKGROUND: Individuals with leg amputations who use passive prostheses have greater metabolic demands than non-amputees likely due to limited net positive work compared to a biological ankle. New powered ankle-foot prostheses can perform net positive mechanical work to aid push-off capabilities, which may reduce metabolic demands. OBJECTIVES: Compare step-to-step transition work and metabolic demand during level and inclined walking using passive and powered ankle-foot prostheses. STUDY DESIGN: Repeated measures. METHODS: Six individuals with transtibial amputation and six able-bodied controls walked at a standardized speed across level ground and up a 5° incline. Calculated measures included mechanical work during step-to-step transitions from the trailing prosthetic to leading intact limb, steady state metabolic rate, and ankle joint kinetics and kinematics. RESULTS: The powered prosthesis generated 63% greater trailing limb step-to-step transition work than the passive during level walking only (p = 0.004). Metabolic rate was lower with the powered prosthesis during level (p = 0.006) but not inclined walking (p = 0.281). The powered prosthesis increased ankle power compared to the passive, to the extent that power was normalized to controls during inclined walking and greater than controls during level walking. CONCLUSION: The powered prosthesis improved ankle power, metabolic rate, and step-to-step transition work on level ground, with few negative consequences on inclines. These results may be used to guide the development and use of actively powered prosthetic devices in high-functioning individuals. CLINICAL RELEVANCE: Overall, powered devices offer biomechanical and metabolic benefits over passive energy storage and return designs on level ground and perform as well as a passive model on inclines. The lower metabolic demand when using the powered device may delay fatigue for individuals with transtibial amputation when walking over level ground.
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Amputación Quirúrgica/rehabilitación , Miembros Artificiales , Metabolismo Energético , Terapia por Ejercicio/métodos , Diseño de Prótesis/instrumentación , Caminata/fisiología , Adulto , Amputación Quirúrgica/métodos , Amputados , Articulación del Tobillo/cirugía , Fenómenos Biomecánicos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Valores de Referencia , Muestreo , Adulto JovenRESUMEN
The ability to navigate stairs step-over-step is an important functional outcome following severe lower leg injury and is difficult for many patients. Ankle-foot orthoses, such as the Intrepid Dynamic Exoskeletal Orthosis (IDEO), are often prescribed to improve function. This study compared stair climbing mechanics between IDEO users and able-bodied control participants. Thirteen IDEO users who sustained severe lower leg injury and 13 controls underwent biomechanical gait analysis. Participants ascended and descended a 16-step instrumented staircase without handrail use at a controlled cadence of 80 steps/min. Peak joint angles, moments, powers, and ground reaction forces, and integrated mechanical work were calculated. Independent t-tests with Bonferroni-Holm corrections were used to compare controls to IDEO and sound limbs. Reduced ankle range of motion on the IDEO limb resulted in compensatory strategies while ascending or descending stairs. During ascent, IDEO users had greater bilateral hip power during pull-up (p<0.007) to compensate for the IDEO limb׳s reduced ankle dorsiflexion (p<0.001) and knee extensor moment (p=0.001) while it was leading, and reduced ankle plantarflexor power while it was trailing (p<0.001). During stair descent, when the IDEO limb had was trailing, it had less ankle dorsiflexion during controlled lowering (p<0.001), resulting in greater vertical ground reaction force (p=0.005) and greater ankle and knee power absorption (p<0.001). Reduced IDEO limb ankle power absorption during weight acceptance (p<0.001) resulted in a large knee extensor moment (p<0.001) on the trailing sound limb to lower the body. Despite gait deviations, IDEO users were able to climb stairs step-over-step unassisted.
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Traumatismos de la Pierna/fisiopatología , Subida de Escaleras , Adaptación Fisiológica , Adulto , Articulación del Tobillo/fisiopatología , Fenómenos Biomecánicos , Ortesis del Pié , Marcha , Humanos , Rodilla/fisiopatología , Articulación de la Rodilla , Traumatismos de la Pierna/terapia , Masculino , Rango del Movimiento Articular , Adulto JovenRESUMEN
Sloped walking requires altered strategies for maintaining dynamic balance relative to level-ground walking, as evidenced by changes in sagittal-plane whole-body angular momentum (H) in able-bodied individuals. The ankle plantarflexor muscles are critical for regulating H, and functional loss of these muscles from transtibial amputation affects this regulation. However, it is unclear if a powered prosthesis, which more closely emulates intact ankle function than a passive energy-storage-and-return prosthesis, affects H differently during sloped walking. Therefore, our purpose was to investigate H in individuals with unilateral transtibial amputation when using powered and passive prostheses. Overall, the range of H was greater in people with a transtibial amputation relative to able-bodied individuals. On a -10° decline, individuals with amputation did not decrease H as much as able-bodied individuals, and had reduced prosthetic limb braking ground reaction forces and knee power absorption. On a +10° incline, individuals with amputation had a greater relative increase of H than able-bodied individuals, a more anterior placement of the prosthetic foot, and higher peak hip power generation. The powered prosthesis condition resulted in a smaller range of H during prosthetic stance relative to the passive condition, although it was still larger than able-bodied individuals. Our results suggest that prosthetic ankle power generation may help regulate dynamic balance during prosthetic stance, but alone is not sufficient for restoring H to that of able-bodied individuals on slopes. Contributions of knee extensor muscles and the biarticular gastrocnemius in regulating H on slopes should be further investigated.
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Miembros Artificiales , Fenómenos Mecánicos , Caminata/fisiología , Adulto , Amputación Quirúrgica , Tobillo/fisiología , Fenómenos Biomecánicos , Femenino , Marcha/fisiología , Humanos , Rodilla/fisiología , Masculino , Rango del Movimiento ArticularRESUMEN
BACKGROUND: Individuals with unilateral transfemoral amputation demonstrate significantly increased rates of osteoarthritis in their sound knee. This increased risk is likely the result of altered knee mechanical loading and gait compensations resulting from limited function in the prosthetic limb. Altered knee loading as calculated using loading rates and peak external knee adduction moments and impulses have been associated with both the development and progression of knee osteoarthritis in other populations. The purpose of this study was to determine if young individuals with transfemoral amputation demonstrate biomechanical indicators of increased knee osteoarthritis risk. METHODS: Fourteen young male Service Members with unilateral transfemoral amputation and 14 able-bodied service members underwent biomechanical gait analysis at three standardized walking velocities. A two-way ANOVA (group × speed) with unpaired comparisons with Bonferroni-Holm post-hoc corrections assessed statistical significance and effect sizes (d) were calculated. FINDINGS: Normalized peak external knee adduction moments and impulses were 25.7% (P < 0.014, d > 0.994) and 27.1% (P < 0.012, d > 1.019) lower, respectively, in individuals with trans-femoral amputation than controls when averaged across speeds, and effect sizes were large. External knee flexor moments were not, however, different between groups and effect sizes were generally small (P > 0.380, d < 0.338). Maximal loading rates were significantly greater in individuals with amputation and effect sizes were large (P < 0.001, d > 1.644). INTERPRETATION: Individuals with transfemoral amputation did not demonstrate biomechanical risk factors for high medial compartment knee joint loads, but the increased loading rates could place the sound knee at greater risk for cartilage or other tissue damage, even if not localized to the medial compartment.