Impact of in-utero exposure to HIV and latent TB on infant humoral responses.

Introduction: Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Methods: Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. Results: In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. Discussion: The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination.

Designing optimal allocations for cancer screening using queuing network models.

Cancer is one of the leading causes of death, but mortality can be reduced by detecting tumors earlier so that treatment is initiated at a less aggressive stage. The tradeoff between costs associated with screening and its benefit makes the decision of whom to screen and when a challenge. To enable comparisons across screening strategies for any cancer type, we demonstrate a mathematical modeling platform based on the theory of queuing networks designed for quantifying the benefits of screening strategies. Our methodology can be used to design optimal screening protocols and to estimate their benefits for specific patient populations. Our method is amenable to exact analysis, thus circumventing the need for simulations, and is capable of exactly quantifying outcomes given variability in the age of diagnosis, rate of progression, and screening sensitivity and intervention outcomes. We demonstrate the power of this methodology by applying it to data from the Surveillance, Epidemiology and End Results (SEER) program. Our approach estimates the benefits that various novel screening programs would confer to different patient populations, thus enabling us to formulate an optimal screening allocation and quantify its potential effects for any cancer type and intervention.

Case reports: the influence of selective voluntary motor control on gait after hamstring lengthening surgery.

BACKGROUND: Preliminary evidence suggests selective voluntary motor control (SVMC), defined as performance of isolated voluntary joint movement on request, may be an important factor affecting functional movement tasks. Individuals with poor SVMC are unable to dissociate hip and knee synergistic movement during the swing phase of gait and have difficulty extending their knee while the hip is flexing during terminal swing regardless of hamstring length. This pattern may limit their ability to take advantage of hamstring-lengthening surgery (HLS) and may explain a lack of improved stride length postoperatively. QUESTIONS/PURPOSES: Provide a preliminary clinical and conceptual framework for using SVMC to predict swing phase parameters of gait after HLS. PATIENTS AND METHODS: We contrasted two patients with spastic diplegia of similar age, gross motor function, and spasticity but with different SVMC scores using the Selective Control Assessment of the Lower Extremity (SCALE). The patients underwent bilateral HLS. Popliteal angles, joint kinematics, step length, stride length, and walking velocity were assessed pre- and postoperatively. RESULT: Popliteal angles, terminal knee extension, and knee range of motion improved for both patients. However, only the patient with higher SCALE scores improved stride length postoperatively. CONCLUSION: Although preliminary, the data suggest that SVMC, as measured by SCALE, may be a prognostic factor for improved stride length after HLS in patients with spastic diplegia. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Joint moment contributions to swing knee extension acceleration during gait in individuals with spastic diplegic cerebral palsy.

The mechanisms contributing to swing phase knee acceleration in individuals with spastic diplegic cerebral palsy (CP) are not well understood, but evidence suggests that selective voluntary motor control (SVMC) may play a role. The purpose of this study was to examine the relationship between lower limb SVMC, measured using Selective Control Assessment of the Lower Extremity (SCALE), and joint moment contributions to swing knee extension acceleration in participants with spastic diplegic CP. Eighteen participants were recruited (mean age=13.8 years, range=6-30 years, Gross Motor Function Classification System Levels I-III). Induced acceleration analysis was performed during the swing phase of gait. Average joint moment contributions to swing knee extension acceleration were calculated. Contributions from stance limb and swing limb joint moments were correlated with SCALE scores using Pearson's correlations. A strong correlation was found (p<0.0001, r=0.85) between SCALE score and the total swing joint moment contributions to swing knee extension acceleration. As SCALE score increased, swing joint moments provided less resistance to knee extension acceleration. No relationship (p=0.18) was found between stance moment contributions to swing knee acceleration and stance limb SCALE scores. Excessive contributions from swing limb joint moments appear to be the factor limiting swing knee extension in spastic diplegic CP gait. Interventions that address negative contributions due to spasticity may not be effective in patients who cannot generate adequate knee extension due to poor SVMC.

Joint moment contributions to swing knee extension acceleration during gait in children with spastic hemiplegic cerebral palsy.

Inadequate peak knee extension during the swing phase of gait is a major deficit in individuals with spastic cerebral palsy (CP). The biomechanical mechanisms responsible for knee extension have not been thoroughly examined in CP. The purpose of this study was to assess the contributions of joint moments and gravity to knee extension acceleration during swing in children with spastic hemiplegic CP. Six children with spastic hemiplegic CP were recruited (age=13.4+/-4.8 years). Gait data were collected using an eight-camera system. Induced acceleration analysis was performed for each limb during swing. Average joint moment and gravity contributions to swing knee extension acceleration were calculated. Total swing and stance joint moment contributions were compared between the hemiplegic and non-hemiplegic limbs using paired t-tests (p<0.05). Swing limb joint moment contributions from the hemiplegic limb decelerated swing knee extension significantly more than those of the non-hemiplegic limb and resulted in significantly reduced knee extension acceleration. Total stance limb joint moment contributions were not statistically different. Swing limb joint moment contributions that decelerated knee extension appeared to be the primary cause of inadequate knee extension acceleration during swing. Stance limb muscle strength did not appear to be the limiting factor in achieving adequate knee extension in children with CP. Recent research has shown that the ability to extend the knee during swing is dependent on the selective voluntary motor control of the limb. Data from individual participants support this concept.

The effect of lower extremity selective voluntary motor control on interjoint coordination during gait in children with spastic diplegic cerebral palsy.

Damage to motor tracts in the periventricular white matter is a primary etiology in spastic diplegic cerebral palsy (CP). These tracts are responsible for the production of selective voluntary motor control (SVMC). Lower extremity motor control has been suggested as being an important predictor of improvement following interventions. While there are multiple impairments in spastic CP, the inability to perform purposeful voluntary movement is a critical factor in determining functional ability that merits investigation. The purpose of this study was to examine the relationship between SVMC ability and hip and knee coordination during the swing phase of gait in participants with spastic CP. Gait analysis and SVMC assessments were conducted for 15 participants with CP. Relative phase analysis was used to calculate the minimum relative phase (MRP) angle during swing; a measurement of interjoint coordination between the hip and the knee. SVMC ability was measured using the Selective Control Assessment of the Lower Extremity (SCALE) tool. Significant correlations were found between SCALE scores and both MRP values (p<0.0001) and duration of out-of-phase movement (p<0.005) during swing. These findings supported our hypothesis that SVMC ability is related to a patient's ability to move in an uncoupled pattern during the swing phase of gait (i.e., extending the knee while flexing the hip). An understanding of influence of SVMC on swing phase gait mechanics may help establish appropriate goals for interventions, in particular hamstring lengthenings.

Can treadmill walking be used to assess propulsion generation?

Instrumented treadmills offer significant advantages for analysis of human locomotion, including recording consecutive steady-state gait cycles, precisely controlling walking speed, and avoiding force plate targeting. However, some studies of hemiparetic walking on a treadmill have suggested that the moving treadmill belt may fundamentally alter propulsion mechanics. Any differences in propulsion mechanics during treadmill walking would be problematic since recent studies assessing propulsion have provided fundamental insight into hemiparetic walking. The purpose of this study was to test the hypothesis that there would be no difference in the generation of anterior/posterior (A/P) propulsion by performing a carefully controlled comparison of the A/P ground reaction forces (GRFs) and impulses in healthy adults during treadmill and overground walking. Gait data were collected from eight subjects walking overground and on a treadmill with speed and cadence controlled. Peak negative and positive horizontal GRFs in early and late stance, respectively, were reduced by less than 5% of body weight (p<0.05) during treadmill walking compared to overground walking. The magnitude of the braking impulse was similarly lower (p<0.05) during treadmill walking, but no significant difference was found between propulsion impulses. While there were some subtle differences in A/P GRFs between overground and treadmill walking, these results suggest there is no fundamental difference in propulsion mechanics. We conclude that treadmill walking can be used to investigate propulsion generation in healthy and by implication clinical populations.

The effect of direct measurement versus cadaver estimates of anthropometry in the calculation of joint moments during above-knee prosthetic gait in pediatrics.

Joint reaction forces, moments and powers are important in interpreting gait mechanics and compensatory strategies used by patients walking with above-knee prostheses. Segmental anthropometrics, required to calculate joint moments, are often estimated using data from cadaver studies. However, these values may not be accurate for patients following amputation as prostheses are composed of non-biologic material. The purpose of this study was to compare joint moments using anthropometrics calculated from cadaver studies versus direct measurements of the residual limb and prosthesis for children with an above-knee amputation. Gait data were collected for four subjects with above-knee prostheses walking at preferred and fast speeds. Joint moments were computed using anthropometrics from cadaver studies and direct measurements for each subject. The difference between these two methods primarily affected the inertia couple (Ialpha term) and the inertial effect due to gravity, which comprised a greater percentage of the total joint moment during swing as compared to stance. Peak hip and knee flexor and extensor moments during swing were significantly greater when calculated using cadaver data (p<0.05). These differences were greater while walking fast as compared to slow speeds. A significant difference was not found between these two methods for peak hip and knee moments during stance. A significant difference was found for peak ankle joint moments during stance, but the magnitude was not clinically important. These results support the use of direct measurements of anthropometry when examining above-knee prosthetic gait, particularly during swing.

Compensatory strategies during normal walking in response to muscle weakness and increased hip joint stiffness.

Compared to young adults, older adults exhibit a slower walking speed, smaller step length, shorter swing phase time and decreased range of motion in their lower extremity joints. The underlying mechanisms causing these gait adaptations is not well understood, with various musculoskeletal parameters being put forth as contributing factors, including increased joint stiffness and decreased isometric muscle strength. The objective of this study was to identify the necessary compensatory mechanisms to overcome such musculoskeletal deficits and regain a normal walking pattern. Understanding these mechanisms has important implications for designing effective rehabilitation interventions for older adults that target specific muscle groups and properties (e.g., isometric strength versus joint stiffness) to improve gait performance. Muscle-actuated forward dynamics simulations of normal walking were analyzed to quantify compensatory mechanisms in the presence of muscle weakness in specific muscle groups and increased hip joint stiffness. Of particular importance were the compensatory mechanisms provided by the plantar flexors, which were shown to be able to compensate for many musculoskeletal deficits, including diminished muscle strength in the hip and knee flexors and extensors and increased hip joint stiffness. This importance was further highlighted when a normal walking pattern could not be achieved through compensatory action of other muscle groups when the uniarticular and biarticular plantar flexor strength was decreased as a group. Thus, rehabilitation or preventative exercise programs may consider focusing on increasing or maintaining plantar flexor strength, which appears critical to maintaining normal walking mechanics.