Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10–15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest

Joint and muscle assessments of the separate effects of Botulinum NeuroToxin-A and lower-leg casting in children with cerebral palsy

Botulinum NeuroToxin-A (BoNT-A) injections to the medial gastrocnemius (MG) and lower-leg casts are commonly combined to treat ankle equinus in children with spastic cerebral palsy (CP). However, the decomposed treatment effects on muscle or tendon structure, stretch reflexes, and joint are unknown. In this study, BoNT-A injections to the MG and casting of the lower legs were applied separately to gain insight into the working mechanisms of the isolated treatments on joint, muscle, and tendon levels. Thirty-one children with spastic CP (GMFCS I-III, age 7.4 +/- 2.6 years) received either two weeks of lower-leg casts or MG BoNT-A injections. During full range of motion slow and fast passive ankle rotations, joint resistance and MG stretch reflexes were measured. MG muscle and tendon lengths were assessed at resting and at maximum dorsiflexion ankle angles using 3D-freehand ultrasound. Treatment effects were compared using non-parametric statistics. Associations between the effects on joint and muscle or tendon levels were performed using Spearman correlation coefficients (p < 0.05). Increased joint resistance, measured during slow ankle rotations, was not significantly reduced after either treatment. Additional joint resistance assessed during fast rotations only reduced in the BoNT-A group (-37.6%, p = 0.013, effect size = 0.47), accompanied by a reduction in MG stretch reflexes (-70.7%, p = 0.003, effect size = 0.56). BoNT-A increased the muscle length measured at the resting ankle angle (6.9%, p = 0.013, effect size = 0.53). Joint angles shifted toward greater dorsiflexion after casting (32.4%, p = 0.004, effect size = 0.56), accompanied by increases in tendon length (5.7%, p = 0.039, effect size = 0.57; r = 0.40). No associations between the changes in muscle or tendon lengths and the changes in the stretch reflexes were found. We conclude that intramuscular BoNT-A injections reduced stretch reflexes in the MG accompanied by an increase in resting muscle belly length, whereas casting resulted in increased dorsiflexion without any changes to the muscle length. This supports the need for further investigation on the effect of the combined treatments and the development of treatments that more effectively lengthen the muscle

The Relationship Between Medial Gastrocnemius Lengthening Properties and Stretch Reflexes in Cerebral Palsy

Stretch reflex hyperactivity in the gastrocnemius of children with spastic cerebral palsy (CP) is commonly evaluated by passively rotating the ankle joint into dorsiflexion at different velocities, such as applied in conventional clinical spasticity assessments. However, surface electromyography (sEMG) collected from the medial gastrocnemius (MG) during such examination reveals unexplained heterogeneity in muscle activation between patients. Recent literature also highlights altered muscle tensile behavior in children with spastic CP. We aimed to document MG muscle and tendon lengthening during passive ankle motion at slow and fast velocity and explore its interdependence with the elicited hyperactive stretch reflex. The ankle of 15 children with CP (11 ± 3 years, GMFCS 9I 6II, 8 bilateral, 7 unilateral) and 16 typically developing children (TDC) was passively rotated over its full range of motion at slow and fast velocity. Ultrasound, synchronized with motion-analysis, was used to track the movement of the MG muscle-tendon junction and extract the relative lengthening of muscle and tendon during joint rotation. Simultaneously, MG sEMG was measured. Outcome parameters included the angular and muscle lengthening velocities 30 ms before EMG onset and the gain in root mean square EMG during stretch, as a measure of stretch reflex activity. Compared to slow rotation, the muscle lengthened less and stretch reflex activity was higher during fast rotation. These velocity-induced changes were more marked in CP compared to TDC. In the CP group, muscle-lengthening velocity had higher correlation coefficients with stretch reflex hyperactivity than joint angular velocity. Muscles with greater relative muscle lengthening during slow rotation had earlier and stronger stretch reflexes during fast rotation. These initial results suggest that ankle angular velocity is not representative of MG muscle lengthening velocity and is less related to stretch reflex hyperactivity than MG muscle lengthening. In addition, muscles that lengthened more during slow joint rotation were more likely to show a velocity-dependent stretch reflex. This interdependence of muscle lengthening and stretch reflexes may be important to consider when administering treatment. However, muscle and tendon lengthening properties alone could not fully explain the variability in stretch reflexes, indicating that other factors should also be investigated

Developing a Trusted Human-AI Network for Humanitarian Benefit

Humans and artificial intelligences (AI) will increasingly participate digitally and physically in conflicts yet there is a lack of trusted communications across agents and platforms. For example, humans in disasters and conflict already use messaging and social media to share information, however, international humanitarian relief organisations treat this information as unverifiable and untrustworthy. AI may reduce the ‘fog-of-war’ and improve outcomes, however current AI implementations are often brittle, have a narrow scope of application and wide ethical risks. Meanwhile, human error causes significant civilian harms even by combatants committed to complying with international humanitarian law. AI offers an opportunity to help reduce the tragedy of war and better deliver humanitarian aid to those who need it. However, to be successful, these systems must be trusted by humans and their information systems, overcoming flawed information flows in conflict and disaster zones that continue to be marked by intermittent communications, poor situation awareness, mistrust and human errors. In this paper, we consider the integration of a communications protocol (the ‘Whiteflag protocol’), distributed ledger technology, and information fusion with artificial intelligence (AI), to improve conflict communications called “Protected Assurance Understanding Situation & Entities” PAUSE. Such a trusted human-AI communication network could provide accountable information exchange regarding protected entities, critical infrastructure; humanitarian signals and status updates for humans and machines in conflicts. Trust-based information fusion provides resource-efficient use of diverse data sources to increase the reliability of reports. AI can be used to catch human mistakes and complement human decision making, while human judgment can direct and override AI recommendations. We examine several case studies for the integration of these technologies into a trusted human-AI network for humanitarian benefit including mapping a conflict zone with civilians and combatants in real time, preparation to avoid incidents and using the network to manage misinformation

Reliability of Processing 3-D Freehand Ultrasound Data to Define Muscle Volume and Echo-intensity in Pediatric Lower Limb Muscles with Typical Development or with Spasticity

This investigation assessed the processer reliability of estimating muscle volume and echo-intensity of the rectus femoris, tibialis anterior and semitendinosus. The muscles of 10 typically developing children (8.15 [1.40] y) and 15 children with spastic cerebral palsy (7.67 [3.80] y; Gross Motor Function Classification System I = 5, II = 5, III = 5) were scanned with 3-D freehand ultrasonography. For the intra-processer analysis, the intra-class correlations coefficients (ICCs) for muscle volume ranged from 0.943–0.997, with relative standard errors of measurement (SEM%) ranging from 1.24%–8.97%. For the inter-processer analysis, these values were 0.853 to 0.988 and 3.47% to 14.02%, respectively. Echo-intensity had ICCs >0.947 and relative SEMs <4% for both analyses. Muscle volume and echo-intensity can be reliably extracted for the rectus femoris, semitendinosus and tibialis anterior in typically developing children and children with cerebral palsy. The need for a single processer to analyze all data is dependent on the size of the expected changes or differences

Medial gastrocnemius volume and echo-intensity after botulinum neurotoxin A interventions in children with spastic cerebral palsy.

AIM: This cross-sectional investigation evaluated whether recurrent botulinum neurotoxin A (BoNT-A) interventions to the medial gastrocnemius have an influence on muscle morphology, beyond Gross Motor Function Classification System (GMFCS) level. METHOD: A cohort of typically developing children (n=67; 43 males, 24 females; median age 9y 11mo [range 7y 10mo-11y 6mo]), a cohort of children with spastic cerebral palsy (CP) naive to BoNT-A interventions (No-BoNT-A; n=19; 10 males, nine females; median age 9y 3mo [range 8y 5mo-10y 10mo]) and a cohort of children with spastic CP with a minimum of three recurrent BoNT-A interventions to the medial gastrocnemius (BoNT-A; n=19; 13 males, six females; median age 9y 8mo [range 7y 3mo-10y 7mo]) were recruited. Three-dimensional freehand ultrasound was used to estimate medial gastrocnemius volume normalized to body mass and echo-intensity. RESULTS: Normalized medial gastrocnemius volume and echo-intensity significantly differed between the two spastic CP cohorts (p≤0.05), with the BoNT-A cohort having larger alterations. Associations between normalized medial gastrocnemius volume and echo-intensity were highest in the No-BoNT-A cohort, followed by the BoNT-A cohort. Multiple regression analyses revealed that both GMFCS level and BoNT-A intervention history were significantly associated with smaller normalized medial gastrocnemius volume and higher echo-intensity. INTERPRETATION: Recurrent BoNT-A interventions may induce alterations to medial gastrocnemius volume and echo-intensity beyond the natural history of the spastic CP pathology. WHAT THIS PAPER ADDS: In spastic cerebral palsy, medial gastrocnemius volumes are smaller and echo-intensities higher compared with typical development. Alterations after botulinum neurotoxin A intervention (BoNT-A) are larger than in no BoNT-A intervention. Gross Motor Function Classification System level and BoNT-A history significantly associate with medial gastrocnemius and echo-intensity alterations

Medial gastrocnemius muscle stiffness cannot explain the increased ankle joint range of motion following passive stretching in children with cerebral palsy.

Stretching is often used to increase/maintain joint range of motion (ROM) in children with cerebral palsy (CP) but the effectiveness of these interventions is limited. Therefore, this study aimed to determine the acute changes in muscle-tendon lengthening properties that contribute to increased ROM after a bout of stretching in children with CP. Eleven children with spastic CP (age:12.1(3)y, 5/6 hemiplegia/diplegia, 7/4 GMFCS level I/II) participated in this study. Each child received 3 sets of 5 × 20 s passive, manual static dorsiflexion stretches separated by 30 s rest, and 60 s rest between sets. Pre- and immediately post-stretching, ultrasound was used to measure medial gastrocnemius fascicle lengthening continuously over the full ROM and an individual common ROM pre- to post-stretching. Simultaneously, 3D motion of two marker clusters on the shank and the foot was captured to calculate ankle angle, and ankle joint torque was calculated from manually applied torques and forces on a 6DoF load cell. After stretching, ROM was increased (9.9° (12.0), P = 0.005). Over a ROM common to both pre and post measurements, there were no changes in fascicle lengthening or torque. The maximal ankle joint torque tolerated by the participants increased (2.9(2.4) Nm, P = 0.003) and at this highest passive torque maximal fascicle length was 2.8(2.4) mm greater (P = 0.009) when compared to before stretching. These results indicate that the stiffness of the muscle fascicles in children with CP remain unaltered by an acute bout of stretching. This article is protected by copyright. All rights reserved

Non-invasive Quantitative Assessment of Muscle Force Based on Ultrasonic Shear Wave Elastography

The objective of this study was to investigate the feasibility of using shear wave elastography (SWE) to indirectly measure passive muscle force and to examine the effects of muscle mass and scan angle. We measured the Young's moduli of 24 specimens from six muscles of four swine at different passive muscle loads under different scan angles (0°, 30°, 60° and 90°) using SWE. Highly linear relationships between Young's modulus E and passive muscle force F were found for all 24 muscle specimens at 0o scan angle with coefficients of determination R2 ranging from 0.984 to 0.999. The results indicate that the muscle mass has no significant effect on the muscle E–F relationship, whereas E–F linearity decreases disproportionately with increased scan angle. These findings suggest that SWE, when carefully applied, can provide a highly reliable tool to measure muscle Young's modulus, and could be used to assess the muscle force quantitatively