Derivation and validation of a clinical prediction rule for upper limb functional outcomes after traumatic cervical spinal cord injury

IMPORTANCE: Traumatic cervical spinal cord injury (SCI) can result in debilitating paralysis. Following cervical SCI, accurate early prediction of upper limb recovery can serve an important role in guiding the appropriateness and timing of reconstructive therapies. OBJECTIVE: To develop a clinical prediction rule to prognosticate upper limb functional recovery after cervical SCI. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study was a retrospective review of a longitudinal cohort study including patients enrolled in the National SCI model systems (SCIMS) database in US. Eligible patients were 15 years or older with tetraplegia (neurological level of injury C1-C8, American Spinal Cord Injury Association [ASIA] impairment scale [AIS] A-D), with early (within 1 month of SCI) and late (1-year follow-up) clinical examinations from 2011 to 2016. The data analysis was conducted from September 2021 to June 2022. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of dependency in eating, bladder management, transfers, and locomotion domains of functional independence measure at 1-year follow-up. Each domain ranges from 1 to 7 with a lower score indicating greater functional dependence. Composite dependency was defined as a score of 4 or higher in at least 3 chosen domains. Multivariable logistic regression was used to predict the outcome based on early neurological variables. Discrimination was quantified using C statistics, and model performance was internally validated with bootstrapping and 10-fold cross-validation. The performance of the prediction score was compared with AIS grading. Data were split into derivation (2011-2014) and temporal-validation (2015-2016) cohorts. RESULTS: Among 2373 patients with traumatic cervical SCI, 940 had complete 1-year outcome data (237 patients [25%] aged 60 years or older; 753 men [80%]). The primary outcome was present in 118 patients (13%), which included 92 men (78%), 83 (70%) patients who were younger than 60 years, and 73 (62%) patients experiencing AIS grade A SCI. The variables significantly associated with the outcome were age (age 60 years or older: OR, 2.31; 95% CI, 1.26-4.19), sex (men: OR, 0.60; 95% CI, 0.31-1.17), light-touch sensation at C5 (OR, 0.44; 95% CI, 0.44-1.01) and C8 (OR, 036; 95% CI, 0.24-0.53) dermatomes, and motor scores of the elbow flexors (C5) (OR, 0.74; 95% CI, 0.60-0.89) and wrist extensors (C6) (OR, 0.61; 95% CI, 0.49-0.75). A multivariable model including these variables had excellent discrimination in distinguishing dependent from independent patients in the temporal-validation cohort (C statistic, 0.90; 95% CI, 0.88-0.93). A clinical prediction score (range, 0 to 45 points) was developed based on these measures, with higher scores increasing the probability of dependency. The discrimination of the prediction score was significantly higher than from AIS grading (change in AUC, 0.14; 95% CI, 0.10-0.18; P \u3c .001). CONCLUSIONS AND RELEVANCE: The findings of this study suggest that this prediction rule may help prognosticate upper limb function following cervical SCI. This tool can be used to set patient expectations, rehabilitation goals, and aid decision-making regarding the appropriateness and timing for upper limb reconstructive surgeries

Personalized practice dosages may improve motor learning in older adults compared to standard of care practice dosages: A randomized controlled trial

Standard dosages of motor practice in clinical physical rehabilitation are insufficient to optimize motor learning, particularly for older patients who often learn at a slower rate than younger patients. Personalized practice dosing (i.e., practicing a task to or beyond one\u27s plateau in performance) may provide a clinically feasible method for determining a dose of practice that is both standardized and individualized, and may improve motor learning. The purpose of this study was to investigate whether personalized practice dosages

Upper limb nerve transfer surgery in patients with tetraplegia

IMPORTANCE: Cervical spinal cord injury (SCI) causes devastating loss of upper extremity function and independence. Nerve transfers are a promising approach to reanimate upper limbs; however, there remains a paucity of high-quality evidence supporting a clinical benefit for patients with tetraplegia. OBJECTIVE: To evaluate the clinical utility of nerve transfers for reanimation of upper limb function in tetraplegia. DESIGN, SETTING, AND PARTICIPANTS: In this prospective case series, adults with cervical SCI and upper extremity paralysis whose recovery plateaued were enrolled between September 1, 2015, and January 31, 2019. Data analysis was performed from August 2021 to February 2022. INTERVENTIONS: Nerve transfers to reanimate upper extremity motor function with target reinnervation of elbow extension and hand grasp, pinch, and/or release. MAIN OUTCOMES AND MEASURES: The primary outcome was motor strength measured by Medical Research Council (MRC) grades 0 to 5. Secondary outcomes included Sollerman Hand Function Test (SHFT); Michigan Hand Outcome Questionnaire (MHQ); Disabilities of Arm, Shoulder, and Hand (DASH); and 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores. Outcomes were assessed up to 48 months postoperatively. RESULTS: Twenty-two patients with tetraplegia (median age, 36 years [range, 18-76 years]; 21 male [95%]) underwent 60 nerve transfers on 35 upper limbs at a median time of 21 months (range, 6-142 months) after SCI. At final follow-up, upper limb motor strength improved significantly: median MRC grades were 3 (IQR, 2.5-4; P = .01) for triceps, with 70% of upper limbs gaining an MRC grade of 3 or higher for elbow extension; 4 (IQR, 2-4; P \u3c .001) for finger extensors, with 79% of hands gaining an MRC grade of 3 or higher for finger extension; and 2 (IQR, 1-3; P \u3c .001) for finger flexors, with 52% of hands gaining an MRC grade of 3 or higher for finger flexion. The secondary outcomes of SHFT, MHQ, DASH, and SF36-PCS scores improved beyond the established minimal clinically important difference. Both early (\u3c12 months) and delayed (≥12 months) nerve transfers after SCI achieved comparable motor outcomes. Continual improvement in motor strength was observed in the finger flexors and extensors across the entire duration of follow-up. CONCLUSIONS AND RELEVANCE: In this prospective case series, nerve transfer surgery was associated with improvement of upper limb motor strength and functional independence in patients with tetraplegia. Nerve transfer is a promising intervention feasible in both subacute and chronic SCI

Personalized practice dosages may improve motor learning in older adults compared to “standard of care” practice dosages: A randomized controlled trial

Standard dosages of motor practice in clinical physical rehabilitation are insufficient to optimize motor learning, particularly for older patients who often learn at a slower rate than younger patients. Personalized practice dosing (i.e., practicing a task to or beyond one's plateau in performance) may provide a clinically feasible method for determining a dose of practice that is both standardized and individualized, and may improve motor learning. The purpose of this study was to investigate whether personalized practice dosages [practice to plateau (PtP) and overpractice (OVP)] improve retention and transfer of a motor task, compared to low dose [LD] practice that mimics standard clinical dosages. In this pilot randomized controlled trial (NCT02898701, ClinicalTrials.gov), community-dwelling older adults (n = 41, 25 female, mean age 68.9 years) with a range of balance ability performed a standing serial reaction time task in which they stepped to specific targets. Presented stimuli included random sequences and a blinded repeating sequence. Participants were randomly assigned to one of three groups: LD (n = 15, 6 practice trials equaling 144 steps), PtP (n = 14, practice until reaching an estimated personal plateau in performance), or OVP (n = 12, practice 100% more trials after reaching an estimated plateau in performance). Measures of task-specific learning (i.e., faster speed on retention tests) and transfer of learning were performed after 2–4 days of no practice. Learning of the random sequence was greater for the OVP group compared to the LD group (p = 0.020). The OVP (p = 0.004) and PtP (p = 0.010) groups learned the repeated sequence more than the LD group, although the number of practice trials across groups more strongly predicted learning (p = 0.020) than did group assignment (OVP vs. PtP, p = 0.270). No group effect was observed for transfer, although significant transfer was observed in this study as a whole (p < 0.001). Overall, high and personalized dosages of postural training were well-tolerated by older adults, suggesting that this approach is clinically feasible. Practicing well-beyond standard dosages also improved motor learning. Further research should determine the clinical benefit of this personalized approach, and if one of the personalized approaches (PtP vs. OVP) is more beneficial than the other for older patients

Amplification and demultiplexing in insulin-regulated Akt protein kinase pathway in adipocytes.

Akt plays a major role in insulin regulation of metabolism in muscle, fat, and liver. Here, we show that in 3T3-L1 adipocytes, Akt operates optimally over a limited dynamic range. This indicates that Akt is a highly sensitive amplification step in the pathway. With robust insulin stimulation, substantial changes in Akt phosphorylation using either pharmacologic or genetic manipulations had relatively little effect on Akt activity. By integrating these data we observed that half-maximal Akt activity was achieved at a threshold level of Akt phosphorylation corresponding to 5-22% of its full dynamic range. This behavior was also associated with lack of concordance or demultiplexing in the behavior of downstream components. Most notably, FoxO1 phosphorylation was more sensitive to insulin and did not exhibit a change in its rate of phosphorylation between 1 and 100 nm insulin compared with other substrates (AS160, TSC2, GSK3). Similar differences were observed between various insulin-regulated pathways such as GLUT4 translocation and protein synthesis. These data indicate that Akt itself is a major amplification switch in the insulin signaling pathway and that features of the pathway enable the insulin signal to be split or demultiplexed into discrete outputs. This has important implications for the role of this pathway in disease

Defining the Functional Domain of Programmed Cell Death 10 through Its Interactions with Phosphatidylinositol-3,4,5-Trisphosphate

Cerebral cavernous malformations (CCM) are vascular abnormalities of the central nervous system predisposing blood vessels to leakage, leading to hemorrhagic stroke. Three genes, Krit1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) are involved in CCM development. PDCD10 binds specifically to PtdIns(3,4,5)P3 and OSM. Using threading analysis and multi-template modeling, we constructed a three-dimensional model of PDCD10. PDCD10 appears to be a six-helical-bundle protein formed by two heptad-repeat-hairpin structures (α1–3 and α4–6) sharing the closest 3D homology with the bacterial phosphate transporter, PhoU. We identified a stretch of five lysines forming an amphipathic helix, a potential PtdIns(3,4,5)P3 binding site, in the α5 helix. We generated a recombinant wild-type (WT) and three PDCD10 mutants that have two (Δ2KA), three (Δ3KA), and five (Δ5KA) K to A mutations. Δ2KA and Δ3KA mutants hypothetically lack binding residues to PtdIns(3,4,5)P3 at the beginning and the end of predicted helix, while Δ5KA completely lacks all predicted binding residues. The WT, Δ2KA, and Δ3KA mutants maintain their binding to PtdIns(3,4,5)P3. Only the Δ5KA abolishes binding to PtdIns(3,4,5)P3. Both Δ5KA and WT show similar secondary and tertiary structures; however, Δ5KA does not bind to OSM. When WT and Δ5KA are co-expressed with membrane-bound constitutively-active PI3 kinase (p110-CAAX), the majority of the WT is co-localized with p110-CAAX at the plasma membrane where PtdIns(3,4,5)P3 is presumably abundant. In contrast, the Δ5KA remains in the cytoplasm and is not present in the plasma membrane. Combining computational modeling and biological data, we propose that the CCM protein complex functions in the PI3K signaling pathway through the interaction between PDCD10 and PtdIns(3,4,5)P3