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In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has more...

Objectives: To investigate changes in external moments in medial meniscus posterior root tear (MMPRT) patients, and the effect of medial meniscus posterior root repair (MMPRR) in restoring normal kinetics. Methods: We present preliminary findings from six subjects with MMPRT, four with MMPRR, and three healthy age-matched control participants (CON). Participants walked on level ground at a self-selected gait speed. Data were collected using high-speed cameras and ground-embedded force plates. Peak knee moments for flexion-extension (KFM and KEM), abduction-adduction (KAbM, KAdM), and internal-external rotation (KERM, KIRM) were calculated using inverse dynamics during the stance phase of gait, and normalized to body mass and height. Group comparisons were conducted using the Kruskal-Wallis and Dunn test with Bonferroni correction. Results were considered statistically significant if p-values were less than 0.05. Results: Both MMPRT and MMPRR groups exhibited significantly lower KFM relative to the CON group, suggesting a strategy to reduce quadriceps activation in both patient groups, which may persist after surgery. MMPRT patients showed significantly diminished KEM relative to both MMR and CON groups, indicating a strategy to reduce external knee forces following injury. MMPRR patients presented KEM that resembled the healthy control group, showing that repair surgery could potentially restore this gait variable. KAbM was statistically higher in the MMPRR and CON groups relative to MMPRT patients, which presented lower KAM than the other groups, suggesting a protective strategy to offload the medial compartment. KERM were significantly higher in the CON group compared to the MMT group, suggesting a protective strategy to avoid excessive external rotation by the MMT group. No significant differences were observed in KIRM across the three groups. Conclusion: MMPRT leads to alterations in gait kinetics, compatible with a protective strategy to unload the knee and compensate for increased medial compartment contact pressures, which are partially restored following root repair. [ABSTRACT FROM AUTHOR] more...

Objectives: To systematically review the effects of meniscal tears on in vivo knee biomechanics, with a focus on kinematic and kinetic outcome measures. Methods: Databases were queried for level I-IV studies that met the following criteria: in vivo studies of gait or motion analysis, cohorts with isolated meniscal pathology, and kinematics and/or kinetics outcome measures. Demographic data, methods of motion analysis, tasks performed, and kinematics and kinetics outcomes were extracted. Standardized mean differences with a random-effects model were calculated to compare cohorts with meniscal tears and healthy controls when outcomes were homogeneous. Results: Thirteen studies were eligible, with a pooled sample of 176 medial meniscal and 74 lateral meniscal tears. Eleven studies assessed gait biomechanics. There was considerable variability in reported outcomes and motion capture methods. Meta-analysis revealed statistically significant decreases in peak knee flexion angle, range of adduction-abduction, and internal-external rotation (p < 0.05) for the pooled sample of lateral meniscus tears. In terms of kinetics, although qualitative evidence in individual studies suggested alterations (e.g., decreased total support moment of the injured limb), quantitative analysis failed to demonstrate significant differences in peak knee flexion moment and peak knee adduction moment (p ≥ 0.05). Conclusion: Lateral meniscus tears significantly impact in vivo knee kinematics across all three planes of motion. No significant differences were observed in the kinetics of medial meniscus tears, and the evidence for their impact on kinematics remains conflicting. Our findings suggest that analyzing more demanding functional tasks may be necessary to detect the biomechanical changes caused by meniscal tears. [ABSTRACT FROM AUTHOR] more...

Anterior Shoulder Instability (ASI) is a common orthopedic condition often resulting in altered shoulder kinematics. Understanding the biomechanics of the unstable shoulder is critical to determine the most appropriate treatment. This study aims to conduct the first systematic review and meta-analysis of three-dimensional (3D) shoulder kinematic studies in ASI patients. A broad search was conducted within PubMed, Scopus, and Cochrane Library following the PRISMA guidelines. All cross-sectional or longitudinal studies with 3D motion analysis describing shoulder kinematics in patients with ASI were included. The quality of each study was assessed using the MINORS criteria. Qualitative and quantitative analyses were performed. Nine studies were included in the qualitative analysis and two in the meta-analysis. The qualitative review detected conflicting evidence for some parameters. The humeral head had a greater anterior translation in unstable shoulders in three of the studies analyzed, while the difference was not significant in one and another found higher variability for global humeral translation for instability patients. Two studies showed decreased rotation range of motion for unstable shoulders while one did not find significant differences. Conflicting results were also found regarding changes in scapulohumeral rhythm and scapular orientation. The meta-analysis indicated a greater scapulohumeral rhythm on the coronal plane for the instability group, suggesting a relatively greater contribution of motion at the glenohumeral joint compared with the scapulothoracic joint for arm abduction, and reduced glenohumeral peak angles for unstable shoulders. Identifying and quantifying kinematic changes associated with ASI are vital for refining treatment interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.) more...

Objective: To determine if chorioamnionitis is associated with an increased risk of adverse 2-year outcomes among infants with hypoxic-ischemic encephalopathy (HIE)., Study Design: This cohort study included all infants with moderate to severe HIE treated with therapeutic hypothermia and enrolled on the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. Clinical chorioamnionitis (CC) was defined as a diagnosis made by a treating obstetrician and histologic chorioamnionitis (HC) was defined as placental inflammation observed on histology. We used proportional odds regression to determine the associations between CC, HC, and an ordinal 2-year neurodevelopmental outcome measure: no neurodevelopmental impairment (NDI), mild NDI, moderate NDI, severe NDI, or death., Results: Of 500 infants, 65 (13%) were exposed to CC. Of 317 infants with placental data available, 125 (39%) were exposed to HC. Infants exposed to CC (odds ratio 0.57, 95% CI 0.34-0.95) and those exposed to HC (odds ratio 0.62, 95% CI 0.40-0.96) had a lower severity of primary outcome than unexposed infants. Infants exposed to chorioamnionitis also had lower frequencies of sentinel events (CC: P = .001; HC: P = .005), central pattern magnetic resonance imaging brain injury (CC: P = .02; HC: P = .02), and electroencephalogram background abnormalities (CC: P = .046; HC: P = .02), compared with unexposed infants., Conclusions: Infants with HIE who were exposed to chorioamnionitis had lower severity of 2-year outcomes than unexposed infants. Our findings suggest that chorioamnionitis may lead to a lower severity of brain dysfunction than other pathophysiologic mechanisms of encephalopathy., Competing Interests: Declaration of Competing Interest The study was funded by the National Institute of Neurologic Disease and Stroke (NINDS) 1U01NS092764 and the National Institute of Child Health and Human Development (NICHD) K23HD109684., (Published by Elsevier Inc.) more...

Objective: To assess the relationship between the Sarnat exam, early electroencephalogram (EEG) background, and death or neurodevelopmental impairment (NDI) at age 2 years among neonates with moderate to severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia., Study Design: Neonates enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial with EEG (n = 463) or amplitude-integrated electroencephalogram (n = 15) reports available on the first day after birth were included in this cohort study. A Sarnat exam was performed between 1 and 6 hours after birth, and neonates were classified into 3 groups of increasing severity based on the number of severe features (none, 1-2, or 3+). EEG background continuity was extracted from reports and categorized as normal, excessively discontinuous, or severely abnormal. The primary outcome was severe NDI or death at age 2., Results: Among 478 neonates with hypoxic-ischemic encephalopathy, EEG background continuity was normal in 186 (39%), excessively discontinuous in 171 (36%), and severely abnormal in 121 (25%). For each additional severe feature on the Sarnat exam, the risk of abnormal EEG background increased by 16% (relative risk 1.16 [95% CI 1.09-1.23]). Both the Sarnat exam and EEG background severity were associated with an increased risk of severe NDI or death. After adjusting for Sarnat exam severity, severe EEG background remained associated with severe NDI and death (relative risk 5.7 [95% CI 3.7-8.9])., Conclusions: The early EEG background provides additional information beyond the Sarnat exam and could be an additional early marker when assessing the severity of HIE., Competing Interests: Declaration of Competing Interest The study was funded by the National Institute of Neurologic Disease and Stroke (NINDS), 1U01NS092764, U01NS092553, R01NS104322, and the National Institute of Child Health and Human Development (NICHD), K23HD109684., (Published by Elsevier Inc.) more...

Knee osteoarthritis (OA) is a chronic disease characterized by increasing prevalence and significant physical, psychological, and economic burdens. Despite extensive research, the definition, risk factors, and effective cost-efficient treatments for knee OA remain unclear. This article aims to revisit primary knee OA, understanding its etiology, and focusing on prevention and individualized nonoperative treatment modalities. This study reviews various aspects of knee OA, including its global prevalence, economic impact, and current treatment strategies. It explores the role of mechanical loading pathways in the disease's onset, highlighting the importance of considering not only the knee but the entire kinetic chain in diagnosis and treatment. Also, it discusses knee anatomy and biomechanics during functional activities, emphasizing the role of neuromuscular control and the influence of proximal and distal joints on knee health. Current treatments focus mainly on symptom management, with limited success in disease prevention and curative interventions. This review underlines the importance of understanding the biomechanical risk factors contributing to knee OA and the necessity of individualized interventions based on biokinetic profile analysis. Knee OA management and prevention necessitate a paradigm shift from viewing it as a localized knee disease to recognizing related mechanical overloads of the human complex motion system. Identifying individual inductive elements is paramount for effective knee OA prevention, management, and rehabilitation. Future research should endeavor to identify movement profile subgroups to establish an early-stage prognosis and the impact of interventions for each group. LEVEL OF EVIDENCE V: Expert opinion based on nonsystematic review., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Importance: Outcomes after hypoxic-ischemic encephalopathy (HIE) are variable. Predicting death or severe neurodevelopmental impairment (NDI) in affected neonates is crucial for guiding management and parent communication., Objective: To predict death or severe NDI in neonates who receive hypothermia for HIE., Design, Setting, and Participants: This prognostic study included participants enrolled in a large US clinical trial conducted in US neonatal intensive care units who were born between January 2017 and October 2019 and followed up to age 2 years. Eligible participants were neonates with moderate-severe HIE born at 36 weeks or more gestation and with 2-year outcome data. Data were analyzed June 2023. External validation was performed with a UK cohort., Exposure: Clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables were curated and examined at 24 hours and following cooling., Main Outcome and Measures: Death or severe NDI at age 2 years. Severe NDI was defined as Bayley Scales of Infant Toddler Development cognitive score below 70, Gross Motor Function Classification System score of 3 or higher, or quadriparesis. Model performance metrics were derived from training, internal, and external validation datasets., Results: Among 424 neonates (mean [SD] gestational age, 39.1 [1.4] weeks; 192 female [45.3%]; 28 Asian [6.6%], 50 Black [11.8%], 311 White [73.3%]), 105 (24.7%) had severe encephalopathy at enrollment. Overall, 59 (13.9%) died and 46 (10.8%) had severe NDI. In the 24-hour model, the combined presence of 3 clinical characteristics-(1) severely abnormal EEG, (2) pH level of 7.11 or below, and (3) 5-minute Apgar score of 0-had a specificity of 99.6% (95% CI, 97.5%-100%) and a positive predictive value (PPV) of 95.2% (95% CI, 73.2%-99.3%). Validation model metrics were 97.9% (95% CI, 92.7%-99.8%) for internal specificity, with a PPV of 77.8% (95% CI, 43.4%-94.1%), and 97.6% (95% CI, 95.1%-99.0%) for external specificity, with a PPV of 46.2% (95% CI, 23.3%-70.8%). In the postcooling model, specificity for T1, T2, or diffusion-weighted imaging (DWI) abnormality in at least 2 of 3 deep gray regions (ie, thalamus, caudate, putamen and/or globus pallidus) plus a severely abnormal EEG within the first 24 hours was 99.1% (95% CI, 96.8%-99.9%), with a PPV of 91.7% (95% CI, 72.8%-97.8%). Internal specificity in this model was 98.9% (95% CI, 94.1%-100%), with a PPV of 92.9% (95% CI, 64.2%-99.0%); external specificity was 98.6% (95% CI, 96.5%-99.6%), with a PPV of 83.3% (95% CI, 64.1%-93.4%)., Conclusions and Relevance: In this prognostic study of neonates with moderate or severe HIE who were treated with therapeutic hypothermia, simple models using readily available clinical, EEG, and MRI results during the hospital admission had high specificity and PPV for death or severe NDI at age 2 years. more...

Therapeutic hypothermia is an effective therapy for moderate-to-severe hypoxic-ischemic encephalopathy (HIE) in infants born at term or near-term in high-resource settings. Yet there remains a substantial proportion of infants who do not benefit or who will have significant disability despite therapeutic hypothermia. Novel investigational therapies that may confer additional neuroprotection by targeting known pathogenic mechanisms of hypoxic-ischemic brain injury are under development. This review focuses on putative neuroprotective agents that have shown promise in animal models of HIE, and that have been translated to clinical studies in neonates with HIE. We include agents that have been studied both with and without concurrent therapeutic hypothermia. Our review therefore addresses not just neonatal HIE in high-resource countries where therapeutic hypothermia is the standard of care, but also neonatal HIE in low- and middle-income countries where therapeutic hypothermia has been shown to be ineffective, and where the greatest burden of HIE-related morbidity and mortality exists., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.) more...

Background: Both perinatal arterial ischemic stroke (PAIS) and hypoxic-ischemic encephalopathy (HIE) can present with neonatal encephalopathy. We hypothesized that among infants undergoing therapeutic hypothermia, presence of PAIS is associated with a higher risk of seizures and a lower risk of persistent encephalopathy after rewarming., Methods: We studied 473 infants with moderate or severe HIE enrolled in the HEAL Trial who received a brain MRI. We defined PAIS as focal ischemic infarct(s) within an arterial distribution, and HIE pattern of brain injury as central gray, peripheral watershed, or global injury. We compared the risk of seizures (clinically suspected or electrographic), and of an abnormal 5-day Sarnat exam, in infants with and without PAIS., Results: PAIS was diagnosed in 21(4%) infants, most of whom (16/21, 76%) also had concurrent HIE pattern of brain injury. Infants with PAIS were more likely to have seizures (RR 2.4, CI 2.8-3.3) and persistent moderate or severe encephalopathy on 5-day Sarnat exam (RR 2.5, 95% CI 1.9-3.4)., Conclusion: Among infants undergoing therapeutic hypothermia, PAIS typically occurs with concurrent HIE pattern brain injury. The higher rate of encephalopathy after rewarming in infants with PAIS may be due to the frequent co-existence of PAIS and HIE patterns of injury., (© 2024. The Author(s).) more...

Background: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE., Methods: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years., Results: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies., Conclusions: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.) more...

Objective: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE)., Design: Secondary analysis of the H igh-dose E rythropoietin for A sphyxia and Encepha L opathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves., Setting: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA., Patients: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE)., Interventions: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training., Main Outcome Measures: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months., Results: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe., Conclusion: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE., Competing Interests: Competing interests: YW, SJ, BC, PH receive support to their institution from the NIH/NINDS for the presented study. FG, HG, KVM, BC, PH receive grants paid to the institution from the NIH and NIH/NINDS, KVM receives grant support from PCORI, and NN receives support from Biogen and UCB Pharma paid to the institution. SEJ receives royalties for editing Avery’s Disease of the Newborn. UM, HG and KVM receive payments for expert testimony. FFG receives grant support for travel/meeting attendance from the NIH. HG and SEJ disclose participation on data safety monitoring board or advisory boards for NIH IACQUIRE (HG) and ALBINO (SEJ). FFG discloses membership of the Societies for Pediatric Research executive council, HG discloses a leadership/fiduciary role within the Pediatric Academic Societies, and NN discloses an unpaid position as board member of Wonderland Child and Family Services. HG discloses stocks/stock options with ELEMENO Health. SEK, TRW, DEM, SLB have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Objective: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE)., Study Design: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2., Results: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3])., Conclusions: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age., Trial Registration: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta., Clinicaltrials: gov/study/NCT02811263., Competing Interests: Declaration of Competing Interest This study was supported by grant 1U01NS092764 and U01NS092553 from the National Institute of Health/National Institute of Neurological Disorders and Stroke (Juul/Wu). The funding institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Background: Latissimus dorsi transfer is a surgical procedure that can be used for treating posterosuperior rotator cuff tears. The procedure leads to improved shoulder function via alterations in the force vector couple around the shoulder. However, there is still no consensus on the biomechanical changes resulting from latissimus dorsi transfer., Methods: We performed a systematic review of the literature on 3D motion analysis studies evaluating the effects of latissimus dorsi transfer on shoulder kinematics. The available data on segment and joint range of motion was extracted and subject to meta-analysis when consistent across the studies., Findings: Our meta-analysis of pre- and post-operative studies revealed a significant improvement in forward flexion and abduction following latissimus dorsi transfer. When comparing the latissimus transferred shoulder with an uninjured contralateral side the meta-analysis found no significant difference in flexion range of motion, while abduction and external rotation was significantly higher in the uninjured shoulders. The overall risk of bias was moderate to high. High heterogeneity was found in the reporting of data, which limited our ability to perform a meta-analysis across the studies for all interest outcomes., Interpretations: Our findings suggest that latissimus dorsi transfer for posterosuperior rotator cuff tears effectively improves shoulder flexion and abduction. External rotation is also expected to improve but at inferior levels as compared to the unaffected side. However, the heterogeneity of the reported data on 3D motion analysis studies highlights the need for better standardization in research and reporting as to conclude the impact of different joints., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

Background: Clavicle fractures are among the most common upper limb fractures in adults, with the midshaft region being the most frequently affected site. Minimally invasive plate osteosynthesis (MIPO) has emerged as an alternative to the traditional open reduction and internal fixation (ORIF) technique, offering potential advantages. The purpose of this study was to conduct a systematic review to explore the results of this technique in the existing literature, with emphasis on the occurrence of surgical complications and functional outcomes and also to provide a comprehensive comparison of MIPO and ORIF in the management of midshaft clavicle fractures., Methods: We conducted a systematic review to evaluate the complication incidence and clinical outcomes of MIPO for midshaft clavicle fractures. We searched PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, the Cochrane Database of Controlled Trials, and the Cochrane Database of Systematic Reviews databases without language or date restrictions. Studies focusing on midshaft clavicle fractures treated with MIPO were included, while other clavicle fractures and nonclinical studies were excluded. The risk of bias was assessed using the Methodological Index for Nonrandomized Studies criteria and the Risk of Bias Tool 2 Cochrane tool. Data synthesis included qualitative analysis, and if applicable, quantitative analysis and meta-analysis. Adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines ensured reporting quality., Results: A total of 107 studies were initially identified, after applying inclusion and exclusion criteria, 22 studies were included for data extraction. These studies involved the evaluation of 714 clavicles treated with the MIPO technique. Of the 714 MIPO cases, 11 cases of implant failure, 5 nonunions, 2 infections, and 28 cases with neurological impairment were observed. Quantitative analysis comparing MIPO with ORIF revealed that MIPO had significantly shorter surgery time (mean difference -12.95, 95% confidence interval [-25.27 to -0.63], P  = .04) and lower occurrence of numbness (odds ratio 0.29, 95% CI [0.15-0.56], P  = .0002) compared to ORIF. Time to bone union, functional outcomes, and other complications were similar between MIPO and ORIF at the final follow-up. An overall moderate risk of bias was found across the studies., Conclusion: The MIPO technique yields good and comparable results to ORIF for midshaft clavicle fractures. Additionally, the MIPO technique may offer advantages such as reduced surgical time and lower chances of neurological impairment., (© 2023 The Author(s).) more...

Background and Objectives: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia., Methods: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site., Results: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12)., Discussion: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care., (© 2023 American Academy of Neurology.) more...

Objectives: In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia., Methods: This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR)., Results: Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI., Conclusions: Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months., (Copyright © 2023 by the American Academy of Pediatrics.) more...

Background: Previous authors have utilized gait kinematics to categorize knee osteoarthritis patients into four distinct profiles: (1) flexed knee; (2) externally rotated knee; (3) stiff knee; and (4) knee varus thrust and rotational rigidity. However, the relationship between these gait profiles and patients' characteristics remains poorly understood. Thus, this study aimed to investigate whether differences in clinical and radiographic characteristics were associated with these four gait profiles., Methods: This cross-sectional study used available data from a previous biomechanical study. Data on the four gait profiles were collected from 42 patients with advanced knee osteoarthritis. Three-dimensional kinematics of the knee was recorded during gait using an optoelectronic system. Subjects were evaluated for knee strength, range of motion, tibial slope, femorotibial angle, radiographic severity, anthropometric measurements, and patient-reported outcomes. Multiple comparisons were made using Dunn's test. The level of significance was set at 5%, and the effect size was calculated., Findings: Body mass index (BMI) was the only variable associated with a specific gait profile: profile 4 (P = 0.01; effect size = P1 × P4: -0.62; P2 × P4: -0.41; P3 × P4: -0.40)., Interpretation: Our findings suggest that most clinical and radiographic characteristics commonly measured in clinical practice did not differ significantly among knee osteoarthritis patients with the four different gait profiles. The only exception was a higher BMI noted in those with gait profile 4; however, it remains unclear whether it can cause varus thrust or rotation rigidity. The incorporation of three-dimensional motion analysis to identify gait profiles provided clinical insights beyond the limitations of traditional clinical assessments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...

Background: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear., Methods: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years., Results: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury., Conclusion: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes., Impact: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes., (© 2023. The Author(s).) more...

Two-dimensional video analysis systems (2DVAS) are commonly used by clinicians and researchers to determine angles during running. The aim of this systematic review (PROSPERO: CRD42022322798) was to synthesize the literature on the criterion validity and reliability of 2DVAS for measuring angles during running compared to three-dimensional motion analysis systems (3DMAS). We searched for articles on MEDLINE/Pubmed, EMBASE, SciELO, and LILACS up to October/2022. We included studies that evaluated the validity of 2DVAS (when compared to 3DMAS) and/or the reliability of 2DVAS measurements of lower limb and trunk angles during running. Qualitative and quantitative analyses were performed. Seven hundred and five studies were found and 17 were included. Ten studies analysed criterion validity between 2DVAS and 3DMAS and the results ranged from poor to excellent, with most of the parameters assessed presenting poor or moderate validity. Inter-rater reliability of 2DVAS was assessed in nine studies and most of the parameters investigated had good to excellent reliability. Intra-rater reliability (between-day processing) of angular running parameters - investigated in ten studies - was considered excellent for most of the parameters analysed. Inter-session reliability was assessed in three studies and was defined as good or excellent for most of the variables assessed. 2DVAS is a reliable method for measuring joint angles during running. However, the validity of 2DVAS compared to 3DMAS ranges from low to moderate for most running parameters. Therefore, based on the available evidence, caution should be taken when applying 2DVAS, particularly for frontal and transverse plane angles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

Background: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo., Methods: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models., Results: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo)., Conclusion: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia., Impact: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.) more...

Objective: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs)., Study Design: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined., Results: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72)., Conclusions: A small increased risk of major thrombotic events was identified in the Epo treatment group., Trial Registration: NCT02811263., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Objective: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes., Study Design: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site., Result: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56)., Conclusion: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study., (© 2023 S. Karger AG, Basel.) more...

Background: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown., Methods: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition., Results: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57)., Conclusions: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)., (Copyright © 2022 Massachusetts Medical Society.) more...

Background: The movement of the arm relative to the trunk results from 3-dimensional (3D) coordinated movements of the glenohumeral (GH) and scapulothoracic (ST) joints and dictates the scapulohumeral rhythm (SHR). Alterations in SHR increase joint overload and may lead to low functional scores, pain, and failures in patients undergoing reverse total shoulder arthroplasty (RSA). The goal of this systematic review and meta-analysis was to examine 3D SHR kinematics after RSA and compare it to that of asymptomatic shoulders., Methods: A systematic review and meta-analysis of articles in English were performed using PubMed, Embase, Cochrane Library, and SciELO. Additional studies were identified by searching bibliographies. Search terms included "Reverse shoulder arthroplasty", "3D", and "scapula". It was selected cross-sectional studies that reported SHR with 3D motion analysis systems in patients who underwent RSA and asymptomatic controls. Two authors independently performed the extraction of articles using predefined data fields, including study quality indicators., Results: Data from four studies were included in quantitative analysis, totaling 48 shoulders with RSA and 63 asymptomatic shoulders. Pooled analyses were based on random-effects model (DerSimonian-Laird). A statistically smaller SHR ratio was observed in the RSA group than that in the control group ( P < .00001), meaning a greater contribution of ST joint in relation to GH joint for arm elevation. The standardized mean difference was -1.16 (95% confidence interval: -1.64, -0.67). A sensitivity analysis with three more studies that had imputed data on control group did not change the direction of the effect. The standardized mean difference on sensitivity analysis was -0.60 ( P  = .03; 95% confidence interval: -1.13, -0.06). It was detected as "not important heterogeneity" within the comparison (I 2 : 22%). Chi-square was not statistically significant (Chi 2 : 3.85), and I 2 was 22%. Tau 2 was not zero (Tau 2 : 0.05). Sensitivity analysis showed an I 2 of 74%, which might represent substantial heterogeneity, Chi-square was not statistically significant (Chi 2 : 23.01), and Tau 2 was not zero (Tau 2 : 0.37)., Conclusion: This study found that RSA shoulders have an increased contribution of ST joint during arm elevation, compared with asymptomatic shoulders. More movement in ST joint in proportion to GH joint increases GH joint contact forces, which could lead to component loosening or other complications. Further studies should address the clinical implications of this kinematic finding., (© 2021 The Author(s).) more...

Objective: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE., Study Design: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system., Results: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities., Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE., Trial Registration: ClinicalTrials.gov: NCT02811263., (Copyright © 2021. Published by Elsevier Inc.) more...

Background and Purpose: Perinatal stroke is a common cause of life-long neurobehavioral compromise. Mesenchymal stromal cells (MSCs) and EPO (erythropoietin) have each demonstrated short-term benefit with delayed administration after stroke, and combination therapy may provide the most benefit. The purpose of this study is to determine the long-term histological and functional efficacy of enhanced, intranasal stem cell therapy (MSC preexposed to EPO) compared with standard MSC or multidose systemic EPO., Methods: Transient middle cerebral artery occlusion or sham surgery was performed in postnatal day (P) 10 Sprague-Dawley rats, who were treated with single-dose intranasal MSC, MSC preexposed to EPO (MSC/EPO), multidose systemic EPO (EPO3; 1000 u/kg per dose×3 every 72 hours), or cell-conditioned media on P13 (day 3 [P13-P19] for EPO), or on P17 (day 7 [P17-P23] for EPO). At 2 months of age, animals underwent novel object recognition, cylinder rearing, and open field testing to assess recognition memory, sensorimotor function, and anxiety in adulthood., Results: MSC, MSC/EPO, and EPO3 improved brain volume when administered at 3 or 7 days after middle cerebral artery occlusion. MSC/EPO also enhanced long-term recognition memory with either day 3 or day 7 treatment, but EPO3 had the most long-term benefit, improving recognition memory and exploratory behavior and reducing anxiety., Conclusions: These data suggest that single-dose MSC/EPO and multidose systemic EPO improve long-term neurobehavioral outcomes even when administration is delayed, although EPO was the most effective treatment overall. It is possible that EPO represents a final common pathway for improved long-term repair, although the specific mechanisms remain to be determined. more...

As the resident macrophages of the brain and spinal cord, microglia are crucial for the phagocytosis of infectious agents, apoptotic cells and synapses. During brain injury or infection, bone-marrow derived macrophages invade neural tissue, making it difficult to distinguish between invading macrophages and resident microglia. In addition to circulation-derived monocytes, other non-microglial central nervous system (CNS) macrophage subtypes include border-associated meningeal, perivascular and choroid plexus macrophages. Using immunofluorescent labeling, flow cytometry and Cre-dependent ribosomal immunoprecipitations, we describe P2ry12-CreER , a new tool for the genetic targeting of microglia. We use this new tool to track microglia during embryonic development and in the context of ischemic injury and neuroinflammation. Because of the specificity and robustness of microglial recombination with P2ry12-CreER , we believe that this new mouse line will be particularly useful for future studies of microglial function in development and disease., Competing Interests: GM, CL, AK, AN, NS, AL, EC, FG, TA No competing interests declared, (© 2020, McKinsey et al.) more...

Background: Newborns with hypoxic-ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment., Methods: Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system., Results: Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality., Conclusion: Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE. more...

Brain injury in the full-term and near-term neonates is a significant cause of mortality and long-term morbidity, resulting in injury patterns distinct from that seen in premature infants and older patients. Therapeutic hypothermia improves long-term outcomes for many of these infants, but there is a continued search for therapies to enhance the plasticity of the newborn brain, resulting in long-term repair. It is likely that a combination strategy utilizing both early and late interventions may have the most benefit, capitalizing on endogenous mechanisms triggered by hypoxia or ischemia. Optimizing care of these critically ill newborns in the acute setting is also vital for improving both short- and long-term outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

Floral induction in Tulipa gesneriana and Lilium longiflorum is triggered by contrasting temperature conditions, high and low temperature, respectively. In Arabidopsis, the floral integrator FLOWERING LOCUS T (FT), a member of the PEBP (phosphatidyl ethanolamine-binding protein) gene family, is a key player in flowering time control. In this study, one PEBP gene was identified and characterized in lily (LlFT) and three PEBP genes were isolated from tulip (TgFT1, TgFT2 and TgFT3). Overexpression of these genes in Arabidopsis thaliana resulted in an early flowering phenotype for LlFT and TgFT2, but a late flowering phenotype for TgFT1 and TgFT3. Overexpression of LlFT in L. longiflorum also resulted in an early flowering phenotype, confirming its proposed role as a flowering time-controlling gene. The tulip PEBP genes TgFT2 and TgFT3 have a similar expression pattern in tulip, but show opposite effects on the timing of flowering in Arabidopsis. Therefore, the difference between these two proteins was further investigated by interchanging amino acids thought to be important for the FT function. This resulted in the conversion of phenotypes in Arabidopsis upon overexpressing the substituted TgFT2 and TgFT3 genes, revealing the importance of these interchanged amino acid residues. Based on all obtained results, we hypothesize that LlFT is involved in creating meristem competence to flowering-related cues in lily, and TgFT2 is considered to act as a florigen involved in the floral induction in tulip. The function of TgFT3 remains unclear, but, based on our observations and phylogenetic analysis, we propose a bulb-specific function for this gene., (© The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

A number of animal models have been used to study hypoxic-ischemic injury, traumatic injury, global hypoxia, or permanent ischemia in both the immature and mature brain. Stroke occurs commonly in the perinatal period in humans, and transient ischemia-reperfusion is the most common form of stroke in neonates. The reperfusion phase is a critical component of injury progression, which occurs over a period of days to weeks, and of the endogenous response to injury. This postnatal day 10 (p10) rat model of transient middle cerebral artery occlusion (tMCAO) creates a unilateral, non-hemorrhagic focal ischemia-reperfusion injury that can be utilized to study the mechanisms of focal injury and repair in the full-term-equivalent brain. The injury pattern that is produced by tMCAO is consistent and highly reproducible and can be confirmed with MRI or histological analyses. The severity of injury can be manipulated through changes in occlusion time and other methods that will be discussed. more...

Objectives: This study aims (i) to compare synovial fluid and serum cartilage oligomeric matrix protein levels in patients with primary knee osteoarthritis and healthy controls, (ii) compare variations of synovial fluid and serum cartilage oligomeric matrix protein levels according to sex, Kellgren-Lawrence grades, and daytime sampling, and (iii) correlate the synovial fluid and serum cartilage oligomeric matrix protein levels with age, severity of disease, and daytime sampling., Patients and Methods: One hundred and twenty-four individuals (44 males, 80 females; median age 66 years; range 42 to 87 years) were diagnosed with primary knee osteoarthritis according to the American College of Rheumatology guidelines. Additionally, 105 healthy healthy individuals (49 males, 56 females; median age 50 years; range 30 to 75 years) were included as the control group. For both groups, a thorough clinical history and physical examination were performed. Moreover, weight-bearing anteroposterior and lateral bending 30 degrees knee X-rays were collected. Cartilage oligomeric matrix protein in serum and synovial fluid was measured by enzyme-linked immunosorbent assay., Results: Total synovial fluid cartilage oligomeric matrix protein levels were considerably higher than total serum levels for both groups. Levels of cartilage oligomeric matrix protein in synovial fluid and serum were higher in patients than in controls for both sexes. However, only cartilage oligomeric matrix protein levels in synovial fluid were higher in female patients. The levels of synovial fluid cartilage oligomeric matrix protein were significantly higher when sampling after 12 pm. A positive correlation was found between synovial fluid and serum cartilage oligomeric matrix protein levels, age, and daytime sampling., Conclusion: These findings may suggest a possible role for synovial fluid and serum cartilage oligomeric matrix protein as a measure for primary knee osteoarthritis. However, more studies need to be performed to address other factors that may influence the levels of cartilage oligomeric matrix protein in synovial fluid and serum., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. more...

Background and Purpose: Stroke is a major cause of neonatal morbidity, often with delayed diagnosis and with no accepted therapeutic options. The purpose of this study is to investigate the efficacy of delayed initiation of multiple dose erythropoietin (EPO) therapy in improving histological and behavioral outcomes after early transient ischemic stroke., Methods: 32 postnatal day 10 (P10) Sprague-Dawley rats underwent sham surgery or transient middle cerebral artery occlusion (tMCAO) for 3h, resulting in injury involving the striatum and parieto-temporal cortex. EPO (1000U/kg per dose×3 doses) or vehicle was administered intraperitoneally starting one week after tMCAO (at P17, P20, and P23). At four weeks after tMCAO, sensorimotor function was assessed in these four groups (6 vehicle-sham, 6 EPO-sham, 10 vehicle-tMCAO and 10 EPO-tMCAO) with forepaw preference in cylinder rearing trials. Brains were then harvested for hemispheric volume and Western blot analysis., Results: EPO-tMCAO animals had significant improvement in forepaw symmetry in cylinder rearing trials compared to vehicle-tMCAO animals, and did not differ from sham animals. There was also significant preservation of hemispheric brain volume in EPO-tMCAO compared to vehicle-tMCAO animals. No differences in ongoing cell death at P17 or P24 were noted by spectrin cleavage in either EPO-tMCAO or vehicle-tMCAO groups., Conclusions: These results suggest that delayed EPO therapy improves both behavioral and histological outcomes at one month following transient neonatal stroke, and may provide a late treatment alternative for early brain injury., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...

Objective: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy., Methods: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system., Results: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05)., Conclusions: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function., (Copyright © 2016 by the American Academy of Pediatrics.) more...

In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a multitude of models for different Central Nervous System (CNS) diseases. These growth factors include erythropoietin (EPO), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor (IGF-1), among others. Despite the promise shown in animal models, the particular growth factors that should be used to maximize both brain protection and repair, and the therapeutic critical period, are not well defined. We will review current pre-clinical and clinical evidence for growth factor therapies in treating different causes of brain injury, as well as issues to be addressed prior to application in humans. more...

Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44-53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE., (© The Authors. Journal compilation © 2015 Mac Keith Press.) more...

Background and Purpose: Stroke is a common cause of neonatal brain injury. The subventricular zone is a lifelong source of newly generated cells in rodents, and erythropoietin (EPO) treatment has shown benefit in different animal models of brain injury. The purpose of this study is to investigate the specific role of exogenous EPO on subventricular zone progenitor cell populations in response to neonatal stroke., Methods: Intraventricular injections of green fluorescent protein (GFP)-expressing lentivirus to label subventricular zone precursor cells were made in postnatal day 1 (P1) Long-Evans rats, which then underwent transient middle cerebral artery occlusion on P7. Middle cerebral artery occlusion and sham rats were treated with either vehicle or EPO (1000 U/kg) at reperfusion, 24 hours, and 7 days later. The density of double-labeled DCx+/GFP+, NeuN+/GFP+, O4+/GFP+, GFAP+/GFP+, as well as single-labeled GFP+ and Ki67+ cells, was calculated to determine cell fate outcome in the striatum at 72 hours and 2 weeks after stroke., Results: There was a significant increase in DCx+/GFP+ and NeuN+/GFP+ neurons and O4+/GFP+ oligodendrocyte precursors, with decreased GFAP+/GFP+ astrocytes at both time points in EPO-middle cerebral artery occlusion animals. There was also a significant increase in GFP+ cells and Ki67+ proliferating cells in EPO compared with vehicle-middle cerebral artery occlusion animals., Conclusions: These data suggest that subventricular zone neural progenitor cells proliferate and migrate to the site of injury after neonatal stroke and multiple doses of EPO, with a shift in cell fate toward neurogenesis and oligodendrogliosis at both early and late time points. The contribution of local cell proliferation and neurogenesis remains to be determined. more...

Background: Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI., Methods: Rats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied., Results: Differences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects., Conclusion: No significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy. more...

Objective: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L)., Methods: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses., Results: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen., Conclusions: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE. more...

Objective: To investigate the effects of neonatal stroke on progenitor cells lining the lateral ventricles., Methods: Intraventricular injection of replication-incompetent green fluorescent protein (GFP)-expressing lentivirus was performed in postnatal day 1 (P1) rats to specifically label radial glia/type B neural stem cells and ependymal cells of the lateral ventricle. A subset of animals was exposed to transient middle cerebral artery occlusion (MCAO) at P7, with mild or moderate injury confirmed by diffusion-weighted MRI and histology. Newborn cells were identified by GFP expression, location and expression of cell type-specific markers in the striatum, cortex and olfactory bulb using confocal microscopy and systematic random sampling., Results: Three weeks lentiviral GFP transduction of cells in the lateral ventricle, abundant GFP-expressing neurons and glia were identified in the rostral migratory stream, olfactory bulb and striatum as expected from labeling the subventricular zone (SVZ) type B neural stem cell lineage. Two weeks following mild or severe focal stroke at P7, no GFP-expressing neurons were detected in striatum or cortex although some single-labeled doublecortin+ immature neurons were detected in the penumbra. The densities of GFP+/ glial fibrillary acidic protein (GFAP)+ astrocytes and GFP+/O4+ oligodendrocytes were reduced in the striatum following MCAO (4.8 +/- 1.02 vs. 2.5 +/- 0.4 cells/high-power field, HPF; p = 0.005; 2.8+/- 1 vs. 0.5 +/- 0.2 cells/HPF, p = 0.008). Furthermore, there was a reduction of GFP+ cells in the olfactory bulb following MCAO (58.8 +/- 14.9 vs. 19.6 +/- 5.4 cells/HPF, p = 0.025). Finally, there was an increased percentage of GFP+/GFAP+ cells (70 vs. 50%), with a decreased proportion of GFP+/O4+ cells (14 vs. 30%) in injured animals., Conclusion: Neurogenesis originating from cells of the lateral ventricle, including SVZ type B cells, is significantly reduced following neonatal stroke. Furthermore, neonatal stroke disrupts gliogenesis in the striatum, decreasing overall numbers of new glia and shifting the population towards astrocytes., (Copyright 2010 S. Karger AG, Basel.) more...

Neonatal brain injury is an important cause of death and disability, with pathways of oxidant stress, inflammation, and excitotoxicity that lead to damage that progresses over a long period of time. Therapies have classically targeted individual pathways during early phases of injury, but more recent therapies such as growth factors may also enhance cell proliferation, differentiation, and migration over time. More recent evidence suggests combined therapy may optimize repair, decreasing cell injury while increasing newly born cells. more...

Neonatal stroke leads to mortality and severe morbidity, but there currently is no effective treatment. Erythropoietin (EPO) promotes cytoprotection and neurogenesis in the short term following brain injury; however, long-term cognitive outcomes and optimal dosing regimens have not been clarified. We performed middle cerebral artery occlusion in postnatal day 10 rats, which were treated with either a single dose of EPO (5 U/g, i.p.) immediately upon reperfusion, or 3 doses of EPO (1 U/g, i.p. each) at 0 h, 24 h, and 7 days after injury. At 3 months after injury, rats treated with 3 doses of EPO did not differ from shams in the Morris water maze, and generally performed better than either rats treated with a single dose or vehicle-treated injured rats. These multiple-dose-treated rats also had increases in hemispheric volume and its subregions. These results suggest that additional, later doses of EPO may be required for cell repair, proliferation, and long-term incorporation into neural networks after neonatal brain injury., ((c) 2009 S. Karger AG, Basel.) more...

Neonatal brain injury is an important cause of death and neurodevelopmental delay. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to both early and late phases of cell damage and death. Therapies targeting these different pathways have shown potential in protecting the brain from ongoing injury. More recent therapies, such as growth factors, have demonstrated an ability to increase cell proliferation and repair over longer periods of time. Even though hypothermia, which decreases cerebral metabolism and possibly affects other mechanisms, may show some benefit in particular cases, no widely effective therapeutic interventions for human neonates exist. In this review, we summarize recent findings in neuroprotection and neurogenesis for the immature brain, including combination therapy to optimize repair. more...

Neonatal stroke leads to mortality and severe morbidity, but there is no effective treatment currently available. Erythropoietin (EPO) has been shown to promote cytoprotection and neurogenesis and decrease subventricular zone morphologic changes following brain injury. The long-term cellular response to EPO has not been defined, and local changes in cell fate decision may play a role in functional improvement. We performed middle cerebral artery occlusion in P10 rats. EPO treatment (5 U/g i.p.) significantly preserved hemispheric brain volume 6 weeks after injury. Furthermore, EPO increased the percentage of newly generated neurons while decreasing newly generated astrocytes following brain injury, without demonstrating long-term differences in the subventricular zone. These results suggest that EPO may neuroprotect and direct cell fate toward neurogenesis and away from gliogenesis in neonatal stroke., (2007 S. Karger AG, Basel) more...

Some studies on neurodevelopmental outcomes after neonatal encephalopathy have suggested that cognitive deficits do not occur in the absence of cerebral palsy. It is increasingly apparent that childhood survivors of overt neonatal encephalopathy may have cognitive impairments, even in the absence of functional motor deficits. The risk of cognitive deficits is related to the severity of neonatal encephalopathy and the pattern of brain injury on neuroimaging, particularly the watershed pattern of injury. A better understanding of the risk factors for cognitive abnormalities after neonatal encephalopathy will ultimately lead to interventions to prevent these deficits. Identifying the full spectrum of neurodevelopmental outcomes after neonatal encephalopathy will also allow care givers to identify children requiring early intervention to maximise their potential for independent function throughout development. more...

The catalytic properties of expressed human cytochromes P4501A1, 1A2, 3A4 and 3A5 with respect to the metabolite distribution for the carcinogen benzo[a]pyrene (BP) and the proximate carcinogen (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene ((-)-BP-7,8-DHD) were determined. P4501A1 formed a higher proportion of the proximate carcinogen from BP than the other isozymes. Both P4501A1 and 1A2 were more selective for oxidation at the benzo ring of BP and showed a greater production of dihydrodiol metabolites than either P4503A4 or 3A5. The formation of diolepoxides from the individual enantiomers of BP-7,8-DHD occurred in a highly stereoselective fashion. more...