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Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions., Competing Interests: MK serves as a consultant to PTC Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lewis, Shetty, Wilson, Huang, Jin, Smithers-Sheedy, Fahey and Kruer.)

Background: Perceived discrimination has been associated with a higher prevalence of e-cigarette use among adult samples. However, little is understood about the relationship between discrimination and various vaping behaviors among college students. Methods : College students completed an online survey about e-cigarette use ( N  = 488; 73.2% women; 52.7% White, 30.5% Black/African American, 6.1% Asian, 5.3% other races, 3.9% Multiracial). Participants completed the Everyday Discrimination Scale and identified which of their identities discrimination was most directed toward. Regressions, controlling for significant covariates of outcomes, examined discrimination in relation to e-cigarette ever use, current use, and frequency of use. Results : A higher discrimination score predicted greater odds of ever vaping compared with never use ( OR  = 1.21, p =.03). Controlling for race ( p =.003), greater discrimination was related to increased likelihood of established vaping (100+ times) versus lighter levels of use ( AOR  = 1.22, p =.04). Discrimination was not associated with likelihood of current vaping ( p >.05). Among e-cigarette users, greater perceived discrimination was related to an increased time spent vaping per day ( β  =1.69, SE  = 0.204, p =.05). Conclusions/Importance: Greater perceived discrimination was associated with more frequent vaping among college students. Current results extend previous findings by suggesting that among college e-cigarette users, those who experience discrimination are more likely to use these products frequently rather than experimentally. Findings can inform the identification and development of resources for students experiencing discrimination to prevent the uptake of e-cigarette use.

Background: Approximately 17% of young adults currently use tobacco, most commonly cigarettes and/or electronic cigarettes (e-cigarettes), followed by other products (i.e., cigarillos, pipe/hookah, smokeless tobacco). Cigarettes have been historically used to control weight. Little is known about use of non-cigarette products for weight control, particularly among non-college young adults. Tobacco use in the military is higher than civilians, and personnel have increased motivation for weight control due to military fitness standards. This population might be vulnerable to use tobacco for this purpose. Purpose: Exploring prevalence, as well as demographic and behavioral correlates, of using tobacco products for weight control, among a large, diverse sample of military young adults. Methods: U.S. Air Force recruits (N = 24,543) completed a questionnaire about tobacco use. Among users of tobacco products, recruits reported if they had ever used that product to maintain their weight. Results: Smokeless tobacco was most commonly used for weight control (12.2%), followed by cigarettes (7.3%), e-cigarettes (5.5%), cigarillos (3.3%), and hookah/pipe (3.2%). Using tobacco for weight control was associated with fewer harm beliefs and more regular use of that product. Among e-cigarette users, having a higher BMI and a lower educational background was associated with ever using this product for weight control. Conclusions: The belief that a tobacco product helps control one's weight might increase the prevalence, and frequency of use, of that product among military young adults. Tobacco cessation programs should assess for this motivation of use and provide education about tobacco harm and alternative strategies for weight maintenance.

Background: The US military has historically higher tobacco use compared to civilians, and tobacco use increases following enlistment. While the military is vulnerable to tobacco use, current surveillance of tobacco among this high-risk population is lacking. Methods: Recently enlisted Airmen ( N  = 43,597) between 2013 and 2018 were asked about tobacco use prior to enlistment across ten products: (1) cigarettes/roll your own tobacco, (2) smokeless tobacco/snus, (3) cigars, cigarillos/little cigars, (4) hookah/pipe, and (5) e-cigarettes. Results: Hookah/pipe use, cigarettes/roll your own, smokeless tobacco/snus, and cigars/little cigars/cigarillos use decreased significantly between 2013 and 2018, while the prevalence of e-cigarette use increased ( p ' s  < 0.0001). The relationships between the time and each tobacco product(s) use outcomes were influenced differently by different age, race, education and marital status. Conclusion: While e-cigarette use has increased in the civilian sector, the use of e-cigarettes among new recruits increased much more drastically (i.e. prevalence 15.3% in 2018). Further, demographic characteristics influenced tobacco trends; specifically, recruits of racial minorities increased their use of e-cigarettes over the past five years faster than Whites. Of concern is what impact this dramatic increase in e-cigarette use will have on overall health and later initiation of combustible tobacco products in the military.

Competing Interests: Competing interests: None declared.

Background: Hypoxic ischemic (HI) insults during pregnancy and birth can result in neurodevelopmental disorders, such as cerebral palsy. We have previously shown that a single dose of umbilical cord blood (UCB) cells is effective at reducing short-term neuroinflammation and improves short and long-term behavioural outcomes in rat pups. A single dose of UCB was not able to modulate long-term neuroinflammation or brain tissue loss. In this study we examined whether multiple doses of UCB can modulate neuroinflammation, decrease cerebral tissue damage and improve behavioural outcomes when followed up long-term., Methods: HI injury was induced in postnatal day 10 (PND10) rat pups using the Rice-Vannucci method of carotid artery ligation. Pups received either 1 dose (PND11), or 3 doses (PND11, 13, 20) of UCB cells. Rats were followed with behavioural testing, to assess both motor and cognitive outcomes. On PND50, brains were collected for analysis., Results: HI brain injury in rat pups caused significant behavioural deficits. These deficits were significantly improved by multiple doses of UCB. HI injury resulted in a significant decrease in brain weight and left hemisphere tissue, which was improved by multiple doses of UCB. HI resulted in increased cerebral apoptosis, loss of neurons and upregulation of activated microglia. Multiple doses of UCB modulated these neuropathologies. A single dose of UCB at PND11 did not improve behavioural or neuropathological outcomes., Conclusions: Treatment with repeated doses of UCB is more effective than a single dose for reducing tissue damage, improving brain pathology and restoring behavioural deficits following perinatal brain injury., 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 © 2020 Elsevier B.V. All rights reserved.)

Aim: To evaluate pain prevalence and characteristics in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) cerebral palsy (CP) motor types., Method: Seventy-five participants with a diagnosis of CP and confirmed dyskinetic or mixed (dyskinetic/spastic) motor type took part in a multisite cross-sectional study. The primary outcome was carer-reported pain prevalence (preceding 2wks) measured using the Health Utilities Index-3. Secondary outcomes were chronicity, intensity, body locations, quality of life, and activity impact., Results: Mean participant age was 10 years 11 months (SD 4y 2mo, range 5-18y). There were 44 males and 31 females and 37 (49%) had predominant dyskinetic CP. Pain was prevalent in 85% and it was chronic in 77% of participants. Fifty-two per cent experienced moderate-to-high carer-reported pain intensity, which was significantly associated with predominant dyskinetic motor types (p=0.008). Pain occurred at multiple body locations (5 out of 21), with significantly increased numbers of locations at higher Gross Motor Function Classification System levels (p=0.02). Face, jaw, and temple pain was significantly associated with predominant dyskinetic motor types (p=0.005). Poorer carer proxy-reported quality of life was detected in those with chronic pain compared to those without (p=0.03); however, chronic pain did not affect quality of life for self-reporting participants., Interpretation: Pain was highly prevalent in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types, highlighting a population in need of lifespan pain management., What This Paper Adds: Chronic pain prevalence in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types is high. Pain occurs across multiple body locations in predominant dyskinetic and mixed (dyskinetic/spastic) motor types. Less recognized locations of pain include the face, jaw, and temple for predominant dyskinetic motor types., (© 2020 Mac Keith Press.)

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Introduction: Military personnel have among the highest rates of tobacco use in the United States. Unfortunately, there are few interventions aimed at reducing tobacco use among this vulnerable population. The current study addresses this need by evaluating the short-term effectiveness of a Brief Tobacco Intervention (BTI), a 40-min group-based intervention designed to reduce contemporary patterns of tobacco use among a sample of US military enlistees during an 11-week period of involuntary tobacco abstinence., Aims and Methods: Participants were 2999 US Air Force Technical Trainees at Joint Base San Antonio-Lackland Air Force Base in San Antonio, Texas from April 2017 through January 2018. Participants were cluster randomized to three conditions: (1) BTI + Airman's Guide to Remaining Tobacco Free (AG), (2) AG intervention, or (3) standard smoking cessation intervention. The primary analysis was a comparison of the interventions' efficacies in preventing tobacco use during Technical Training, conducted using a generalized estimating equations logistic regression model controlling for covariates. Multiple imputation was used to account for loss to follow-up., Results: There was not a significant difference by condition in the use of tobacco products at follow-up (p = .454). The BTI + AG condition did produce short-term changes in perceived harm, intentions to use tobacco, knowledge about tobacco products, and normative beliefs., Conclusions: These findings suggest that while the intervention was effective in the short term, it was not potent enough over a 12-week period to prevent Airmen from initiating tobacco use. Future studies should examine whether adding a booster session or media campaign enhances the effectiveness of the intervention., Implications: Despite the fact that most Airmen believe they will remain tobacco free following the ban in Technical Training, a large percentage of these Airmen resume and initiate tobacco use during this high-risk period. As a result, there is a need for interventions targeting the range of tobacco available to military trainees during a teachable moment when they report intentions to remain tobacco free. The current study shows that a BTI has promise in reducing long-term tobacco use, when coupled with additional interventions, such as a booster session or a media campaign., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The current study aimed to observe potential seasonal fluctuations in weight and self-weighing behavior among a diverse sample of adults engaged in a behavioral weight loss intervention., Methods: Active duty personnel (N = 248) were randomized to either a counselor-initiated or self-paced 12-month behavioral weight loss intervention promoting daily self-weighing. Body weight and self-weighing frequency were collected from electronic scales (e-scales) provided at baseline., Results: Overall, participants lost weight from winter to spring (p = 0.02) and gained weight from fall to winter (p < 0.001). No demographic differences in weight changes were observed. Participants self-weighed less frequently during summer compared to spring (p < 0.0001), less in fall compared to summer (p < 0.0001), and less in winter compared to fall (p < 0.0001). In multivariate models, weight change and self-weighing frequency during the previous season, as well as days since randomization and intervention intensity were associated with seasonal weight changes., Conclusions: This study is the first to observe seasonal fluctuations of weight and self-weighing behavior among adults actively engaged in a weight loss intervention, consistent with research in the general population. Findings highlight the importance of acknowledging seasonal influence within weight loss programs and trials., Level of Evidence: Level I, randomized controlled trial.

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems., Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system., Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption., Exposures: Ultra-rapid exome sequencing., Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge., Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%)., Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

Introduction: Military personnel are at high risk for tobacco use, particularly during the first year of military service. Technical Training follows an 8½ week tobacco ban during basic military training and is a vulnerable time for personnel to both reinitiate and initiate tobacco use. Thus, this can be a crucial time to promote tobacco policies and interventions. However, there is limited research examining when, how, and where personnel access tobacco during the first year of service, particularly among users of newer products (eg, electronic cigarettes[e-cigarettes]). Thus, the purpose of the current study is to explore the timing, source, and location of tobacco use during Technical Training across all types of products. Furthermore, this study will examine differences in demographic characteristics and prior tobacco history in relationship to these tobacco behaviors., Materials and Methods: Participants were U.S. Air Force recruits completing Technical Training (2017-2018). Protocol was approved by the Institutional Review Board at the 59th Medical Wing of the U.S. Air Force. During the first week of Technical Training, Airmen were consented to participate in the study and completed a questionnaire about demographics and tobacco use history. Next, Airmen were randomized to receive one of three tobacco prevention interventions as part of military training. At a 3-month follow-up, during the last week of Technical Training, consented participants completed a questionnaire about current tobacco use. Airmen reported when (ie, first month vs. after), how (ie, "bummed" from another airman, bought on or off base, received from the internet or event), and where (ie, designated smoking areas on base, off base, bar or club, friend's house, cigar lounge, hookah bar, or vape shop) they used tobacco during Technical Training. Descriptive statistics were used to examine these behaviors across all tobacco products. Additionally, Wilcoxon-Mann-Whitney and Kruskal-Wallis tests compared differences in demographic characteristics and baseline tobacco use in relationship to these tobacco behaviors., Results: No significant differences were found when comparing prior users and first-time users in relationship to tobacco behaviors during Technical Training; however, significant differences in educational background and age were found in regard to the source and location of tobacco use. Additionally, how and where Airmen first used tobacco during Technical Training differed across products. Cigarettes and smokeless tobacco were equally likely to be bought on or off base and most commonly first used at a designated smoking area on base. However, e-cigarettes, cigarillos/little cigars, and hookah were more likely to be bought off base, and first used at a specialty store (ie, vape shop, hookah bar, or cigar lounge)., Conclusions: Tobacco use behaviors during Technical Training differed depending on the type of product. Specifically, new and emerging products were more likely to be bought off base and first used at a specialty store. Thus, military polices regulating on base tobacco pricing might not reduce the growing prevalence of e-cigarettes. Future policies might consider addressing the density of off-base tobacco retailers to reduce the high rates of tobacco use in this population., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To explore the lived experience of chronic pain and dyskinesia in children and adolescents with cerebral palsy., Methods: A convergent parallel mixed methods design was undertaken. First, a quantitative cross-sectional study of participants able to self-report their quality of life was undertaken. This study characterised pain chronicity, intensity, body locations, and quality of life. Second, semi-structured interviews were undertaken with a subset of children and adolescents experiencing chronic pain., Results: Twenty-five children and adolescents took part in the cross-sectional study, 23 of whom experienced chronic pain and 13 of moderate intensity. Pain was often located in multiple bodily regions (6/21), with no trends in quality of life outcomes detected. Eight participated in semi-structured interviews, which identified three key themes including 'lives embedded with dyskinesia', 'real world challenges of chronic pain', and 'still learning strategies to manage their pain and dyskinesia'., Conclusions: A high proportion of children and adolescents with cerebral palsy and dyskinesia who were able to self-report experienced chronic pain. The physical and emotional impacts of living with chronic pain and dyskinesia existed along a spectrum, from those with lesser to greater extent of their impacts. Children and adolescents may benefit from targeted chronic pain education and management within bio-psychosocial models.

Background: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs., Methods: Surgery was performed in twin-bearing pregnant ewes at 88 days' gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 10 6 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized., Results: FGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs., Conclusions: Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.

Competing Interests: Competing Interests. The authors declare that they have no conflicts of interest.

PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

Context: Cerebral palsy (CP) is a motor disorder affecting movement, muscle tone and posture due to damage to the foetal or infant brain. The subsequent lack of ambulation, nutritional deficiencies, anticonvulsant use and hormonal deficiencies have been implicated in the low bone mass associated with this condition., Objective: To assess changes in areal bone mineral density (aBMD) during adolescence and young adulthood in individuals with CP. The effect of ambulation, nutrition, hypogonadism on longitudinal changes in aBMD is also examined., Design: Retrospective longitudinal study., Setting and Participants: Forty-five subjects with CP who had longitudinal dual-energy X-ray absorptiometry (DXA) scans at a single tertiary hospital between 2006 and 2018., Results: Mean age at first DXA was 19.4 years (range: 10-36 years), 57.8% were male and 80% were nonambulatory. The mean Z-scores at baseline were <-2.0 at all sites - lumbar spine (LS), femoral neck (FN), total hip (TH) and total body (TB). The median change in aBMD was +1.2%-1.9% per year in all subjects but in those <20 years of age, the median change was 4%-8% per year. Z-scores across all sites remained stable over time. Reduced functional state as measured by the gross motor functional classification scale (GMFCS) had a small negative effect on aBMD over time., Conclusion: In adolescents with CP, low bone mass was evident from the baseline DXA. However, significant bone accrual occurred during the second decade, followed by bone maintenance in young adulthood. Future studies should focus on optimizing bone health from early childhood., (© 2019 John Wiley & Sons Ltd.)

Background: Chorioamnionitis and fetal inflammation are principal causes of neuropathology detected after birth, particularly in very preterm infants. Preclinical studies show that umbilical cord blood (UCB) cells are neuroprotective, but it is uncertain if allogeneic UCB cells are a feasible early intervention for preterm infants. In contrast, mesenchymal stem cells (MSCs) are more readily accessible and show strong anti-inflammatory benefits. We aimed to compare the neuroprotective benefits of UCB versus MSCs in a large animal model of inflammation-induced preterm brain injury. We hypothesized that MSCs would afford greater neuroprotection., Methods: Chronically instrumented fetal sheep at 0.65 gestation received intravenous lipopolysaccharide (150 ng; 055:B5, n = 8) over 3 consecutive days; or saline for controls (n = 8). Cell-treated animals received 10 8 UCB mononuclear cells (n = 7) or 10 7 umbilical cord MSCs (n = 8), intravenously, 6 h after the final lipopolysaccharide dose. Seven days later, cerebrospinal fluid and brain tissue was collected for analysis., Results: Lipopolysaccharide induced neuroinflammation and apoptosis, and reduced the number of mature oligodendrocytes. MSCs reduced astrogliosis, but UCB did not have the same effect. UCB significantly decreased cerebral apoptosis and protected mature myelinating oligodendrocytes, but MSCs did not., Conclusion: UCB appears to better protect white matter development in the preterm brain in response to inflammation-induced brain injury in fetal sheep.

We examined the U.S. holiday period impact on weight gain, self-weighing, and treatment success among adults in a weight loss intervention (N=171). Using electronic scales, body weight and self-weighing frequency were compared by time period [i.e., pre-holiday, holiday (November 15-January 1), post-holiday]. Self-weighing was less frequent during holiday period (p<.01), and longer intervention engagement was associated with weight gain (p<.0001) during this time. Enrollment during holiday period was associated with 2.3% 12-month weight loss. Holiday period enrollment might be beneficial for preventing holiday weight gain and facilitating successful intervention outcomes., (Published by Elsevier Ltd.)

Introduction: Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age., Methods and Analyses: We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety., Ethics and Dissemination: This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants., Trial Registration Number: ACTRN12617001515381; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

Background: Hypoxic ischemic (HI) insult in term babies at labor or birth can cause long-term neurodevelopmental disorders, including cerebral palsy (CP). The current standard treatment for term infants with hypoxic ischemic encephalopathy (HIE) is hypothermia. Because hypothermia is only partially effective, novel therapies are required to improve outcomes further. Human umbilical cord blood cells (UCB) are a rich source of stem and progenitor cells making them a potential treatment for neonatal HI brain injury. Recent clinical trials have shown that UCB therapy is a safe and efficacious treatment for confirmed cerebral palsy. In this study, we assessed whether early administration of UCB to the neonate could improve long-term behavioral outcomes and promote brain repair following neonatal HI brain injury. Methods: HI brain injury was induced in postnatal day (PND) 7 rat pups via permanent ligation of the left carotid artery, followed by a 90 min hypoxic challenge. UCB was administered intraperitoneally on PND 8. Behavioral tests, including negative geotaxis, forelimb preference and open field test, were performed on PND 14, 30, and 50, following brains were collected for assessment of neuropathology. Results: Neonatal HI resulted in decreased brain weight, cerebral tissue loss and apoptosis in the somatosensory cortex, as well as compromised behavioral outcomes. UCB administration following HI improved short and long-term behavioral outcomes but did not reduce long-term histological evidence of brain injury compared to HI alone. In addition, UCB following HI increased microglia activation in the somatosensory cortex compared to HI alone. Conclusion: Administration of a single dose of UCB cells 24 h after HI injury improves behavior, however, a single dose of cells does not modulate pathological evidence of long-term brain injury.

Introduction: Effective recruitment and subsequent enrollment of diverse populations is often a challenge in randomized controlled trials, especially those focused on weight loss. In the civilian literature, individuals identified as racial and ethnic minorities, men, and younger and older adults are poorly represented in weight loss interventions. There are limited weight loss trials within military populations, and to our knowledge, none reported participant characteristics associated with enrollment. There may be unique motives and barriers for active duty personnel for enrollment in weight management trials. Given substantial costs and consequences of overweight and obesity in the U.S. military, identifying predictors and limitations to diverse enrollment can inform future interventions within this population. The study aims to describe the recruitment, screening, and enrollment process of a military weight loss intervention. Demographic and lifestyle characteristics of military personnel lost between screening and randomization are compared to characteristics of personnel randomized in the study and characteristics of the Air Force in general., Materials and Methods: The Fit Blue study, a randomized controlled behavioral weight loss trial for active duty personnel, was approved by the Institutional Review Board of the Wilford Hall Ambulatory Surgical Center in San Antonio, TX, USA and acknowledged by the Institutional Review Board at the University of Tennessee Health Science Center. Logistic regressions compared participant demographics, anthropometric data, and health behaviors between personnel that attended a screening visit but were not randomized and those randomized. Multivariable models were constructed for the likelihood of being randomized using a liberal entry and stay criteria of 0.10 for the p-values in a stepwise variable selection algorithm. Descriptive statistics compared the randomized Fit Blue cohort demographics to those of the U.S. Air Force., Results: In univariate analyses, older age (p < 0.02), having a college degree or higher (p < 0.007) and higher military rank (p < 0.02) were associated with completing the randomization process. The randomized cohort reported a lower percentage of total daily kilocalories for fat compared to the non-randomized cohort (p = 0.033). The non-randomized cohort reported more total minutes and intensity of physical activity (p = 0.073). In the multivariate model, only those with a college degree or higher were 3.2 times more likely to go onto randomization. (OR = 3.2, 95% CI = 2.0, 5.6, p < 0.0001). The Fit Blue study included a higher representation of personnel who identified as African American (19.4% versus 15.0%) and Hispanic/Latino (22.7% versus 14.3%) compared with the U.S. Air Force in general; however, men were underrepresented (49.4% versus 80.0%). TABLE I.Comparisons of Demographic Characteristics of Randomized Fit Blue Cohort to Screened Non-Randomized CohortFit Blue Randomized Participants (N = 248)Non-Randomized Cohort (N = 111)All Screened Participants (N = 359)p-ValueSex N (%)0.73 Male122 (49.2)52 (46.8)174 (48.5) Female126 (50.8)59 (53.2)183 (51.5)Age Mean (±SD) years34 (±7.5)32 (±6.7)33 (±7.3)0.02Race N (%)0.89 African American49 (19.8)22 (19.8)71 (19.8) Caucasian163 (65.7)75 (67.6)238 (66.3) Other36 (14.5)14 (12.2)50 (13.9)Ethnicity N (%)0.59 Hispanic/Latino56 (22.6)28 (25.2)84 (23.4) Non-Hispanic/Latino192 (77.4)83 (74.8)275 (76.6)Education N (%)<0.0001 Less than college degree123 (49.6)82 (73.9)205 (57.1) College degree or greater125 (50.4)29 (26.1)154 (42.9)Marital status N (%)0.83 Single/never married40 (16.1)20 (18)60 (16.7) Married/living as married169 (68.1)72 (64.9)241 (67.1) Separated/divorced39 (15.7)19 (17.1)58 (16.2)Number of additional adults in household N (%)0.82 046 (18.5)22 (19.8)68 (18.9) 1162 (65.3)73 (65.8)235 (65.5) 231 (12.5)14 (12.6)45 (12.5) 3 or more9 (3.6)2 (1.8)11 (3.1)Number of children in household N (%)0.56 091 (36.7)37 (33.3)128 (35.7) 159 (23.8)23 (20.7)82 (22.8) 257 (23)26 (23.4)83 (23.1) 3 or more41 (16.5)25 (22.5)66 (18.4)Years in service mean (± SD)12 (±6.6)11 (±6.1)12 (±6.4)0.20Military gradeaN (%)0.02 E1-E434 (13.7)19 (17.1)53 (14.8) E5-E6105 (42.3)58 (52.3)163 (45.4) E7-E952 (21)21 (18.9)73 (20.3) O1-O317 (6.9)9 (8.1)26 (7.2) O4-O639 (15.7)4 (3.6)43 (12)Branch0.68 Army4 (1.6)1 (0.9)5 (1.4) Air Force234 (94.4)105 (94.6)339 (94.4) Navy8 (3.2)5 (4.5)13 (3.6) Marine Corp2 (0.8)0 (0.0)2 (0.6)BMI (m2/kg) N (%)30.6 (±2.7)30.4 (±2.9)30.6 (±2.8)BMI category N (%)0.76 Overweight115 (46.4)52 (48.1)167 (46.9) Obese133 (53.6)56 (51.9)189 (53.1)aMilitary ranking; Enlisted (E) categories: E1-E4 (enlisted), E5-E6 (non-commissioned officers), E7-E9 (senior non-commissioned officers) and two Officer categories (O): O1-O3 (Company Grade Officer) and O4-O6 (Field Grade Officer); standard deviation (SD).Table II.Comparisons of Anthropometric Characteristics of Randomized Fit Blue Cohort to Screened Non-Randomized CohortFit Blue Randomized Participants (N = 248)Non-Randomized Cohort (N = 111)All Screened Participants (N = 359)p-ValuePhysical activity Total physical activity2525 (±3218)2840 (±2541)2621 (±3028)0.027 (mean (±SD) minutes per week) Total sedentary physical activity5046 (±239)472 (±221)494 (±234)0.35 (mean (±SD) minutes per week) Vigorous physical activity34 (±145)54 (±152)40 (±147)0.036 (mean (±SD) minutes per week)Dietary intake Total sweetened beverages (kcal per day)165 (±206)152.9 (±166)160.8 (±194)0.80 Fruit and vegetable consumption (cups per day)3 (±1)3 (±1)3 (±1)0.52 Dietary fat (% total kcal)35 (±4)34 (±4)35 (±4)0.033., Conclusions: Accounting for all influencing characteristics, higher educational status was the only independent predictor of randomization. Perhaps, highly educated personnel are more invested in a military career, and thus, more concerned with consequences of failing required fitness tests. Thus, it may be important for future weight loss interventions to focus recruitment on less-educated personnel. Results suggest that weight loss interventions within a military population offer a unique opportunity to recruit a higher prevalence of males and individuals who identify as racial or ethnic minorities which are populations commonly underrepresented in weight loss research., (© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Tobacco use in cancer survivors remains a significant problem, however, the use of non-cigarette tobacco products (NCTPs) in this population is less understood. This study examined prevalence and correlates of tobacco use among cancer survivors who were never, current, and former cigarette users. Tobacco-related behaviors and quitting attitudes were compared between survivors dually using cigarettes and electronic cigarettes (ECs) and cigarette-only users., Methods: In this cross-sectional study, patients at Mid-South cancer centers (n = 629; 50.4% never, 17.8% current, and 31.8% former cigarette users) responded to an anonymous questionnaire about tobacco-related behaviors and quitting attitudes., Results: Among current cigarette users, 27.7% reported using two or more tobacco products. Most commonly, 15.2% of cigarettes users were using ECs. Compared to cigarette only use, dual use of tobacco products was associated with male gender (p < 0.0001), being single (p = 0.009), and a lung cancer diagnosis (p < 0.0001). Dual users of cigarettes and ECs were more likely to report a readiness to quit cigarettes within 6 months (p = 0.0317) and that a physician recommended ECs as a quit resource (p = 0.0361) compared to cigarette-only users., Conclusions: Results suggest that using more than one tobacco product is common among cancer survivor cigarette users. Dual use of cigarettes and ECs was associated with an increased readiness for cigarette cessation and a physician recommendation of ECs. Targeting potential dual use of tobacco products, particularly cigarettes and ECs, might be beneficial for cigarette cessation among cancer survivors.

Context: Bone fragility in cerebral palsy (CP) is secondary to a complex interplay of functional, hormonal, and nutritional factors that affect bone remodelling. A greater understanding of bone microarchitectural changes seen in CP should assist therapeutic decision making., Objective: To examine the relationship between trabecular bone score (TBS), BMD and fractures in adults with CP; the influence of clinical factors and body composition on bone microarchitecture were explored., Design: Retrospective cross-sectional study., Setting and Participants: 43 adults (25 male) with CP of median age 25 years (interquartile range 21.4-33.9) who had evaluable dual-energy X-ray absorptiometry imaging of the lumbar spine from a single tertiary hospital between 2005-March 2018., Results: 24/43 (55.8%) of patients had TBS values indicating intermediate or high risk of fracture (<1.31). TBS correlated with areal BMD at the lumbar spine, femoral neck and total body. TBS was significantly associated with arm and leg lean mass, with adjustment for age, gender and height (adjusted R 2  = 0.18, p = 0.042 for arm lean mass; adjusted R 2  = 0.19, p = 0.036 for leg lean mass). There was no difference in TBS when patients were grouped by fracture status, anticonvulsant use, gonadal status or use of PEG feeding. TBS was lower in non-ambulatory patients compared with ambulatory patients (1.28 vs 1.37, p = 0.019)., Conclusions: Abnormal bone microarchitecture, as measured by TBS, was seen in >50% of young adults with CP. TBS correlated with both areal BMD and appendicular lean mass. Maintaining muscle function is likely to be important for bone health in young adults with CP and needs to be confirmed in further studies., (Copyright © 2018. Published by Elsevier Inc.)

Fetal growth restriction (FGR) and prematurity are associated with high risk of brain injury and long-term neurological deficits. FGR infants born preterm are commonly exposed to mechanical ventilation, but it is not known whether ventilation differentially induces brain pathology in FGR infants compared with appropriate for gestational age (AGA) infants. We investigated markers of neuropathology in moderate- to late-preterm FGR lambs, compared with AGA lambs, delivered by caesarean birth and ventilated under standard neonatal conditions for 24 h. FGR was induced by single umbilical artery ligation in fetal sheep at 88-day gestation (term, 150 days). At 125-day gestation, FGR and AGA lambs were delivered, dried, intubated, and commenced on noninjurious ventilation, with surfactant administration at 10 min. A group of unventilated FGR and AGA lambs at the same gestation was also examined. Over 24 h, circulating pH, Po 2 , and lactate levels were similar between groups. Ventilated FGR lambs had lower cerebral blood flow compared with AGA lambs ( P = 0.01). The brain of ventilated FGR lambs showed neuropathology compared with unventilated FGR, and unventilated and ventilated AGA lambs, with increased apoptosis (caspase-3), blood-brain barrier dysfunction (albumin extravasation), activated microglia (Iba-1), and increased expression of cellular oxidative stress (4-hydroxynonenal). The neuropathologies seen in the ventilated FGR brain were most pronounced in the periventricular and subcortical white matter but also evident in the subventricular zone, cortical gray matter, and hippocampus. Ventilation of preterm FGR lambs increased brain injury compared with AGA preterm lambs and unventilated FGR lambs, mediated via increased vascular permeability, neuroinflammation and oxidative stress.

Objective: Changes in beliefs about self-weighing were examined across time in a behavioral weight loss intervention., Methods: Active duty military personnel (n = 248) enrolled in a 12-month counselor-initiated or self-paced intervention based on the Look AHEAD (Action for Health in Diabetes) Intensive Lifestyle Intervention. Using an electronic scale, participants were asked to self-weigh daily. Self-weighing perceptions were compared from baseline to 4 months (weight loss phase), from 4 months to 12 months (weight maintenance phase), and from baseline to 12 months (full intervention), as well as across time by behavioral and demographic characteristics., Results: Overall, participants perceived self-weighing as more helpful and positive, less frustrating, and making them less self-conscious after the weight loss phase. After weight maintenance, individuals believed self-weighing was less helpful and positive, more frustrating and anxiety provoking, and making them more self-conscious. However, after the intervention, participants still viewed self-weighing as more helpful and positive and less frustrating than at baseline. Weight change, self-weighing behavior prior to the intervention, and intervention condition were associated with perception change. Controlling for these influencing factors, differences in gender, BMI, age, ethnicity, and race were observed in how beliefs changed across time., Conclusions: Results suggest engaging in a weight loss intervention promoting daily self-weighing increases positive and decreases negative beliefs about self-weighing., (© 2018 The Obesity Society.)

Traumatic pericardial rupture is a rare event with high mortality. We present the case of a 15-year-old boy who sustained thoracic and abdominal trauma secondary to motor vehicle collision, with a delayed diagnosis of traumatic pericardial rupture with cardiac herniation. Out of concern for torsion and hemodynamic collapse, surgical repair was advised. We have developed a novel surgical approach to this rare condition, utilizing a combination of thoracoscopic and open surgical techniques. The guiding principles of our repair include the utilization of fenestrated pieces of bovine pericardium to create a tension free repair, minimizing the likelihood of pericardial effusion, and returning the cardiac mass to normal anatomic position., (© 2018 Forum Multimedia Publishing, LLC.)

Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P < .05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P = .02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings., (© 2018 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd.)

Background: It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. Recently, human clinical trials have reported safety and some efficacy following treatment of cerebral palsy using umbilical cord blood (UCB) cells. UCB is made up of many different cell types, including endothelial progenitor cells (EPCs), T regulatory cells (Tregs), and monocyte-derived suppressor cells (MDSCs). How each cell type contributes individually towards reducing neuroinflammation and/or repairing brain injury is not known. In this study, we examined whether human (h) UCB, or specific UCB cell types, could reduce peripheral and cerebral inflammation, and promote brain repair, when given early after perinatal HI brain injury., Methods: HI brain injury was induced in postnatal day (PND) 7 rat pups and cells were administered intraperitoneally on PND 8. Behavioral testing was performed 7 days post injury, and then, brains and spleens were collected for analysis., Results: We found in vitro that all UCB cell types, except for EPCs, were immunomodulatory. Perinatal HI brain injury induced significant infiltration of CD4+ T cells into the injured cerebral hemisphere, and this was significantly reduced by all hUCB cell types tested. Compared to HI, UCB, Tregs, and EPCs were able to reduce motor deficits, reduce CD4+ T cell infiltration into the brain, and reduce microglial activation. In addition to the beneficial effects of UCB, EPCs also significantly reduced cortical cell death, returned CD4+ T cell infiltration to sham levels, and reduced the peripheral Th1-mediated pro-inflammatory shift., Conclusion: This study highlights that cells found in UCB is able to mediate neuroinflammation and is an effective neuroprotective therapy. Our study also shows that particular cells found in UCB, namely EPCs, may have an added advantage over using UCB alone. This work has the potential to progress towards tailored UCB therapies for the treatment of perinatal brain injury.

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation., Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation., Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS., Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions., (© 2018 S. Karger AG, Basel.)

Cerebral palsy is the most common cause of physical disability in children, and there is no cure. Umbilical cord blood (UCB) cell therapy for the treatment of children with cerebral palsy is currently being assessed in clinical trials. Although there is much interest in the use of UCB stem cells for neuroprotection and neuroregeneration, the mechanisms of action are not fully understood. Further, UCB contains many stem and progenitor cells of interest, and we will point out that individual cell types within UCB may elicit specific effects. UCB is a clinically proven source of hemotopoietic stem cells (HSCs). It also contains mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and immunosupressive cells such as regulatory T cells (Tregs) and monocyte-derived supressor cells. Each of these cell types may be individual candidates for the prevention of brain injury following hypoxic and inflammatory events in the perinatal period. We will discuss specific properties of cell types in UCB, with respect to their therapeutic potential and the importance of optimal timing of administration. We propose that tailored cell therapy and targeted timing of administration will optimize the results for future clinical trials in the neuroprotective treatment of perinatal brain injury.

Background: The American College of Surgeons and the American Geriatrics Society have suggested that preoperative cognitive screening should be performed in older surgical patients. We hypothesized that unrecognized cognitive impairment in patients without a history of dementia is a risk factor for development of postoperative complications., Methods: We enrolled 211 patients 65 yr of age or older without a diagnosis of dementia who were scheduled for an elective hip or knee replacement. Patients were cognitively screened preoperatively using the Mini-Cog and demographic, medical, functional, and emotional/social data were gathered using standard instruments or review of the medical record. Outcomes included discharge to place other than home (primary outcome), delirium, in-hospital medical complications, hospital length-of-stay, 30-day emergency room visits, and mortality. Data were analyzed using univariate and multivariate analyses., Results: Fifty of 211 (24%) patients screened positive for probable cognitive impairment (Mini-Cog less than or equal to 2). On age-adjusted multivariate analysis, patients with a Mini-Cog score less than or equal to 2 were more likely to be discharged to a place other than home (67% vs. 34%; odds ratio = 3.88, 95% CI = 1.58 to 9.55), develop postoperative delirium (21% vs. 7%; odds ratio = 4.52, 95% CI = 1.30 to 15.68), and have a longer hospital length of stay (hazard ratio = 0.63, 95% CI = 0.42 to 0.95) compared to those with a Mini-Cog score greater than 2., Conclusions: Many older elective orthopedic surgical patients have probable cognitive impairment preoperatively. Such impairment is associated with development of delirium postoperatively, a longer hospital stay, and lower likelihood of going home upon hospital discharge.

Context: Spina bifida (SB) can lead to changes in body composition and bone mineral density (BMD) through diminished ambulation, renal impairment, and anticonvulsant medication. With increased life expectancy, diseases such as obesity and osteoporosis are emerging comorbidities in SB, with limited data to guide management., Objective: To examine the relationship between cardiometabolic factors, body composition, BMD, and minimal trauma fractures (MTFs) in adults with SB., Design: Retrospective cross-sectional study., Setting and Participants: Forty-nine adults with SB (median age, 32.7 years; interquartile range, 22.6 to 39.0) who had undergone dual-energy x-ray absorptiometry imaging at a single tertiary hospital from 2004 to 2015., Results: The mean body mass index was 31.7 ± 7.5 kg/m2; 26 (53.1%) were obese. Using age- and sex-matched fat percentiles from the National Health and Nutrition Examination Survey III, 62.5% had a total body percentage fat greater than the 95th percentile. Low bone mass (defined as a Z-score of ≤-2.0) was present in 21.9% at the L1 vertebra and in 35.1% at the femoral neck. Ten (20.4%) had a history of MTFs. A BMD or Z-score at L1, femoral neck, or total body site did not correlate with the occurrence of MTF. Fat mass was significantly and positively associated with BMD after adjustment for age, sex, and height and accounted for 18.6% of the variance in BMD ( P = 0.005). The prevalence of metabolic comorbidities, such as hypertension (20.4%) and obstructive sleep apnea (16.3%), was high., Conclusions: Obesity and low BMD are common in young adults with SB. An increased fat mass correlated significantly with BMD. The prevalence of metabolic complications in patients with SB is increased and deserves further study.

Melatonin (MLT) is an endogenous hormone that controls circadian cycle. MLT has additional important properties that make it appealing as a neuroprotective agent-it is a potent anti-oxidant, with anti-apoptotic and anti-inflammatory properties. MLT is safe for administration during pregnancy or to the newborn after birth, and can reduce white matter brain injury under conditions of chronic fetal hypoxia. Accordingly, in the current study, we examined whether an intermediate dose of MLT could restore white matter brain development when administered after an acute hypoxic ischemic (HI) insult in preterm fetal sheep. Fifteen fetal sheep at 95-98 days gestation were instrumented with femoral artery and vein catheters, and a silastic cuff placed around the umbilical cord. At 102 days gestation, the cuff was inflated, causing complete umbilical cord occlusion for 25 min in 10 fetuses, to induce acute severe HI. Five HI fetuses received intravenous MLT for 24 h beginning at 2 h after HI. The remaining five fetuses were administered saline alone. Ten days after HI, the fetal brain was collected from each animal and white and gray matter neuropathology assessed. HI caused a significant increase in apoptotic cell death (TUNEL+), activated microglia (Iba-1+), and oxidative stress (8-OHdG+) within the subventricular and subcortical white matter. HI reduced the total number of oligodendrocytes and CNPase+ myelin density. MLT administration following HI decreased apoptosis, inflammation and oxidative stress within the white matter. MLT had intermediate benefits for the developing white matter: it increased oligodendrocyte cell number within the periventricular white matter only, and improved CNPase+ myelin density within the subcortical but not the striatal white matter. MLT administration following HI was also associated with improved neuronal survival within the cortex. Neuropathology in preterm infants is complex and mediated by multiple mechanisms, including inflammation, oxidative stress and apoptotic pathways. Treatment with MLT presents a safe approach to neuroprotective therapy in preterm infants but appears to have brain region-specific benefits within the white matter.

Fetal growth restriction (FGR) is a common complication of pregnancy and, in severe cases, is associated with elevated rates of perinatal mortality, neonatal morbidity, and poor neurodevelopmental outcomes. The leading cause of FGR is placental insufficiency, with the placenta failing to adequately meet the increasing oxygen and nutritional needs of the growing fetus with advancing gestation. The resultant chronic fetal hypoxia induces a decrease in fetal growth, and a redistribution of blood flow preferentially to the brain. However, this adaptation does not ensure normal brain development. Early detection of brain injury in FGR, allowing for the prediction of short- and long-term neurodevelopmental consequences, remains a significant challenge. Furthermore, in FGR infants the detection and diagnosis of neuropathology is complicated by preterm birth, the etiological heterogeneity of FGR, timing of onset of growth restriction, its severity, and coexisting complications. In this review, we examine existing and emerging diagnostic tools from human and preclinical studies for the detection and assessment of brain injury in FGR fetuses and neonates. Increased detection rates, and early detection of brain injury associated with FGR, will offer opportunities for developing and assessing interventions to improve long-term outcomes.

Objective: To compare information obtained from preterm magnetic resonance imaging (MRI; 31-34 weeks) brain scan to that done at term equivalent age., Study Design: Prospective observational study of premature infants with evidence or suspicion of parenchymal brain injury on cranial ultrasound. Brain injury on two scans scored using a scoring system and analyzed., Results: Fourteen infants with a median (range) gestation at birth of 28 (25-29) weeks and birth weight of 1254 (680-1557) grams were studied. There was a strong correlation between the brain injury scores for the two scans (Spearman ρ=0.87, P=0.001) with excellent agreement between two radiologists (interclass correlation coefficient 0.9-0.94). There was also a high level of agreement between the preterm and term MRI two scores (Intraclass correlation coefficient, 0.79 (0.53-0.94))., Conclusions: Preterm MRI is a feasible option for the assessment of preterm brain injury and analysis of data obtained from scan at preterm age is comparable to that obtained at term equivalent age.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1 . The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context., Competing Interests: Authors' Contributions: J.H.L. and Y.J.C. collated and reviewed all clinical and radiological data. G.I.R. performed quantitative PCR analysis, with assistance from N.K., M.B., T.A.B., A.C.E.B., M.L.C., A.M.C., C.C., R.C.D., F.R.D., N.D., B. De A., V. De G., C.G.E.L. De G., I.D., C De L., A.E., M.C.F., P.F., A.F., E.F., M.P.G., N.R.G., M.H., M.A.K., N.L., J.-P.S.-M.L., M.A.L., S.S.M., R.M., L.M.-S., G.M., M.M., V.N., S.O., J.D.O.-E., B.P.-D., F.P., K.M.R., M.R., F.R., P.R.-P., A.R., T.I.S., M.B.T., A.T., F.U., N.U., A.V., and A.W. provided clinical samples and critically reviewed clinical and immunological patient data. Y.J.C. conceived the study and wrote the initial draft with the assistance of G.I.R. All authors critically reviewed the article and agreed to its publication. Financial Disclosure None of the authors have any financial disclosure to report., (Georg Thieme Verlag KG Stuttgart · New York.)

Although prematurity and hypoxic-ischaemic injury are well-recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one-third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention., (© 2017 Mac Keith Press.)

Chorioamnionitis is a major cause of preterm birth and brain injury. Bacterial invasion of the chorion and amnion, and/or the placenta, can lead to a fetal inflammatory response, which in turn has significant adverse consequences for the developing fetal brain. Accordingly, there is a strong causal link between chorioamnionitis, preterm brain injury and the pathogenesis of severe postnatal neurological deficits and cerebral palsy. Currently there are no treatments to protect or repair against brain injury in preterm infants born after pregnancy compromised by intrauterine infection. This review describes the injurious cascade of events in the preterm brain in response to a severe fetal inflammatory event. We will highlight specific periods of increased vulnerability, and the potential effects of therapeutic intervention with cell-based therapies. Many clinical trials are underway to investigate the efficacy of stem cells to treat patients with cerebral palsy. Stem cells, obtained from umbilical cord tissue and cord blood, normally discarded after birth, are emerging as a safe and potentially effective therapy. It is not yet known, however, which stem cell type(s) are the most efficacious for administration to preterm infants to treat brain injury-mediated inflammation. Individual stem cell populations found in cord blood and tissue, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), have a number of potential benefits that may specifically target preterm inflammatory-induced brain injury. MSCs have strong immunomodulatory potential, protecting against global and local neuroinflammatory cascades triggered during infection to the fetus. EPCs have angiogenic and vascular reparative qualities that make them ideal for neurovascular repair. A combined therapy using both MSCs and EPCs to target inflammation and promote angiogenesis for re-establishment of vital vessel networks is a treatment concept that warrants further investigation.

Hypoxic-ischemic encephalopathy (HIE) is a recognizable and defined clinical syndrome in term infants that results from a severe or prolonged hypoxic-ischemic episode before or during birth. However, in the preterm infant, defining hypoxic-ischemic injury (HII), its clinical course, monitoring, and outcomes remains complex. Few studies examine preterm HIE, and these are heterogeneous, with variable inclusion criteria and outcomes reported. We examine the available evidence that implies that the incidence of hypoxic-ischemic insult in preterm infants is probably higher than recognized and follows a more complex clinical course, with higher rates of adverse neurological outcomes, compared to term infants. This review aims to elucidate the causes and consequences of preterm hypoxia-ischemia, the subsequent clinical encephalopathy syndrome, diagnostic tools, and outcomes. Finally, we suggest a uniform definition for preterm HIE that may help in identifying infants most at risk of adverse outcomes and amenable to neuroprotective therapies.

Background: Preexisting cognitive impairment is emerging as a predictor of poor postoperative outcomes in seniors. We hypothesized that preoperative cognitive screening can be performed in a busy preadmission evaluation center and that cognitive impairment is prevalent in elective geriatric surgical patients., Methods: We approached 311 patients aged 65 years and older presenting for preoperative evaluation before elective surgery in a prospective, observational, single-center study. Forty-eight patients were ineligible, and 63 declined. The remaining 200 were randomly assigned to the Mini-Cog (N =100) or Clock-in-the-Box [CIB; N = 100)] test. Study staff administered the test in a quiet room, and 2 investigators scored the tests independently. Probable cognitive impairment was defined as a Mini-Cog ≤ 2 or a CIB ≤ 5., Results: The age of consenting patients was 73.7 ± 6.4 (mean ± SD) years. There were no significant differences between patients randomly assigned to the Mini-Cog and CIB test in age, weight, gender, education, ASA physical status, or Charlston Index. Overall, 23% of patients met criteria for probable cognitive impairment, and prevalence was virtually identical regardless of the test used; 22% screened with the Mini-Cog and 23% screened with the CIB scored as having probable cognitive impairment (P = 1.0 by χ analysis). Both tests had good interrater reliability (Krippendroff α = 0.86 [0.72-0.93] for Mini-Cog and 1 for CIB)., Conclusions: Preoperative cognitive screening is feasible in most geriatric elective surgical patients and reveals a substantial prevalence of probable cognitive impairment in this population.

Context: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited., Objective: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored., Design: Retrospective cross-sectional study., Setting and Participants: Forty-five adults with CP (mean age, 28.3 ± 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015., Results: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of ≤ -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07-9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; β = -0.582; P = .002) and FN Z-score (R(2) = 0.428; β = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients., Conclusions: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD.

Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, but new therapeutic strategies are required. Umbilical cord blood (UCB) mononuclear cells have potent anti-inflammatory properties and may reduce neuropathology. This study examined whether autologous UCB mononuclear cells were neuroprotective when administered to newborn lambs at 12 h after birth asphyxia. At caesarean section, birth asphyxia was induced by clamping the umbilical cord until mean arterial blood pressure decreased to 18-20 mmHg. Asphyxia (n = 20) or control (n = 11) lambs were resuscitated and maintained, with magnetic resonance spectroscropy (MRS) performed at 12 and 72 h, and were then killed at 72 h. Cord blood was collected once the cord was clamped, and mononuclear cells were isolated and labelled fluorescently and administered to control (n = 3) or asphyxia (n = 8) lambs. Asphyxia induced a significant increase in cellular apoptosis (caspase-3 immunopositive) within all brain regions examined, including cortex, hippocampus, thalamus, striatum and subcortical white matter (P < 0.01 vs. control). Additionally, asphyxia induced significant and widespread astrogliosis and increased inflammatory cells (activated microglia and macrophages). The administration of UCB mononuclear cells (asphyxia+UCB) significantly decreased neuronal apoptosis, astrogliosis and inflammation (P < 0.05 vs. asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetylaspartate (P < 0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, and reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials., (© 2015 Wiley Periodicals, Inc.)

Moderate to severe neonatal hypoxic ischemic encephalopathy remains an important cause of infant death and childhood disability. Early and accurate diagnosis of encephalopathy is difficult but critical for timely intervention. Thus, we have utilized a clinically relevant large animal model of asphyxia in-utero, followed by immediate lamb delivery, resuscitation and clinical care over the next 72h for assessment of potential biomarkers of brain injury. In-utero asphyxia was induced in twelve near-term lambs and outcomes compared with seven controls. Asphyxia resulted in bradycardia (97±12beats/min), hypotension (12.1±1mm Hg) and metabolic acidosis (pH6.9±0.02; base-excess -13.8±0.8mmol/l). 72h following asphyxia, cerebrospinal concentrations of malondialdehyde and S100B were elevated 2-fold and 5-fold, respectively, in asphyxic lambs compared to control lambs. Magnetic resonance spectroscopy (MRS) at 72h showed a significant decrease in n-acetyl aspartate: choline ratio in asphyxia lambs compared to that observed at 12h (0.56±0.23 vs. 0.82±0.15, respectively); lactate:choline ratio was not changed over this time. Marked neuropathology was observed in asphyxia lambs with neuronal degeneration in the hippocampus, thalamus, striatum and cortex. Astrogliosis was observed in the hippocampus and thalamus. Early blood markers of metabolic state showed limited predictive value of histological damage at 72h. MRS outcomes at 72h showed a modest but significant correlation with histological evidence of neuronal brain injury (lactate:N-acetyl aspartate ratio in the thalamus r(2)=0.2, p<0.01). MRS at 72h was best able to detect established brain injury, but a combination of biomarkers over multiple phases of injury may be able to assess the evolution of neonatal brain injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matter of the developing brain. Nearly 90% of preterm infants who later develop spastic CP have evidence of periventricular white matter injury. There are currently no treatments targeted at protecting the immature preterm brain. Umbilical cord blood (UCB) contains a diverse mix of stem and progenitor cells, and is a particularly promising source of cells for clinical applications, due to ethical and practical advantages over other potential therapeutic cell types. Recent studies have documented the potential benefits of UCB cells in reducing brain injury, particularly in rodent models of term neonatal hypoxia-ischemia. These studies indicate that UCB cells act via anti-inflammatory and immuno-modulatory effects, and release neurotrophic growth factors to support the damaged and surrounding brain tissue. The etiology of brain injury in preterm-born infants is less well understood than in term infants, but likely results from episodes of hypoperfusion, hypoxia-ischemia, and/or inflammation over a developmental period of white matter vulnerability. This review will explore current knowledge about the neuroprotective actions of UCB cells and their potential to ameliorate preterm brain injury through neonatal cell administration. We will also discuss the characteristics of UCB-derived from preterm and term infants for use in clinical applications.

Background and Purpose: Voxel-based analysis has suggested that deep gray matter rather than cortical regions is initially affected in adult Niemann-Pick type C. We sought to examine a range of deep gray matter structures in adults with NPC and relate these to clinical variables., Materials and Methods: Ten adult patients with NPC (18-49 years of age) were compared with 27 age- and sex-matched controls, and subcortical structures were automatically segmented from normalized T1-weighted MR images. Absolute volumes (in cubic millimeters) were generated for a range of deep gray matter structures and were compared between groups and correlated with illness variables., Results: Most structures were smaller in patients with NPC compared with controls. The thalamus, hippocampus, and striatum showed the greatest and most significant reductions, and left hippocampal volume correlated with symptom score and cognition. Vertex analysis of the thalamus, hippocampus, and caudate implicated regions involved in memory, executive function, and motor control., Conclusions: Thalamic and hippocampal reductions may underpin the memory and executive deficits seen in adult NPC. Volume losses in other subcortical regions may also be involved in the characteristic range of motor, psychiatric, and cognitive deficits seen in the disease.