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The use of sensory and mechanical perturbations applied during walking has grown in popularity due to their ability to elicit instability relevant to falls. However, the vast majority of perturbation studies on walking balance are performed on a treadmill at a fixed speed.The aim of this study was to quantify the effects of mediolateral optical flow perturbations on walking speed and balance outcomes in young adults walking with fixed-speed and self-paced treadmill controllers.Fifteen healthy young adults (8 female, age: 23.1 ± 4.6 yrs) completed four five-minute randomized walking trials in a speed-matched virtual reality hallway. In two of the trials, we added continuous mediolateral optical flow perturbations to the virtual hallway. Trials with and without optical flow perturbations were performed with either a fixed-speed or self-paced treadmill controller. We measured walking speed, balance outcomes (step width, margin of stability, local dynamic instability) and gait variability (step width variability and margin of stability variability).We found significant increases in step width (+20%, p = 0.004) and local dynamic instability (+11%, p = 0.008) of participants while responding to optical flow perturbations at a fixed treadmill speed. We found no significant differences in these outcome measures when perturbations were applied on a self-paced treadmill. Instead, participants walked 5.7% slower between the self-paced treadmill controller conditions when responding to optical flow perturbations (1.48 ± 0.13 m/s vs. 1.57 ± 0.16 m/s, p = 0.005).Our findings suggest that during walking, when presented with a balance challenge, an individual will instinctively reduce their walking speed in order to better preserve stability. However, comparisons to prior literature suggest that this response may depend on environmental and/or perturbation context. Cumulatively, our results point to opportunities for leveraging self-paced treadmill controllers as a more ecologically-relevant option in balance research with potential clinical applications in diagnostics and rehabilitation.

BACKGROUND: The optimal anastomotic techniques in esophagectomy to minimize rates of anastomotic leakage and conduit necrosis are not known. The aim of this study was to assess whether the anastomotic technique was associated with anastomotic failure after esophagectomy in the international Oesophago-Gastric Anastomosis Audit cohort.METHODS: This prospective observational multicenter cohort study included patients undergoing esophagectomy for esophageal cancer over 9 months during 2018. The primary exposure was the anastomotic technique, classified as handsewn, linear stapled, or circular stapled. The primary outcome was anastomotic failure, namely a composite of anastomotic leakage and conduit necrosis, as defined by the Esophageal Complications Consensus Group. Multivariable logistic regression modeling was used to identify the association between anastomotic techniques and anastomotic failure, after adjustment for confounders.RESULTS: Of the 2238 esophagectomies, the anastomosis was handsewn in 27.1%, linear stapled in 21.0%, and circular stapled in 51.9%. Anastomotic techniques differed significantly by the anastomosis sites (P < .001), with the majority of neck anastomoses being handsewn (69.9%), whereas most chest anastomoses were stapled (66.3% circular stapled and 19.3% linear stapled). Rates of anastomotic failure differed significantly among the anastomotic techniques (P < .001), from 19.3% in handsewn anastomoses, to 14.0% in linear stapled anastomoses, and 12.1% in circular stapled anastomoses. This effect remained significant after adjustment for confounding factors on multivariable analysis, with an odds ratio of 0.63 (95% CI, 0.46-0.86; P = .004) for circular stapled versus handsewn anastomosis. However, subgroup analysis by anastomosis site suggested that this effect was predominantly present in neck anastomoses, with anastomotic failure rates of 23.2% versus 14.6% versus 5.9% for handsewn versus linear stapled anastomoses versus circular stapled neck anastomoses, compared with 13.7% versus 13.8% versus 12.2% for chest anastomoses.CONCLUSIONS: Handsewn anastomoses appear to be independently associated with higher rates of anastomotic failure compared with stapled anastomoses. However, this effect seems to be largely confined to neck anastomoses, with minimal differences between techniques observed for chest anastomoses. Further research into standardization of anastomotic approach and techniques may further improve outcomes.

Study question Is it safe to use metabolic imaging to measure nicotinamide adenine dinucleotide (NADH) associated auto-fluorescence during embryo development using adapted confocal microscopy? Summary answer Non-invasive metabolic imaging is safe as no differences were observed between controls and illuminated embryos in terms of embryo development, blastocyst formation and implantation potential. What is known already Developing non-invasive methods that are reliable to assess oocyte and embryo quality has been a significant aim for assisted reproductive technologies. Changes in metabolic activity could lead to cell death or abnormal embryo development and low implantation potential. This could potentially be predicted by incorporating non-invasive measurements of metabolism. Metabolic imaging in embryos has been investigated through complex methodologies, however, scientific evidence for its utility during embryo development using simple technology remains unexplored. Measurements of metabolic activity could be a useful tool as the auto-fluorescence of molecules such as NADH is a straightforward representation of mitochondrial function. Study design, size, duration Super-ovulated female mice (n = 30) were subjected to mating with 10 males. In-vivo produced embryos collected at the 2-cell stage were divided in control group (n = 151), sham control group (n = 151) and illuminated group (n = 152). Illuminated embryos were assessed for NADH levels during embryo development every 3 hours using arbitrary units of autofluorescence (AU). Produced blastocysts were assessed for total cell and inner-cell-mass (ICM) number (Oct4 immuno-staining) and implantation potential through outgrowth assays in separate experiments. Participants/materials, setting, methods F1 (CBA/C57Bl6) mouse strain was used. NADH auto-fluorescence levels were measured during embryo development using adapted confocal microcopy (Olympus FV1200). A confocal Z-stacking function was used to record 15 focal planes using a 20x/0.95NA air objective of entire embryos, opening the confocal pinhole system completely. Then, images were collected and analysed using FIJI software (version: 2.0.0-rc-69/1.52n;ImageJ). Blastocyst cell number, formation rates and outgrowth rates for 4 days post blastocyst formation were compared between study groups. Main results and the role of chance Embryo culture experiments showed no significant differences in blastocyst formation rates between study groups (Control: 71.7%; Sham: 64.9%; Illuminated 71.7%; p > 0.05). Similarly, the total number of cells (Control: 82.9±5.6; Sham: 76.5±3.3; Illuminated: 77.1±4.2; ± Standard error of mean [SEM]) and ICM cells (Control: 10.8±1.3; Sham: 9.4±0.7; Illuminated: 11.9±0.8; ± SEM) did not differ between groups (p > 0.05). Outgrowth assays presented similar outgrowth areas during day5 to day8 post-blastocyst development between study groups (p > 0.05). Illuminated embryos presented significantly different NADH activity levels during embryo development, particularly between the 2-cell stage (987.1±36.2AU), morulae stage (1226±31.5AU) and blastocyst stage (649±42.9AU; ± SEM; p Limitations, reasons for caution The study was conducted using a mouse model focused in early embryo development and implantation potential. Thus, studies on live birth are required to fully assess safety to further validate potential wider applications. Validation in ageing models is also required to assess potential applications for embryo selection. Wider implications of the findings Non-invasive measurements of metabolic activity could be applied to determine embryo metabolic activity using simple and safe technology. Further applications could link the use of simple non-invasive metabolic imaging with the latest time-lapse technology and artificial intelligence applications. Trial registration number N/A

Background Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells. Methods We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo. Results We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Conclusions Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.

Objective This study aimed to determine if delayed cord clamping (DCC) affected brain myelin water volume fraction (VFm) and neurodevelopment in term infants. Study Design This was a single-blinded randomized controlled trial of healthy pregnant women with term singleton fetuses randomized at birth to either immediate cord clamping (ICC) (≤ 20 seconds) or DCC (≥ 5 minutes). Follow-up at 12 months of age consisted of blood work for serum iron indices and lead levels, a nonsedated magnetic resonance imaging (MRI), followed within the week by neurodevelopmental testing. Results At birth, 73 women were randomized into one of two groups: ICC (the usual practice) or DCC (the intervention). At 12 months, among 58 active participants, 41 (80%) had usable MRIs. There were no differences between the two groups on maternal or infant demographic variables. At 12 months, infants who had DCC had increased white matter brain growth in regions localized within the right and left internal capsules, the right parietal, occipital, and prefrontal cortex. Gender exerted no difference on any variables. Developmental testing (Mullen Scales of Early Learning, nonverbal, and verbal composite scores) was not significantly different between the two groups. Conclusion At 12 months of age, infants who received DCC had greater myelin content in important brain regions involved in motor function, visual/spatial, and sensory processing. A placental transfusion at birth appeared to increase myelin content in the early developing brain. Key Points

Purpose Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. Because numerous clinical trials have not improved survival from DIPG over standard radiation therapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease. Vascular damage caused by radiation therapy can increase the permeability of tumor blood vessels and promote tumor cell death. Methods and Materials To investigate the impact of endothelial cell death on tumor response to radiation therapy in DIPG, we used dual recombinase (Cre + FlpO) technology to generate primary brainstem gliomas which lack ataxia telangiectasia mutated (Atm) in the vasculature. Results Here, we show that Atm–deficient tumor endothelial cells are sensitized to radiation therapy. Furthermore, radiosensitization of the vasculature in primary gliomas triggered an increase in total tumor cell death. Despite the observed increase in cell killing, in mice with autochthonous DIPGs treated with radiation therapy, deletion of Atm specifically in tumor endothelial cells failed to improve survival. Conclusions These results suggest that targeting the tumor cells, rather than endothelial cells, during radiation therapy will be necessary to improve survival among children with DIPG.

BACKGROUND: Existing clinical assessments of balance and functional mobility have poor predictive accuracy for prospectively identifying post-stroke fallers, which may be due to a lack of ecological complexity that is typical of community-based fall incidents. RESEARCH QUESTION: Does an obstacle-crossing test at hospital discharge predict fall status of ambulatory stroke survivors 3 months after discharge? METHODS: Ambulatory stroke survivors being discharged home completed an obstacle-crossing test at hospital discharge. Falls were tracked prospectively for 3 months after discharge. Logistic regression examined the relationship between obstacle-crossing at discharge (pass/fail) and fall status (faller/non-faller) at 3 months post discharge. RESULTS: 45 participants had discharge obstacle test and 3-month fall data. 21 (47%) participants experienced at least one fall during follow-up, with 52% of the falls occurring within the first month after discharge. Of the 21 fallers, 14 failed the obstacle-crossing test (67% sensitivity). Among the 24 non-fallers, 20 passed the obstacle-crossing test (83% specificity). The area under the receiver operating characteristic curve was 0.75 (95% CI 0.60-0.90). Individuals who failed the obstacle-crossing test were 10.00 (95% CI: 2.45-40.78) times more likely to fall in the first 3 months after discharge. The unadjusted logistic regression model correctly classified 76% of the subjects. After adjusting for age, sex, days post stroke, and post-stroke disability, the odds ratio remained significant at 6.93 (95% CI: 1.01-47.52) and correctly classified 79.5% of the participants. SIGNIFICANCE: The obstacle-crossing test may be a useful discharge assessment to identify ambulatory stroke survivors being discharged home who are likely to fall in the first 3 months post discharge. Modifications to improve the obstacle-crossing test sensitivity should be explored further.

Keeping the umbilical cord intact after delivery facilitates transition from fetal to neonatal circulation and allows a placental transfusion of a considerable amount of blood. A delay of at least 3 minutes improves neurodevelopmental outcomes in term infants. Although regarded as common sense and practiced by many midwives, implementation of delayed cord clamping into practice has been unduly slow, partly because of beliefs regarding theoretic risks of jaundice and lack of understanding regarding the long-term benefits. This article provides arguments for delaying cord clamping for a minimum of 3 minutes.

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research., Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

Background and purpose Despite evidence that falls can be prevented with specific exercise interventions such as the Otago Exercise Program (OEP), translation of these programs into practice is limited in rural and medically underserved areas. The Community Health and Mobility Partnership (CHAMP) addresses this problem through a community-based implementation of the OEP in rural Appalachia where medical resources are scarce. The purpose of this study was to examine the effects of the CHAMP on physical performance and balance confidence in community-dwelling older adults. Methods This study was a retrospective analysis of quasi-longitudinal data. Older adults received fall screenings at local senior centers. Those with increased fall risk received individualized OEP home exercises and were advised to return for monthly follow-up visits. Three physical performance measures-Timed Up and Go test (TUG), Four-Stage Balance Test (4SBT), and chair rise test (CRT)-and the Activities-specific Balance Confidence scale (ABC) were assessed at the initial visit (IV) and each follow-up visit. Two groups were created to distinguish participants who returned for their second follow-up (F2) visit within 3 months from those who returned between 3 and 6 months. Within-group change from IV to F2 was calculated using repeated-measures t tests. Repeated-measures 2-way analyses of variance were used to test for main and interaction effects of group and visit. Results and discussion One hundred thirty CHAMP participants aged 76.1 (SD = 8.1) years demonstrated statistically and clinically significant improvements in the 3 physical performance measures (mean 4SBT: IV 29.5 seconds, F2 31.5 second, P = .001), (mean TUG: IV 12.7 seconds, F2 11.9 seconds, P = .021), (mean CRT: IV 0.258 stands/second, F2 0.290 stands/second, P = .002), but not in balance confidence (mean ABC: IV 62.2, F2 64.4, P = .154). A significant interaction of group by visit for the TUG was observed, suggesting that better TUG performance was associated with quicker return for follow-up. Conclusions Results indicated that program participants improved from IV to F2 in measures related to fall risk.

Objective To investigate the effects of community transition programs for adults with traumatic spinal cord injury (tSCI) on hospital readmissions and quality of life (QOL). Data Sources Seven databases (PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Google Scholar, the Joanna Briggs Institute database, OTseeker, and PEDro) and reference lists of relevant articles were searched from inception through March 2020. Study Selection Original research studies were included that (1) evaluated interventions designed to support individuals aged 18-65 years with newly acquired tSCI in navigating the transition from subacute care to the community and (2) reported data for QOL or hospital readmission outcomes. Searches identified 4694 studies, and 26 of these met the selection criteria. Data Extraction Two reviewers independently screened and assessed all studies, extracting information about study type, methodological strengths and weaknesses, participant and intervention characteristics, comparator, and significant results. Any discrepancies were resolved by a third reviewer. Data Synthesis Studies were grouped according to primary intervention: peer mentoring (n=8), telehealth (n=5), education (n=5), independent living (n=3), occupational therapy (n=1), counseling (n=1), and patient navigation (n=4). Reviewers used the Let Evidence Guide Every Decision appraisal tool rubric to grade the body of evidence for each intervention type. Moderate level evidence supports the positive effects of peer mentoring, and low level evidence indicates positive effects of telehealth, education, independent living, and occupational therapy interventions. Peer mentoring, telehealth, and patient navigation were the only intervention types that included hospital readmission outcomes. Of these, peer mentoring had the most evidence, with 3 of the 4 studies that included hospital readmission outcomes demonstrating statistically significant improvements. Conclusions In general, there is a paucity of high-quality evidence with sufficiently similar characteristics to demonstrate and compare benefits from program participation. When high quality studies have been conducted, they have obtained mixed results. Of the different intervention types, peer mentorship has the strongest supporting evidence. Further research is needed to identify specific intervention components that are most effective in improving QOL and reducing hospital readmission for specific subgroups of individuals recovering from tSCI.

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children.In vitroandin vivodisease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS).In vitroHTS results predicted variablein vivoresponse to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.

Placental transfusion results in a significant decrease in the risk of death for extremely preterm infants. With immediate cord clamping (ICC), these infants can leave up to one-half of their normal circulating in utero blood volume in the placenta. Extremely preterm infants are at highest risk of harm from ICC yet are currently the most likely to receive ICC. Receiving a placenta transfusion provides infants with life-saving components and enhanced perfusion. We present some lesser-known but important effects of placental transfusion. New research reveals that enhanced vascular perfusion causes an organ's endothelial cells to release angiocrine responses to guide essential functions. High progesterone levels and pulmonary artery pressure in the first few hours of life assist with neonatal adaptation. We propose that lack of essential blood volume may be a major factor contributing to inflammation, morbidities, and mortality that preterm infants frequently encounter.

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53 deficient but not p53 wild-type gliomas following radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, Nqo1. Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

African American men face a stark prostate cancer (PCa)‐related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome‐based “protein signature” for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2‐fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry‐based proteomic analysis of serum exosomes identified seven unique and fifty‐five overlapping proteins (up‐ or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute‐phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA‐hT cells secreted exosomes strongly induced a proinflammatory M2‐phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6‐fold) in exosomes from African Americans with PCa, but a lesser loading (0.6‐fold) was observed in exosomes from Caucasian men with PCa compared to race‐matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.

Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children’s Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request. Electronic supplementary material The online version of this article (10.1007/s00401-020-02171-5) contains supplementary material, which is available to authorized users.

This was a retrospective analysis of quasi-longitudinal data from an ongoing, community-based falls prevention program. The purpose was to identify participant characteristics predicting improvement on physical performance measures associated with falls risk. Community-dwelling older adults &ge, 60 years old participated in a community-based implementation of the Otago Exercise Program (OEP). Participants with increased falls risk (n = 353) were provided with individualized exercises from OEP and were invited to return for monthly follow-up. One hundred twenty-eight participants returned for at least two follow-up visits within 6 months of their initial visit (mean time to second follow-up = 93 days with standard deviation = 43 days). Outcome measures assessed at initial and all follow-up visits included Four Stage Balance Test (4SBT), Timed Up and Go test (TUG), and Chair Rise Test (CRT). Distributions were examined, and results were categorized to depict improvement from initial visit (IVT) to second follow-up visit (F2). Key predictor variables were included in multivariable linear or logistic regression models. Improved 4SBT performance was predicted by greater balance confidence. Better TUG performance at F2 was predicted by no use of assistive device for walking, higher scores on cognitive screening, and better IVT TUG performance. Improvement on CRT was predicted by younger age and lower scores on cognitive screening. While improvements on each of the three measures were predicted by a unique combination of variables, these variables tended to be associated with less frailty.

Background: A basal bolus insulin regimen requires multiple daily insulin injections, which might discourage patient adherence. As a potential solution, a mealtime insulin-delivery system—a 3-day wearable bolus-only patch—was designed to manually administer mealtime insulin discreetly by actuating buttons through clothing, without the need for multiple needle sticks. Method: Extensive functional testing of the patch included dose accuracy (from initial fill of the device to empty), pressure-vacuum leak testing, last-dose lockout and occlusion detection (safety alert features that lock the dosing buttons when no insulin is delivered), assessments of insulin drug stability, toxicological risk (including chemical testing), and system biocompatibility. Results: Dosing accuracy was 2 units ±10% (with U-100 insulin) over a range of environmental conditions, with ≥95% reliability and confidence. The fluid seal performance and the safety alert features performed with ≥95% reliability and ≥95% confidence. The system met acceptable standards for insulin (U-100 lispro and aspart) stability for its intended 3-day use, in addition to the operational requirements. The toxicological risk assessment and demonstrated biocompatibility suggested that the patch is safe for human use. Conclusions: Benchtop performance showed that the bolus-only patch is a safe, accurate, and reliable device for mealtime insulin delivery.

To determine if umbilical cord milking is detrimental in compromised term/near-term infants. A retrospective analysis of infants with abnormal cord gases (cord arterial or venous pH of ≤ 7.1 or base deficit > −12). We collected maternal risk factors, cord management, birth, and neonatal outcomes during hospitalization. We found 157 infants who met the criteria for abnormal cord gases. Thirty-six of those had umbilical cord milking at delivery. There was no significant difference in neonatal outcomes, but fewer infants in the cord milking group needed resuscitation (38 vs. 56%, p = 0.07) and ongoing respiratory support (19 vs. 31%, p = 0.16) compared to the immediate clamping group. While not significant, infants who received cord milking at birth needed less resuscitation and ongoing respiratory support. This study suggests that umbilical cord milking appears to be a safe therapy when acidosis is present and when resuscitation is needed.

Cell surface or intracellular antigens expressed in pediatric brain tumors are potential targets for chimeric antigen receptor (CAR) or ab (T-cell receptor) TCR T-cell immunotherapy. At present it remains unknown what cell surface antigens are suitable CAR targets for pediatric brain tumors; in addition, cell surface expression of HLA class I, a molecule critical for ab TCR T-cell recognition, has not been systemically studied in these tumors. Therefore, we set out to assess expression of five CAR targets (IL13Ra2, HER2, EphA2, B7-H3, GD2) and HLA class I. We established and validated a flow cytometry-based method to profile CAR targets and HLA class I expression from pediatric patient-derived xenograft (PDX) samples. To date, we profiled 53 PDX samples, including medulloblastoma, HGG, DIPG, ATRT, and ependymoma. We found that antigen expression has high intra- and inter-PDX sample variability with B7-H3 and IL13Ra2 being most consistently expressed. We confirmed these findings using conventional IHC for B7-H3 with PDX samples and patient tissue microarrays. HLA class I was present on the cell surface of HGGs and DIPGs, however significantly down-regulated in 26 out of 36 other brain tumor types. Finally, matched fresh tissue and PDX sample analysis revealed that cells derived from PDX models are indeed representative of fresh tissue. Our results indicate that more than one antigen needs to be targeted to achieve a more complete tumor clearance. In addition, variable expression of HLA class I suggests that pediatric brain tumors have developed immune evasion strategies to prevent recognition by conventional T cells.

Background Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20–30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. Methods Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. Results A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal–external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). Conclusion The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients., Early recurrence after surgery for adenocarcinoma of the oesophagus is common. A risk prediction model was derived using modern machine learning methods that accurately predicts risk of early recurrence using postoperative pathology. Machine learning may help

The Royal Navy’s Role 2 Afloat (R2A) capability has now been firmly established in support of United Kingdom (UK) troops on contingency operations such as humanitarian aid and disaster relief operations. This article reviews the current capability of R2A to deliver medical care to children and pregnant women, including the challenges facing the deployed Biomedical Scientist (BMS).

Ripening in nonclimacteric fruits such as grape involves complex chemical changes that have a profound influence on the accumulation of flavor and aroma compounds distinct to a particular grape genotype. In this study, proteome characterization of wine type bronze muscadine grape (Vitis rotundifolia cv. Carlos), primarily grown in the Southeastern United States was performed during berry ripening. Stage-specific protein expression was obtained among different stages of berries. Differential analysis showed the expression of 522 proteins that regulate diverse biological processes and metabolic pathways. Of these, 30 proteins are associated with the production of key phenolic compounds, whereas 25 are associated with the production of muscadine aroma compounds. These proteins are involved in the phenylpropanoid pathway, terpene synthesis, fatty acid derived volatiles and esters that affect muscadine berry flavor and aroma characteristics. Further, gene expression analysis during ripening validated the expression pattern of 12 proteins. Catechin, epicatechin, and four stilbenes were quantified to correlate observed proteome changes. This study not only revealed biochemical changes during muscadine berry ripening but also offers indicators for marker-assisted breeding to enhance organoleptic properties of muscadine grape to improve its flavor and aroma properties.

An assessment of fractionated mouse hippocampal peptides was conducted. Protein extract from a single mouse hippocampus was enzymatically digested and fractionated by IEF. Aliquots of fractions were pooled into fewer, more complex samples. The unfractionated lysate, fractions, and pooled fractions were subjected to LC-MS/MS analysis. Samples consisting of many individual fractions had more protein identifications, greater protein sequence coverage, and quantified proteins with more spectral counts than protein extract that was unfractionated or pooled into fewer LC-MS/MS samples. Additionally, prefractionation reduced the median CV for spectral counts as much as 33%. However, the relative gain in proteome resolution was found to saturate with increasing fractionation extent. This study demonstrates how prefractionation by offline IEF can improve the resolution of proteomic investigations of the mouse hippocampus, and that a data-driven pooling methodology can reduce excessive and cost-ineffective fractionation.

Pediatric brain tumors comprise a distinct spectrum of diseases compared to adult brain tumors and are distinguished by their unique clinical and histopathological features, developmental context, mutation burden, and genomic, epigenomic, and transcriptomic alterations. Access to in vivo models that recapitulate pediatric brain tumors has been limited and inadequate to represent these heterogeneous diseases. Here we introduce the Pediatric Brain Tumor Portal (PBTP, pbtp.stjude.cloud), an open resource to access molecular characterization, including whole-genome sequencing, whole-exome sequencing, RNA-seq, and DNA methylome profiling, of patient-derived orthotopic xenograft (PDOX) models of pediatric brain tumors. The portal will host more than 70 models, which currently include pediatric High-Grade Glioma (pHGG), Medulloblastoma, Atypical Teratoid/Rhabdoid Tumors (AT/RT), Ependymoma, and Embryonal Tumors with Multilayered Rosettes (ETMR), and reflects close to ten years of effort to generate and extensively characterize in vivo models that recapitulate primary pediatric brain tumors. PBTP is a database-driven and user-friendly platform that enables multi-omics views of PDOX and matched patient tumor and germline samples at multiple levels to help identify appropriate lines for studies of tumorigenesis or preclinical testing. To evaluate the representation of different molecular features within a disease subgroup, we implemented various visualization tools for searching and comparing somatic mutations, gene expression profiles, and methylation groups of our models and matched patient tumors. Details for each tumor including de-identified clinical data, histology, growth characteristics, DNA methylation classification, mutation status, and copy number variations are also readily available for side-by-side comparison. Furthermore, in vitro chemical sensitivity profiling is presented for selected models with matched cell lines. Users can investigate genes of interest for single nucleotide variants, small insertions and deletions, copy number variations, gene fusions, and mRNA expression in PDOX and matched patient tumors. This portal has been integrated into the St. Jude Cloud platform, through which users can explore patient and PDOX sequencing data in the context of larger cohort data sets and download raw genomics data files. PBTP provides a platform to share PDOX models with in-depth genome/epigenome-wide characterization to support advances in basic and translational research in pediatric brain tumors. *co-first, #co-corresponding Citation Format: Paige S. Dunphy, Ke Xu, Darrell T. Gentry, Chen He, Kimberly Mercer, Xiaoyan Zhu, Kyle Smith, Brian Gudenas, Sarah Robinson, Junyuan Zhang, Lawryn H. Kasper, Chang-Hyuk Kwon, Laura D. Hover, Jon D. Larson, Nathaniel Twarog, Aksana Vasilyeva, Nedra Robison, Daniel Alford, Cynthia Williams, Anthony Woodard, Xin Zhou, Edgar Sioson, J. Robert Michael, Austyn Trull, Irina McGuire, Brandon McMahan, Swapnali Mohite, Ashok Boddu, Kirby Birch, Clay McLeod, Michael A. Dyer, Paul Klimo, Frederick A. Boop, Amar Gajjar, Christopher L. Tinkle, Giles Robinson, Brent A. Orr, Jason Chiang, Paul A. Northcott, Jinghui Zhang, Keith Perry, Gang Wu, Anang A. Shelat, Ed Suh, Martine F. Roussel, Suzanne J. Baker. St. Jude Pediatric Brain Tumor Portal: Cloud-based resource for patient-derived orthotopic xenograft (PDOX) models of pediatric high-grade glioma, ependymoma, and CNS embryonal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6144.

The lateral destination and potential decomposition of soil organic matter mobilized by soil erosion depends on factors such as the amount and type of precipitation, topography, the nature of mobilized organic matter (OM), potential mixing with mineral particles, and the stabilization mechanisms of the soil OM. This study examined how the relative distribution of carbon (C) and nitrogen (N) in different OM fractions varied in soils from eroding slopes and in eroded sediments in a series of low-order forested catchments in the western Sierra Nevada, California. We found that precipitation amount played a major role in mobilizing OM. More than 40% of the OM exported from these forested catchments was free particulate OM, or OM physically protected inside relatively less stable macroaggregates, compared to OM inside microaggregates or chemically associated with soil minerals. Years with high amounts of precipitation generally transported more mineral-associated OM, with lower C and N concentrations, while sediment transported in drier years was more enriched in unprotected, coarse particulate OM derived from surficial soils. When incubated under the same conditions, sediment C (from material captured in settling basins) produced 72–97% more CO 2 during decomposition than soil C did. Our results suggest that without stabilization through burial or reconfigured organomineral associations, this sediment OM is prone to decomposition, which may contribute to little to no terrestrial CO 2 sink induced from erosion in these Mediterranean montane forest ecosystems.

The Royal Navy’s Role 2 Afloat (R2A) capability has now been firmly established in support of United Kingdom (UK) troops on contingency operations such as humanitarian aid and disaster relief operations. This article reviews the current capability of R2A to deliver medical care to children and pregnant women, including the challenges facing the deployed Biomedical Scientist (BMS).

The Role 2 Afloat (R2A) capability is now firmly established on several maritime platforms using the 370 Module (afloat) equipment. This year has seen the appointment on board ships that support R2A of a new full-time role, the Medical Module Manager (MMM), who is responsible for the equipment on board. This article outlines the new role.

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle-aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co-occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.

We evaluated a subset of infants with suspected intrauterine growth restriction or birth weights small for gestational age enrolled in a study of delayed cord clamping for preterm infants. Compared with immediate clamping, delayed cord clamping was associated with no apparent harm and less suspected necrotizing enterocolitis. Trial registration ClinicalTrials.gov : NCT00818220 and NCT01426698.

INDIAN PEDIATRICS 747 VOLUME 52__SEPTEMBER 15, 2015 At any point in fetal life, approximately 30% of the fetus’ blood volume is circulating through the placenta where all respiratory and many metabolic functions occur. At birth, allowing this blood to be redistributed to the infant provides up to 50% more iron-rich red blood cells in the circulation [1]. These red blood cells contribute to higher iron stores in infancy [2]. Placental transfusion which facilitates this blood transfer is accomplished in one of three ways: delayed cord clamping (DCC); milking the umbilical cord (UCM) before separating it from the placenta; or clamping and cutting the umbilical cord and milking after cutting (CUCM). Most studies contrast these methods to immediate cord clamping (ICC), the dominant world-wide practice. In term infants, placental transfusion can result in increased iron stores during the first 6 months of life [2]. To date, ferritin, a marker of iron stores, has not been measured in early or late preterm infants in studies of placental transfusion. Measuring ferritin is important because adequate iron is essential for normal brain development, especially during the critical first year when the most rapid brain growth occurs. A recent study of 400 Swedish term infants demonstrated that DCC increased ferritin levels by 48% at 4 months of age. At 4 years of age, those children who had a placental transfusion had higher fine motor and social-emotional scores [3]. In this issue of Indian Pediatrics, Kumar, et al. [4] are the first to report ferritin levels in late preterm infants born between 32 and 36 weeks gestational age [4]. Using CUCM with three milkings, they found ferritin levels almost double at 6 weeks of age in infants who received C-UCM (n=91) when compared to infants (n=86) who received ICC. They also report significantly higher bilirubin levels and an increased need for phototherapy in the C-UCM group. This is in direct contrast to most recent studies on placental transfusion. These important findings suggest the need for further follow-up of these children to determine long-term developmental effects and weigh risks versus benefits. There is no meta-analysis for late preterm infants with placental transfusion. Only two other studies specifically address this age group. The first examined infants between 34-36 weeks (n=41) and compared a 3-minute delay versus ICC [5]. They found higher hemoglobin levels at 1 day and 10 weeks without any difference in jaundice [5]. Ranjit, et al. [6] randomized 94 infants between 30 and 366/7 weeks to either DCC (at least 2 minutes) or ICC. They found higher hematocrit and ferritin levels at 6 weeks of age. The DCC group had longer duration of phototherapy but no difference in the incidence of significant jaundice.

OBJECTIVE: Knee and hip osteoarthritis (OA) are known risk factors for falls, but whether they together additionally contribute to falls risk is unknown. This study utilizes a biracial cohort of men and women to examine the influence of lower limb OA burden on the risk for future falls. METHODS: A longitudinal analysis was performed using data from 2 time points of a large cohort. The outcome of interest was falls at follow up. Covariates included age, sex, race, body mass index, a history of prior falls, symptomatic OA of the hip and/or knee, a history of neurologic or pulmonary diseases, and current use of narcotic medications. Symptomatic OA was defined as patient reported symptoms and radiographic evidence of OA in the same joint. Logistic regression analyses were used to determine associations between covariates and falls at follow-up. RESULTS: The odds of falling increased with an increasing number of lower limb symptomatic OA joints: those with 1 joint had 53% higher odds, those with 2 joints had 74% higher odds, those with 3-4 OA joints had 85% higher odds. When controlling for covariates, patients who had symptomatic knee or hip OA had an increased likelihood of falling (aOR 1.39 95% CI [1.02, 1.88]; aOR 1.60 95% CI [1.14, 2.24], respectively). CONCLUSIONS: This study reveals the risk for falls increases with additional symptomatic OA lower limb joints and confirms that symptomatic hip and knee OA are important risk factors for falls. © 2014 American College of Rheumatology. Language: en

The Role 2 Afloat (R2A) capability is now firmly established on several maritime platforms using the 370 Module (afloat) equipment. This year has seen the appointment on board ships that support R2A of a new full-time role, the Medical Module Manager (MMM), who is responsible for the equipment on board. This article outlines the new role.

Recently there have been a number of studies and presentations on the importance of providing a placental transfusion to the newborn. Early cord clamping is an avoidable, unphysiologic intervention that prevents the natural process of placental transfusion. However, placental transfusion, although simple in concept, is affected by multiple factors, is not always straightforward to implement, and can be performed using different methods, making this basic procedure important to discuss. Here, we review three placental transfusion techniques: delayed cord clamping, intact umbilical cord milking and cut-umbilical cord milking, and the evidence in term and preterm newborns supporting this practice. We will also review several factors that influence placental transfusion, and discuss perceived risks versus benefits of this procedure. Finally, we will provide key straightforward concepts and implementation strategies to ensure that placental-to-newborn transfusion can become routine practice at any institution.