Utilization of a Novel Scoring System in Predicting 30-day Mortality in Acute Pulmonary Embolism, the CLOT-5 Pilot Study.

OBJECTIVES: To construct a new scoring system utilizing biomarkers, vitals, and imaging data to predict 30-day mortality in acute pulmonary embolism (PE). BACKGROUND: Acute PE, a well-known manifestation of venous thromboembolic disease, is responsible for over 100,000 deaths worldwide yearly. Contemporary management algorithms rely on a multidisciplinary approach to care via PE response teams (PERT) in the identification of low, intermediate, and high-risk patients. The PESI and sPESI scores have been used as cornerstones of the triage process in assigning risk of 30-day mortality for patients presenting with acute PE; however, the specificity of these scoring systems has often come into question. METHODS: This study retrospectively analyzed 488 patients with acute PE who were managed at a tertiary care institution with either conservative therapy consisting of low molecular weight or unfractionated heparin, advanced therapies consisting of catheter directed therapies, aspiration thrombectomy, or a combination of these therapies, or surgical embolectomy. The CLOT-5 score was designed to include vital signs, biomarkers, and imaging data to predict 30-day mortality in patients presenting with acute PE. RESULTS: The CLOT-5 score had an area under the curve (AUC) of 0.901 with a standard error of 0.29, while the PESI and sPESI scores had an AUC and standard errors of 0.793 ±- 0.43 and 0.728 ± 0.55, respectively. CONCLUSIONS: When incorporated into the management algorithms of national PERT programs, the CLOT-5 score may allow for rapid and comprehensive assessment of patients with acute PE at high risk for clinical decompensation, leading to early escalation of care where appropriate.

A Meta-analysis of Standard Versus Ultrasound-Assisted Catheter-Directed Thrombolysis in the Management of Acute Pulmonary Embolism.

Background: Standard catheter-directed thrombolysis (SCDT) harnesses the therapeutic benefit of systemic thrombolytics while minimizing bleeding complications in patients presenting with pulmonary embolism (PE). Ultrasound-assisted catheter-directed thrombolysis (USAT) theoretically improves upon SCDT by disrupting fibrin and increasing the surface area exposed to thrombolytic agent. However, it is unclear if this translates into improved outcomes. Methods: A systematic search of prior publications comparing SCDT and USAT in patients with intermediate or high-risk PE was conducted. Primary outcomes of interest were bleeding events, ICU and hospital length of stay. Secondary outcomes included changes in pulmonary artery systolic pressure (PASP), mean pulmonary artery pressure (mPAP), and right ventricle to left ventricle diameter (RV/LV) ratio. Studies that lacked comparison groups were excluded. Bias assessments were performed using the Cochrane tools for randomized and nonrandomized studies. Data was collated utilizing the Cochrane Review Manager software, and all analyses assumed random effects. Results: Our search yielded 7 observational studies and 1 randomized control trial. The studies included a total of 543 patients who underwent either SCDT (n = 273) or USAT (n = 270) for intermediate or high-risk PE. The synthesized analysis showed no significant differences in bleeding between the groups. There were no differences in ICU or hospital lengths of stay, changes in PASP, or mPAP. Reductions in RV/LV ratio were greater with SCDT (mean difference, -0.16; 95% CI, -0.27 to -0.06; P = .003). Conclusions: In comparison to SCDT, USAT did not result in improved clinical or hemodynamic outcomes in patients presenting with PE. Results were limited by heterogeneity among the included studies.

ID-Seg: an infant deep learning-based segmentation framework to improve limbic structure estimates.

Infant brain magnetic resonance imaging (MRI) is a promising approach for studying early neurodevelopment. However, segmenting small regions such as limbic structures is challenging due to their low inter-regional contrast and high curvature. MRI studies of the adult brain have successfully applied deep learning techniques to segment limbic structures, and similar deep learning models are being leveraged for infant studies. However, these deep learning-based infant MRI segmentation models have generally been derived from small datasets, and may suffer from generalization problems. Moreover, the accuracy of segmentations derived from these deep learning models relative to more standard Expectation-Maximization approaches has not been characterized. To address these challenges, we leveraged a large, public infant MRI dataset (n = 473) and the transfer-learning technique to first pre-train a deep convolutional neural network model on two limbic structures: amygdala and hippocampus. Then we used a leave-one-out cross-validation strategy to fine-tune the pre-trained model and evaluated it separately on two independent datasets with manual labels. We term this new approach the Infant Deep learning SEGmentation Framework (ID-Seg). ID-Seg performed well on both datasets with a mean dice similarity score (DSC) of 0.87, a mean intra-class correlation (ICC) of 0.93, and a mean average surface distance (ASD) of 0.31 mm. Compared to the Developmental Human Connectome pipeline (dHCP) pipeline, ID-Seg significantly improved segmentation accuracy. In a third infant MRI dataset (n = 50), we used ID-Seg and dHCP separately to estimate amygdala and hippocampus volumes and shapes. The estimates derived from ID-seg, relative to those from the dHCP, showed stronger associations with behavioral problems assessed in these infants at age 2. In sum, ID-Seg consistently performed well on two different datasets with an 0.87 DSC, however, multi-site testing and extension for brain regions beyond the amygdala and hippocampus are still needed.

Structural brain measures among children with and without ADHD in the Adolescent Brain and Cognitive Development Study cohort: a cross-sectional US population-based study.

BACKGROUND: Structural neuroimaging research has identified a variety of abnormalities in cortical and subcortical structures in children with ADHD. However, studies to date have not employed large, non-referred samples, complete with data on potential confounding variables. Here, we tested for differences in structural MRI measures among children with and without ADHD using data from the Adolescent Brain and Cognitive Development (ABCD) Study, the largest paediatric brain imaging study in the USA. METHODS: In this cross-sectional study, we used baseline demographic, clinical, and neuroimaging data from the ABCD Study, which recruited children aged 9-10 years between Sept 1, 2016, and Aug 31, 2018, representative of the sociodemographic features of the US population. ADHD was diagnosed by parent report of symptoms. Neuroimaging data underwent centralised quality control and processing by the ABCD team. Linear mixed effects models were used to estimate Cohen's d values associated with ADHD for 79 brain measures of cortical thickness, cortical area, and subcortical volume. We used a novel simulation strategy to assess the ability to detect significant effects despite potential diagnostic misclassification. FINDINGS: Our sample included 10 736 participants (5592 boys, 5139 girls; 5692 White, 2165 Hispanic, 1543 Black, 221 Asian, and 1100 of other race or ethnicity), of whom, 949 met the criteria for ADHD and 9787 did not. In the full model, which included potential confounding variables selected a priori, we found only 11 significant differences across the 79 brain measures after false discovery rate correction, all indicating reductions in brain measures among participants with ADHD. Cohen's d values were small, ranging from -0·11 to -0·06, and were not meaningfully changed by using a more restrictive comparison group or alternative diagnostic methods. Simulations indicated adequate statistical power to detect differences even if there was substantial diagnostic misclassification. INTERPRETATION: In a sample representative of the general population, children aged 9-10 years with ADHD differed only modestly on structural brain measures from their unaffected peers. Future studies might need to incorporate other MRI modalities, novel statistical approaches, or alternative diagnostic classifications, particularly for research aimed at developing ADHD diagnostic biomarkers. FUNDING: Edwin S Webster Foundation and Duke University, NC, USA.

Targeted intraspinal injections to assess therapies in rodent models of neurological disorders.

Despite decades of research, pharmacological therapies for spinal cord motor pathologies are limited. Alternatives using macromolecular, viral, or cell-based therapies show early promise. However, introducing these substances into the spinal cord, past the blood-brain barrier, without causing injury is challenging. We describe a technique for intraspinal injection targeting the lumbar ventral horn in rodents. This technique preserves motor performance and has a proven track record of translation into phase 1 and 2 clinical trials in amyotrophic lateral sclerosis (ALS) patients. The procedure, in brief, involves exposure of the thoracolumbar spine and dissection of paraspinous muscles over the target vertebrae. Following laminectomy, the spine is affixed to a stereotactic frame, permitting precise and reproducible injection throughout the lumbar spine. We have used this protocol to inject various stem cell types, primarily human spinal stem cells (HSSCs); however, the injection is adaptable to any candidate therapeutic cell, virus, or macromolecule product. In addition to a detailed procedure, we provide stereotactic coordinates that assist in targeting of the lumbar spine and instructional videos. The protocol takes ~2 h per animal.

No Illusion of Forever.

A mother and nurse expertly cares for her dangerously immunocompromised sons while making every day count.

Human neural stem cell transplantation improves cognition in a murine model of Alzheimer's disease.

Stem cell transplantation offers a potentially transformative approach to treating neurodegenerative disorders. The safety of cellular therapies is established in multiple clinical trials, including our own in amyotrophic lateral sclerosis. To initiate similar trials in Alzheimer's disease, efficacious cell lines must be identified. Here, we completed a preclinical proof-of-concept study in the APP/PS1 murine model of Alzheimer's disease. Human neural stem cell transplantation targeted to the fimbria fornix significantly improved cognition in two hippocampal-dependent memory tasks at 4 and 16 weeks post-transplantation. While levels of synapse-related proteins and cholinergic neurons were unaffected, amyloid plaque load was significantly reduced in stem cell transplanted mice and associated with increased recruitment of activated microglia. In vitro, these same neural stem cells induced microglial activation and amyloid phagocytosis, suggesting an immunomodulatory capacity. Although long-term transplantation resulted in significant functional and pathological improvements in APP/PS1 mice, stem cells were not identified by immunohistochemistry or PCR at the study endpoint. These data suggest integration into native tissue or the idea that transient engraftment may be adequate for therapeutic efficacy, reducing the need for continued immunosuppression. Overall, our results support further preclinical development of human neural stem cells as a safe and effective therapy for Alzheimer's disease.

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice.

The hippocampus has been the target of stem cell transplantations in preclinical studies focused on Alzheimer's disease, with results showing improvements in histological and behavioral outcomes. The corpus callosum is another structure that is affected early in Alzheimer's disease. Therefore, we hypothesize that this structure is a novel target for human neural stem cell transplantation in transgenic Alzheimer's disease mouse models. This study demonstrates the feasibility of targeting the corpus callosum and identifies an effective immunosuppression regimen for transplanted neural stem cell survival. These results support further preclinical development of the corpus callosum as a therapeutic target in Alzheimer's disease.

Milestone achievement in emerging adulthood in spina bifida: a longitudinal investigation of parental expectations.

AIM: To assess changes over time in parents' expectations of adult milestone achievement (college attendance, full-time job attainment, independent living, marriage, parenthood) for young people with spina bifida, to examine how expectancies relate to actual milestone achievement, and to compare milestone achievement in emerging adults with spina bifida with that of peers with typical development. METHOD: Sixty-eight families of children with spina bifida (mean age 8y 4mo, 37 males, 31 females) and 68 families of children with typical development (mean age 8y 6mo, 37 males, 31 females) participated at Time 1. At all subsequent timepoints, parents of young people with spina bifida were asked to rate their expectations of emerging adulthood milestone achievement. At Time 7, when participants were 22 to 23 years old, milestone achievement was assessed. RESULTS: Parents of young people with spina bifida lowered their expectations over time for most milestones; parents of children with higher cognitive ability reported decreases of lower magnitude. Parent expectancies were optimistic and unrelated to actual milestone achievement. Emerging adults with spina bifida were less likely than individuals with typical development to achieve all milestones. INTERPRETATION: Optimistic parental expectations may be adaptive for children with spina bifida and their families, although it is important for families to set realistic goals. Healthcare providers serve a key role in helping families of young people with spina bifida prepare for emerging adulthood.

Dietary Reversal Ameliorates Short- and Long-Term Memory Deficits Induced by High-fat Diet Early in Life.

A high-fat diet (HFD), one of the major factors contributing to metabolic syndrome, which is associated with an increased risk of neurodegenerative diseases, leads to insulin resistance and cognitive impairment. It is not known whether these alterations are improved with dietary intervention. To investigate the long-term impact of a HFD on hippocampal insulin signaling and memory, C57BL6 mice were placed into one of three groups based on the diet: a standard diet (control), a HFD, or a HFD for 16 weeks and then the standard diet for 8 weeks (HF16). HFD-induced impairments in glucose tolerance and hippocampal insulin signaling occurred concurrently with deficits in both short- and long-term memory. Furthermore, these conditions were improved with dietary intervention; however, the HFD-induced decrease in insulin receptor expression in the hippocampus was not altered with dietary intervention. Our results demonstrate that memory deficits due to the consumption of a HFD at an early age are reversible.

Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.

Global positioning system derived performance measures are responsive indicators of physical activity, disease and the success of clinical treatments in domestic dogs.

OBJECTIVE: To assess the use of Global Positioning System receiver (GPS) derived performance measures for differentiating between: 1) different outdoor activities in healthy dogs; 2) healthy dogs and those with osteoarthritis; 3) osteoarthritic dogs before and after treatment with non-steroidal anti-inflammatory analgesia. DESIGN: Prospective study. ANIMALS: Ten healthy dogs and seven dogs with osteoarthritis of the elbow joint (OA dogs). PROCEDURE: Healthy dogs were walked on a standard route on-lead, off-lead and subjected to playing activity (chasing a ball) whilst wearing a GPS collar. Each dog was walked for five consecutive days. Dogs with OA were subjected to a single off-lead walk whilst wearing a GPS collar, and then administered oral Carprofen analgesia daily for two weeks. OA dogs were then subjected to the same walk, again wearing a GPS collar. RESULTS: GPS derived measures of physical performance could differentiate between on-lead activity, off-lead activity and playing activity in healthy dogs, and between healthy dogs and OA dogs. Variation in the performance measures analysed was greater between individual dogs than for individual dogs on different days. Performance measures could differentiate healthy dogs from OA dogs. OA Dogs treated with Carprofen analgesia showed improvements in their physical performance, which returned to values indistinguishable from those of healthy dogs on nearly all the measures assessed. CONCLUSIONS AND CLINICAL RELEVANCE: GPS derived measures of physical performance in dogs are objective, easy to quantify, and can be used to gauge the effects of disease and success of clinical treatments. Specific stimuli can be used to modulate physical performance beyond the self-governed boundaries that dogs will naturally express when allowed to exercise freely without stimulation.

A histopathological survey of the razor clam Ensis macha (Pharidae) along the Patagonian Argentina coast.

This is the first study performed to determine the health status of the razor clam, Ensis macha, including six different populations along Argentina Patagonian coast and one of Chile. The parasites and pathologies affecting E. macha were analyzed and their prevalence and mean intensity values were calculated. To establish which factors affect the presence and intensity of infection, Generalized Linear Models (GLMs) were applied. Basophilic inclusions, ciliates, coccidians protozoans and turbellarians were found. We report an Aporocotylidae digenean and hemocyte infiltrations. None of the parasites is OIE (World Organisation for Animal Health) notifiable, and none seemed to be pathogenic, with the exception of the digenean. The prevalence of the parasites was affected mainly by environmental factors (such as site of sampling and season) instead of intrinsic conditions of the clam (such as size, condition index, sex and gonadal stage). On the other hand, the maximum intensity of parasites was not only related with cold seasons but also with the partially spawned gonadal stage of E. macha. During this stage, the clams would need to store energy for the next gametogenesis cycle, might be more susceptible to infection by the parasites.

Occurrence, function and evolutionary origins of '2A-like' sequences in virus genomes.

2A is an oligopeptide sequence mediating a ribosome 'skipping' effect, producing an apparent 'cleavage' of polyproteins. First identified and characterized in picornaviruses, '2A-like' sequences are found in other mammalian viruses and a wide range of insect viruses. Databases were analysed using a motif conserved amongst 2A/2A-like sequences. The newly identified 2A-like sequences (30 aa) were inserted into a reporter polyprotein to determine their cleavage activity. Our analyses showed that these sequences fall into two categories. The majority mediated very high (complete) cleavage to separate proteins and a few sequences mediated cleavage with lower efficiency, generating appreciable levels of the uncleaved form. Phylogenetic analyses of 2A-like sequences and RNA-dependent RNA polymerases (RdRps) indicated multiple, independent, acquisitions of these sequences at different stages during virus evolution. Within a virus family, 2A sequences are (probably) homologous, but diverge due to other evolutionary pressures. Amongst different families, however, 2A/2A-like sequences appear to be homoplasic.

Evidence-based assessment in pediatric psychology: measures of psychosocial adjustment and psychopathology.

OBJECTIVE: To provide an evidence-based review of measures of psychosocial adjustment and psychopathology, with a specific focus on their use in the field of pediatric psychology. METHODS: As part of a larger survey of pediatric psychologists from the Society of Pediatric Psychology e-mail listserv (American Psychological Association, APA, Division 54), 37 measures were selected for this psychometric review. Measures that qualified for the review fell into one of the following three categories: (a) internalizing or externalizing rating scales, (b) broad-band rating scales, and (c) self-related rating scales. RESULTS: Psychometric characteristics (i.e., three types of reliability, two types of validity) were strong for the majority of measures reviewed, with 34 of the 37 measures meeting "well-established" evidence-based assessment (EBA) criteria. Strengths and weaknesses of existing measures were noted. CONCLUSIONS: Recommendations for future work in this area of assessment are presented, including suggestions that more fine-grained EBA criteria be developed and that evidence-based "profiles" be devised for each measure.

Practice and education: partnering to address the perioperative nursing shortage.

With the growing shortage of nurses in the workforce, perioperative leaders are facing a significant challenge in recruiting new nurses who are committed to perioperative nursing. One medical center in northern Florida developed a successful summer externship program to introduce nursing students to the perioperative environment. The program incorporates both didactic and clinical experiences. Students who complete the program are better prepared and motivated to choose a career in perioperative nursing. The retention rate for nurses from the externship program who were hired into the OR in which the program was conducted was 89% after two years.