Feasibility of Concussion Essentials: A multimodal intervention for persisting post-concussion symptoms among children and adolescents.

This study examined the feasibility of "Concussion Essentials" (CE), an individualized, multimodal intervention for persisting post-concussion symptoms (pPCS). Thirteen 6-18 year-olds with pPCS at 1-month post-concussion, as determined by the Post Concussion Symptom Inventory - Parent Report (PCSI-P), completed education, physiotherapy, and psychology modules, for up to 8-weeks or until pPCS resolved. Intervention participants were matched to a longitudinal observational cohort who received usual care (n = 13). The study enrolled 70% of participants symptomatic on screening and the dropout rate was <30% between baseline and post-programme assessments (4-weeks to 3-months post-injury). Symptoms improved for 100% of CE participants, with the number of symptomatic items on the PCSI-P reducing from 4-weeks, Median (IQR) = 14.0 (8.0-19.0) to 3-months, Median (IQR) = 1.0 (0.0-5.0). Comparatively, symptoms improved for approximately half of matched usual care participants. CE participants (n = 8) and their parents (n = 11) completed acceptability questionnaires. Most parents (91%) agreed CE was acceptable for children with concussion. All participants agreed CE was appropriate for concussion, while approximately 88% agreed they enjoyed the intervention and would recommend CE to others. Findings suggest CE is a feasible and acceptable treatment for paediatric pPCS. Further investigation within a larger scale randomized clinical trial is warranted.

White matter fiber morphology in persisting postconcussive symptoms and posttraumatic headache after pediatric concussion: a fixel-based analysis.

OBJECTIVE: Posttraumatic headache (PTH) represents the most common acute and persistent postconcussive symptom (PCS) in children after concussion, yet there remains a lack of valid and objective biomarkers to facilitate risk stratification and early intervention in this patient population. Fixel-based analysis of diffusion-weighted imaging, which overcomes constraints of traditional diffusion tensor imaging analyses, can improve the sensitivity and specificity of detecting white matter changes postconcussion. The aim of this study was to investigate whole-brain and tract-based differences in white matter morphology, including fiber density (FD) and fiber bundle cross-section (FC) area in children with PCSs and PTH at 2 weeks after concussion. METHODS: This prospective longitudinal study recruited children aged 5-18 years who presented to the emergency department of a tertiary pediatric hospital with a concussion sustained within the previous 48 hours. Participants underwent diffusion-weighted MRI at 2 weeks postinjury. Whole-brain white matter statistical analysis was performed at the level of each individual fiber population within an image voxel (fixel) to compute FD, FC, and a combined metric (FD and bundle cross-section [FDC]) using connectivity-based fixel enhancement. Tract-based Bayesian analysis was performed to examine FD in 23 major white matter tracts. RESULTS: Comparisons of 1) recovered (n = 27) and symptomatic (n = 16) children, and those with 2) PTH (n = 13) and non-PTH (n = 30; overall mean age 12.99 ± 2.70 years, 74% male) found no fiber-specific white matter microstructural differences in FD, FC, or FDC at 2 weeks postconcussion, when adjusting for age and sex (family-wise error rate corrected p value > 0.05). Tract-based Bayesian analysis showed evidence of no effect of PTH on FD in 10 major white matter tracts, and evidence of no effect of recovery group on FD in 3 white matter tracts (Bayes factor < 1/3). CONCLUSIONS: Using whole-brain fixel-wise and tract-based analyses, these findings indicate that fiber-specific properties of white matter microstructure are not different between children with persisting PCSs compared with recovered children 2 weeks after concussion. These data extend the limited research on white matter fiber-specific morphology while overcoming limitations inherent to traditional diffusion models. Further validation of our findings with a large-scale cohort is warranted.

Discovery of Alpha-1-Antichymotrypsin as a Marker of Delayed Recovery from Concussion in Children.

Of the four million children who experience a concussion each year, 30-50% of children will experience delayed recovery, where they will continue to experience symptoms more than two weeks after their injury. Delayed recovery from concussion encompasses emotional, behavioral, physical, and cognitive symptoms, and as such, there is an increased focus on developing an objective tool to determine risk of delayed recovery. This study aimed to identify a blood protein signature predictive of delayed recovery from concussion in children. Plasma samples were collected from children who presented to the Emergency Department at the Royal Children's Hospital, Melbourne, within 48h post-concussion. This study involved a discovery and validation phase. For the discovery phase, untargeted proteomics analysis was performed using single window acquisition of all theoretical mass spectra to identify blood proteins differentially abundant in samples from children with and without delayed recovery from concussion. A subset of these proteins was then validated in a separate participant cohort using multiple reaction monitoring and enzyme linked immunosorbent assay. A blood protein signature predictive of delayed recovery from concussion was modeled using a Support Vector Machine, a machine learning approach. In the discovery phase, 22 blood proteins were differentially abundant in age- and sex-matched samples from children with (n = 9) and without (n = 9) delayed recovery from concussion, six of whom were chosen for validation. In the validation phase, alpha-1-ACT was shown to be significantly lower in children with delayed recovery (n = 12) compared with those without delayed recovery (n = 28), those with orthopedic injuries (n = 7) and healthy controls (n = 33). A model consisting of alpha-1-ACT concentration stratified children based on recovery from concussion with an 0.88 area under the curve. We have identified that alpha-1-ACT differentiates between children at risk of delayed recovery from those without delayed recovery from concussion. To our knowledge, this is the first study to identify alpha-1-ACT as a potential marker of delayed recovery from concussion in children. Multi-site studies are required to further validate this finding before use in a clinical setting.

Psychological Predictors of Mental Health Difficulties After Pediatric Concussion.

Children often experience mental health difficulties after a concussion. Yet, the extent to which a concussion precipitates or exacerbates mental health difficulties remains unclear. This study aimed to examine psychological predictors of mental health difficulties after pediatric concussion. Children (5 to <18 years of age, M = 11.7, SD = 3.3) with concussion were recruited in a single-site longitudinal prospective cohort study conducted at a tertiary children's hospital (n = 115, 73.9% male). The primary outcomes included internalizing (anxious, depressed, withdrawn behaviors), externalizing (risk-taking, aggression, attention difficulties), and total mental health problems, as measured by the Child Behavior Checklist at 2 weeks (acute) and 3 months (post-acute) after concussion. Predictors included parents' retrospective reports of premorbid concussive symptoms (Post-Concussion Symptom Inventory; PCSI), the child and their family's psychiatric history, child-rated perfectionism (Adaptive-Maladaptive Perfectionism Scale), and child-rated resilience (Youth Resilience Measure). Higher premorbid PCSI ratings consistently predicted acute and post-acute mental health difficulties. This relationship was significantly moderated by child psychiatric history. Furthermore, pre-injury learning difficulties, child psychiatric diagnoses, family psychiatric history, lower resilience, previous concussions, female sex, and older age at injury were associated with greater mental health difficulties after concussion. Pre-injury factors accounted for 23.4-39.9% of acute mental health outcomes, and 32.3-37.8% of post-acute mental health outcomes. When acute mental health was factored into the model, a total of 47.0-68.8% of variance was explained by the model. Overall, in this sample of children, several pre-injury demographic and psychological factors were observed to predict mental health difficulties after a concussion. These findings need to be validated in future research involving larger, multi-site studies that include a broader cohort of children after concussion.

Capillary blood protein markers of posttraumatic headache in children after concussion.

OBJECTIVE: Posttraumatic headache (PTH) represents the most common acute and persistent symptom in children after concussion, yet there is no blood protein signature to stratify the risk of PTH after concussion to facilitate early intervention. This discovery study aimed to identify capillary blood protein markers, at emergency department (ED) presentation within 48 hours of concussion, to predict children at risk of persisting PTH at 2 weeks postinjury. METHODS: Capillary blood was collected using the Mitra Clamshell device from children aged 8-17 years who presented to the ED of the Royal Children's Hospital, Melbourne, Australia, within 48 hours of sustaining a concussion. Participants were followed up at 2 weeks postinjury to determine PTH status. PTH was defined per clinical guidelines as a new or worsened headache compared with preinjury. An untargeted proteomics analysis using data-independent acquisition (DIA) was performed. Principal component analysis and hierarchical clustering were used to reduce the dimensionality of the protein dataset. RESULTS: A total of 907 proteins were reproducibly identified from 82 children within 48 hours of concussion. The mean participant age was 12.78 years (SD 2.54 years, range 8-17 years); 70% of patients were male. Eighty percent met criteria for acute PTH in the ED, while one-third of participants with follow-up experienced PTH at 2 weeks postinjury (range 8-16 days). Hemoglobin subunit zeta (HBZ), cystatin B (CSTB), beta-ala-his dipeptidase (CNDP1), hemoglobin subunit gamma-1 (HBG1), and zyxin (ZYX) were weakly associated with PTH at 2 weeks postinjury based on up to a 7% increase in the PTH group despite nonsignificant Benjamini-Hochberg adjusted p values. CONCLUSIONS: This discovery study determined that no capillary blood protein markers, measured at ED presentation within 48 hours of concussion, can predict children at risk of persisting PTH at 2 weeks postinjury. While HBZ, CSTB, CNDP1, HBG1, and ZYX were weakly associated with PTH at 2 weeks postinjury, there was no specific blood protein signature predictor of PTH in children after concussion. There is an urgent need to discover new blood biomarkers associated with PTH to facilitate risk stratification and improve clinical management of pediatric concussion.

Interactive effects of climate-atmospheric cycling on aquatic communities and ecosystem shifts in mountain lakes of southeastern Tibetan Plateau.

Recent climate warming and atmospheric reactive nitrogen (Nr) deposition are affecting a broad spectrum of physical, ecological and human systems that may be irreversible on a century time scale and have the potential to cause regime shifts in ecological systems. These changes may alter the limnological conditions with important but still unclear effects on lake ecosystems. We present changes in cladoceran with comparisons to diatom assemblages over the past ~200 years from high-resolution, well-dated sediment cores retrieved from six high mountain lakes in the southeastern (SE) margin of the Tibetan Plateau. Our findings suggest that warming and the exponential increase of atmospheric Nr deposition are the major drivers of ecological regime changes. Shifts in cladoceran and diatom communities in high alpine lakes began over a century ago and intensified since 1950 CE, indicating a regional-scale response to anthropogenic climate warming. Zooplankton in the forest lakes showed asynchronous trajectories, with increased Nr deposition as a significant explanatory factor. Forest lakes with higher dissolved organic carbon (DOC) concentrations partially buffered the impacts of Nr deposition with little structural change, while lakes with low DOC display symptoms of resilience loss related to Nr deposition. Biological community compositional turnover in subalpine lakes has shown marked shifts, equivalent to those of low-elevation lakes strongly affected by direct human impacts. This suggests that local effects override climatic forcing and that lake basin features modified by anthropogenic activity act as basin-specific filters of common forcing. Our results indicate that snow and glacial meltwaters along with nutrient enrichment related to climate warming and atmospheric Nr deposition, represent major threats for lake ecosystems, even in remote areas. We reveal that climate and atmospheric contaminants will further impact ecological conditions and alter aquatic food webs in higher altitude biomes if climate and anthropogenic forcing continue.

Fatigue recovery and connected factors following paediatric concussion.

OBJECTIVE: Using a biopsychosocial framework and the three-factor fatigue model, we aimed to (1) plot recovery of fatigue over the 3 months following paediatric concussion and (2) explore factors associated with persisting fatigue during the first 3 months postconcussion. METHODS: 240 children and adolescents aged 5-18 years (M=11.64, SD=3.16) completed assessments from time of injury to 3 months postinjury. Separate linear mixed effects models were conducted for child and parent ratings on the PedsQL-Multidimensional Fatigue Scale to plot recovery across domains (General, Cognitive, Sleep/Rest) and Total fatigue, from 1 week to 3 months postinjury. Two-block hierarchical regression analyses were then conducted for parent and child ratings of fatigue at each time point, with age, sex and acute symptoms in block 1 and child and parent mental health variables added to block 2. RESULTS: There was a significant reduction in both child and parent ratings across the 3 months postinjury for all fatigue domains (all p<0.001). For both child and parent fatigue ratings, child mental health was the most significant factor associated with fatigue at all time points. Adding child and parent mental health variables in the second block of the regression substantially increased the variance explained for both child and parent ratings of fatigue. CONCLUSION: Our findings confirm that fatigue improves during the first 3 months postconcussion and highlights the importance of considering child and parent mental health screening when assessing patients with persisting postconcussive symptoms.

Not all (cells) who wander are lost: Upstream migration as a pervasive mode of amoeboid cell motility.

Leukocytes possess the ability to migrate upstream-against the direction of flow-on surfaces of specific chemistry. Upstream migration was first characterized in vitro for T-cells on surfaces comprised of intracellular adhesion molecule-1 (ICAM-1). Upstream migration occurs when the integrin receptor αLß2 (also known as lymphocyte function-associated antigen-1, or LFA-1) binds to ICAM-1. LFA-1/ICAM-1 interactions are ubiquitous and are widely found in leukocyte trafficking. Upstream migration would be employed after cells come to arrest on the apical surface of the endothelium and might confer an advantage for both trans-endothelial migration and tissue surveillance. It has now been shown that several other motile amoeboid cells which have the responsibility of trafficking from blood vessels into tissues, such as Marginal zone B cells, hematopoietic stem cells, and neutrophils (when macrophage-1 antigen, Mac-1, is blocked), can also migrate upstream on ICAM-1 surfaces. This review will summarize what is known about the basic mechanisms of upstream migration, which cells have displayed this phenomenon, and the possible role of upstream migration in physiology and tissue homeostasis.

Transarterial therapies in patients with hepatocellular carcinoma eligible for transarterial embolization: a US cost-effectiveness analysis.

OBJECTIVES: To assess the cost-effectiveness of transarterial radioembolization (TARE) versus conventional transarterial chemoembolization (cTACE) and drug-eluting beads chemoembolization (DEE-TACE) for patients with unresectable early- to intermediate-stage hepatocellular carcinoma (HCC). DESIGN: A cohort-based Markov model with a five-year time horizon was developed to evaluate the cost-effectiveness of the three embolization treatments. Upon entering the model, patients with HCC received either TARE or one of the two other embolization treatments. Patients remained in a "watch and wait" state for tumor downstaging that allowed them to move to health states such as liver transplant, resection, systemic therapies, or cure. Clinical input parameters were retrieved from the published literature, and where values could not be sourced, assumptions were made and validated by clinical experts. Health benefits were quantified using quality-adjusted life years (QALYs). Cost input parameters were obtained from various sources, including the Medicare Cost Report, IBM® Micromedex RED BOOK, and published literature. RESULTS: At five years, TARE was found to be cost-saving (saving $15,779 per person compared to cTACE) and produced 0.33 more QALYs per person than cTACE. TARE cost $13,696 more but produced 0.33 more QALYs than DEE-TACE, with an incremental cost-effectiveness ratio of $41,474 per QALY gained at five years. After accounting for parameter uncertainty, the likelihood of TARE being cost-effective was at least 90% against all comparators at a cost-effectiveness threshold of $100,000 per QALY gained. CONCLUSIONS: TARE produces more QALYs than cTACE and DEE-TACE, with a high probability of being cost-effective against both comparators.

The Barcelona Clinic Liver Cancer guideline recommends the use of transarterial radioembolization (TARE), conventional (cTACE), or drug-eluting bead transarterial chemoembolization (DEE-TACE) for treating hepatocellular carcinoma (HCC). This study evaluated the cost-effectiveness of TARE versus two alternative embolization treatments (cTACE and DEE-TACE) in treating patients with unresectable early- to intermediate-stage HCC.A cohort-based Markov model was developed to analyze the costs and benefits of these treatments from a US healthcare perspective within a 5-year time horizon. A 20-year time horizon was assessed as a scenario. In the model, patients were assigned to receive TARE, cTACE, or DEE-TACE and remained in the "watch and wait" stage for tumor downstaging. Data used in the model was taken from previous studies and in consultation with clinical experts. The benefits of the treatments were measured by considering the impact on the patient's quality of life. The costs associated with the treatments were obtained from various sources, including reports, publicly available databases, and published literature.The findings show that TARE is not only cost-saving compared to cTACE but also results in a higher number of quality-adjusted life years (QALYs) per person. While TARE was more expensive than DEE-TACE, it produced more QALYs, further indicating more favorable patient outcomes and overall treatment effectiveness. These findings could potentially impact resource allocation and decision-making for the treatment of HCC.

Examining post-concussion white matter change in a pediatric sample.

Diffusion-Weight Imaging (DWI) is increasingly used to explore a range of outcomes in pediatric concussion, particularly the neurobiological underpinnings of symptom recovery. However, the DWI findings within the broader pediatric concussion literature are mixed, which can largely be explained by methodological heterogeneity. To address some of these limitations, the aim of the present study was to utilize internationally- recognized criteria for concussion and a consistent imaging timepoint to conduct a comprehensive, multi-parametric survey of white matter microstructure after concussion. Forty-three children presenting with concussion to the emergency department of a tertiary level pediatric hospital underwent neuroimaging and were classified as either normally recovering (n = 27), or delayed recovering (n = 14) based on their post-concussion symptoms at 2 weeks post-injury.We combined multiple DWI metrics across four modeling approaches using Linked Independent Component Analysis (LICA) to extract several independent patterns of covariation in tissue microstructure present in the study cohort. Our analysis did not identify significant differences between the symptomatic and asymptomatic groups and no component significantly predicted delayed recovery. If white matter microstructure changes are implicated in delayed recovery from concussion, these findings, alongside previous work, suggest that current diffusion techniques are insufficient to detect those changes at this time.

Mouse primary follicles experience slow growth rates after activation and progressive increases that influence the duration of the primary follicle phase†.

There are conflicting estimates of the duration of mouse primary follicle development. An accurate determination is needed for studies examining preantral follicle survival and mathematical modeling of folliculogenesis. Primary follicle granulosa cell proliferation rates are low and variable, which may explain the variation in duration estimates. In the present study, female C57Bl6/J mice were exposed to bromodeoxyuridine for 48 hours, to label the proliferating granulosa cells in a large proportion of primary follicles. The bromodeoxyuridine-containing water was then withdrawn and replaced with drug-free water and the mice were euthanized at 0, 1, 3, 6, 10, or 13 days post-bromodeoxyuridine withdrawal. Granulosa cells were bromodeoxyuridine labeled in 48% of primary follicles at day 0, but this decreased to 5% over the 13-day period, as the labeled primary follicles progressed to the secondary follicle stage. Curve-fitting estimated that the last of the bromodeoxyuridine-labeled primary follicles would progress to the secondary stage by 13.7 days. Mathematical models that assumed constant rates of primary follicle proliferation were fitted to the data, but the observed pattern of bromodeoxyuridine-labeled primary follicle disappearance could not be replicated. The level of immunoreactivity for bromodeoxyuridine and proliferating-cell nuclear antigen in primary follicles revealed follicles with no granulosa cell proliferation during the 48-h bromodeoxyuridine-exposure period had resumed proliferation 1 or 3 days later. Therefore, primary follicle granulosa cells proliferate after follicle activation, but proliferation rates gradually increase as the follicle develops. Prior estimates of primary follicle duration are inaccurate due to the assumption that follicles develop at a constant rate.

Cerebral blood flow in children with persisting postconcussive symptoms and posttraumatic headache at 2 weeks postconcussion.

OBJECTIVE: Persisting postconcussive symptoms (pPCS), particularly headache, can significantly disrupt children's recovery and functioning. However, the underlying pathophysiology of these symptoms remains unclear. The goal in this study was to determine whether pPCS are related to cerebral blood flow (CBF) at 2 weeks postconcussion. The authors also investigated whether variations in CBF can explain the increased risk of acute posttraumatic headache (PTH) in female children following concussion. METHODS: As part of a prospective, longitudinal study, the authors recruited children 5-18 years old who were admitted to the emergency department of a tertiary pediatric hospital with a concussion sustained within 48 hours of admission. Participants underwent pseudocontinuous arterial spin labeling MRI at 2 weeks postconcussion to quantify global mean gray and white matter perfusion (in ml/100 g/min). Conventional frequentist analysis and Bayesian analysis were performed. RESULTS: Comparison of recovered (n = 26) and symptomatic (n = 12) groups (mean age 13.15 years, SD 2.69 years; 28 male) found no differences in mean global gray and white matter perfusion at 2 weeks postconcussion (Bayes factors > 3). Although female sex was identified as a risk factor for PTH with migraine features (p = 0.003), there was no difference in CBF between female children with and without PTH. CONCLUSIONS: Global CBF was not associated with pPCS and female PTH at 2 weeks after pediatric concussion. These findings provide evidence against the use of CBF measured by arterial spin labeling as an acute biomarker for pediatric concussion recovery.

Cost Burden and Cost Influencers of Inferior Vena Cava Filter Placement and Retrieval among Medicare Beneficiaries with Acute Venous Thromboembolism.

PURPOSE: To examine the frequency, costs, and cost influencers of inferior vena cava filters (IVCFs) placements and retrievals among a national sample of patients using Medicare data. MATERIALS AND METHODS: This retrospective cohort study used the U.S. Medicare 100% database, a nationally representative sample of all U.S. patients aged ≥65 years, from 2014 through 2020. Procedures and clinical characteristics were identified from the diagnosis and procedure codes on Medicare claims. Beneficiaries aged ≥65 years with newly diagnosed venous thromboembolism (VTE) were identified and followed to obtain data on IVCF placements and retrievals. Data on the costs of the index IVCF procedures and any subsequent IVCF placements and retrievals were obtained. Multivariate models were used to estimate the impact of patient and clinical characteristics on costs. RESULTS: Among 501,216 patients with newly diagnosed VTE, 4,995 (1%) received an IVCF placement; of these, 1,215 (24.3%) had a retrieval procedure. Beneficiaries with IVCF placements and retrievals differed from a demographic and clinical perspective than from those without. Costs varied by the site of service, VTE acuity, and VTE type. Cost influencers included age, race, census region, service location, and VTE type. CONCLUSIONS: IVCF placement costs were driven by baseline patient characteristics (age, race, geographic residence, acute VTE diagnosis, and inpatient site of service), whereas retrieval costs were driven by age and deep vein thrombosis diagnosis. Strategies to mitigate the retrieval costs or the need to retrieve IVCFs may reduce the overall cost burden of IVCFs.

Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling.

Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.

Autophagy inhibition impairs leukemia stem cell function in FLT3-ITD AML but has antagonistic interactions with tyrosine kinase inhibition.

The FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML). FLT3 tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy but fail to target leukemia stem cells (LSC) and do not generate sustained responses. Autophagy is an important cellular stress response contributing to hematopoietic stem cells (HSC) maintenance and promoting leukemia development. Here we investigated the role of autophagy in regulating FLT3-ITD AML stem cell function and response to TKI treatment. We show that autophagy inhibition reduced quiescence and depleted repopulating potential of FLT3-ITD AML LSC, associated with mitochondrial accumulation and increased oxidative phosphorylation. However, TKI treatment reduced mitochondrial respiration and unexpectedly antagonized the effects of autophagy inhibition on LSC attrition. We further show that TKI-mediated targeting of AML LSC and committed progenitors was p53-dependent, and that autophagy inhibition enhanced p53 activity and increased TKI-mediated targeting of AML progenitors, but decreased p53 activity in LSC and reduced TKI-mediated LSC inhibition. These results provide new insights into the role of autophagy in differentially regulating AML stem and progenitor cells, reveal unexpected antagonistic effects of combined oncogenic tyrosine kinase inhibition and autophagy inhibition in AML LSC, and suggest an alternative approach to target AML LSC quiescence and regenerative potential.

Improving subacute management of post concussion symptoms: a pilot study of the Melbourne Paediatric Concussion Scale parent report.

Aim: To pilot a modification of the Post Concussion Symptom Inventory, the Melbourne Paediatric Concussion Scale (MPCS) and examine its clinical utility. Materials & methods: A total of 40 families of concussed children, aged 8-18 years, were recruited from the emergency department. Parent responses to the MPCS in the emergency department and 2-weeks post injury determined child symptomatic status. Association between MPCS symptom endorsement and symptomatic group status was examined. Results: All additional MPCS items were endorsed by at least 25% of the parents of symptomatic children at 2 weeks. MPCS items were classified into nine symptom domains, with most falling in mood, neurological, autonomic and vestibular domains. Conclusion: The additional items and domain classifications in the MPCS have the potential to improve subacute diagnostic precision, monitoring of clinical recovery and identification of appropriate interventions post pediatric concussion.

Population-Based Disparities in Inferior Vena Cava Filter Procedures Among Medicare Enrollees With Acute Venous Thromboembolism.

PURPOSE: Venous thromboembolism (VTE) imposes a significant clinical and financial burden on patients and society. Inferior vena cava filters (IVCFs) are considered for patients with absolute contraindications or failures of anticoagulation. However, studies examining the population-based disparities of IVCF placement and retrieval are limited. The association between patient and clinical characteristics in the likelihood of and time to IVCF placement and retrievals in a nationally representative cohort was examined. METHODS: Medicare patients aged ≥65 years with index VTE claims between 2015 and 2018 were followed through 2019 to identify IVCF placements and retrievals. Rates were compared using survival analysis methods. RESULTS: Of the 516,978 patients with VTE diagnoses, 5,864 (1.1%) had IVCFs placed, and 1,884 (32.1%) of those underwent retrieval procedures. Placement and retrieval rates varied significantly by demographics, comorbidity burden, and geographic region. From Cox regression, older age (hazard ratio [HR], 1.26; P < .0001), higher baseline comorbidity (Elixhauser) score (HR, 1.07; P < .0001), and outpatient (vs inpatient) site of VTE service (HR, 2.11; P < .0001) were associated with increased frequency of IVCF placement. The rate of retrieval was significantly lower for men (HR, 0.83; P = .0393), patients with higher comorbidity scores (HR, 0.95; P = .0037), and those with outpatient (vs inpatient) VTE sites of service (HR, 0.77; P = .0173). Neither facility- nor county-level characteristics were significantly associated with placements or retrievals. CONCLUSIONS: This large cohort of Medicare beneficiaries with newly diagnosed VTE demonstrated inequities in IVCF placement and retrieval.

Identification and Subtyping of Salmonella Isolates Using Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF).

Subtyping of bacterial isolates of the same genus and species is an important tool in epidemiological investigations. A number of phenotypic and genotypic subtyping methods are available; however, most of these methods are labor-intensive and time-consuming and require considerable operator skill and a wealth of reagents. Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF), an alternative to conventional subtyping methods, offers a rapid, reproducible method for bacterial identification with a high sensitivity and specificity and at minimal cost. The purpose of this study was to determine the feasibility of using MALDI-TOF to differentiate between six Salmonella serovars recovered from experimental microcosms inoculated with known strains of Salmonella. Following the establishment of a MALDI-TOF reference library for this project, the identity of 843 Salmonella isolates recovered from these microcosms was assessed using both MALDI-TOF and conventional methods (serotyping/PCR). All 843 isolates were identified as being Salmonella species. Overall, 803/843 (95%) of these isolates were identified similarly using the two different methods. Positive percent agreement at the serovar level ranged from 79 to 100%, and negative percent agreement for all serovars was greater than 98%. Cohen's kappa ranged from 0.85 to 0.98 for the different serovars. This study demonstrates that MALDI-TOF is a viable alternative for the rapid identification and differentiation of Salmonella serovars.