Healthcare Cost of Multiple Sclerosis and in Relation to Disability Level in Alberta.

BACKGROUND: We aimed to (1) report updated estimates of direct healthcare costs for people living with MS (pwMS), (2) contrast costs to a control population and (3) explore differences between disability levels among pwMS. METHODS: Administrative data were used to identify adult pwMS (MS cohort) and without (control cohort) in Alberta, Canada; disability level (based on the Expanded Disability Status Scale) among pwMS was estimated. One- and two-part generalized linear models with gamma distribution were used to estimate the incremental direct healthcare cost (2021 $CDN) of MS during a 1-year observation period. RESULTS: Adjusting for confounders, the total healthcare cost ratio was higher in the MS cohort (n = 13,089) versus control (n = 150,080) (5.24 [95% CI: 5.08, 5.41]) with a predicted incremental cost of $15,016 (95% CI: $14,497, $15,535) per person-year. Among the MS cohort, total predicted direct healthcare costs were higher with greater disability, $14,430 (95% CI: $13,980, $14,880) to $58,697 ($51,514, $65,879) per person-year in mild and severe disability, respectively. The primary health resource cost component shifted from disease-modifying therapies in mild disability to supportive care in moderate and severe disability. CONCLUSION: Adult pwMS had greater direct healthcare costs than those without. Extrapolating to the population level (where 14,485 adult pwMS were identified in the study), it is estimated that $218 million per year in healthcare costs may be attributable to MS in Alberta. The significantly larger economic impact associated with greater disability underscores the importance of preventing or delaying disease progression and functional impairment in MS.

uPAR Immuno-PET in Pancreatic Cancer, Aging, and Chemotherapy-Induced Senescence.

Identifying cancer therapy resistance is a key time-saving tool for physicians. Part of chemotherapy resistance includes senescence, a persistent state without cell division or cell death. Chemically inducing senescence with the combination of trametinib and palbociclib (TP) yields several tumorigenic and prometastatic factors in pancreatic cancer models with many potential antibody-based targets. In particular, urokinase plasminogen activator receptor (uPAR) has been shown to be a membrane-bound marker of senescence in addition to an oncology target. Methods: Here, 2 antibodies against murine uPAR and human uPAR were developed as immuno-PET agents to noninvasively track uPAR antigen abundance. Results: TP treatment increased cell uptake both in murine KPC cells and in human MiaPaCa2 cells. In vivo, subcutaneously implanted murine KPC tumors had high tumor uptake with the antimurine uPAR antibody independently of TP in young mice, yet uPAR uptake was maintained in aged mice on TP. Mice xenografted with human MiaPaCa2 tumors showed a significant increase in tumor uptake on TP therapy when imaged with the antihuman uPAR antibody. Imaging with either uPAR antibody was found to be more tumor-selective than imaging with [18F]FDG or [18F]F-DPA-714. Conclusion: The use of radiolabeled uPAR-targeting antibodies provides a new antibody-based PET imaging candidate for pancreatic cancer imaging as well as chemotherapy-induced senescence.

Neighborhood ethnoracial diversity and positive psychotic symptoms among youth at high-risk and healthy comparisons.

Neighborhood ethnoracial composition has been associated with schizophrenia, but mechanisms are unclear. This study investigates the moderators and mediators of the association between neighborhood ethnoracial diversity and positive symptoms among youth at clinical high-risk for psychosis (CHR-P) and healthy comparisons (HC). Data were collected as part of The North American Prodrome Longitudinal Study and included 492 youth at CHR-P and 136 HCs. Neighborhood ethnoracial diversity measures the probability that two people chosen at random will be from different ethnoracial groups. Attenuated positive symptoms were derived from the Scale of Prodromal Symptoms. Peer victimization and discriminatory experiences were constructed as latent variables. Using structural equation modeling, this study tested the relationship of these variables and included the following covariates: age, sex, neighborhood poverty, and depressive symptoms. Greater neighborhood ethnoracial diversity was associated with reduced positive symptoms among ethnoracial minorities at CHR-P (ß=-3.78; 95 % CI [-6.61, -0.84]). Fewer life events of peer victimization (ß=-0.13; 95 % CI [-0.24, -0.03]) leading to perceived ethnoracial discrimination (ß=0.56; 95 % CI [0.45, 0.67]) mediated 15.06 % of this association. These findings deepen our understanding of the social determinants of psychosis and may help develop effective interventions to prevent psychosis, especially among ethnoracial minority youth at high risk.

Proximal Tubule Secretory Clearance, Injury, and Kidney Viability in Cirrhosis.

OBJECTIVES: Cirrhosis affects all structures of the kidney, in particular the tubules which are responsible for secretion of protein-bound metabolites and electrolyte/water homeostasis. Yet, prevailing assessments of kidney function focus solely on glomerular filtration rate (GFR) which may incompletely reflect these processes. We sought to characterize markers of tubular function, injury, and viability in patients with and without cirrhosis. METHODS: We recruited outpatients undergoing liver transplantation evaluation for a collection of plasma and 24-hour urine, matching by GFR to control participants without cirrhosis. We measured urinary kidney injury molecule-1 (KIM-1), a marker of proximal tubular injury, as well as epidermal growth factor (EGF), a marker of viability necessary for tubular epithelial cell proliferation after injury. We also estimated secretory clearance by measuring several highly secreted endogenous metabolites in urine and plasma. RESULTS: We recruited 39 patients with cirrhosis (mean MELD-Na 17±4, Child-Pugh 8±2, eGFR 66±20 ml/min/1.73m2) and 58 GFR-matched controls without cirrhosis (eGFR 66±21 ml/min/1.73m2). Urinary KIM-1 was 4.4-fold higher than controls (95% CI:2.9-6.5), and EGF averaged 7.41-fold higher than controls (95% CI:2.15-25.53). We found that of 8 solutes, 5 had significantly greater kidney clearance in cirrhosis (1.3-2.1-fold higher): indoxyl sulfate, p-cresol sulfate, pyridoxic acid, tiglylglycine, and xanthosine. CONCLUSIONS: Cirrhosis was characterized by molecular signs of tubular injury in stable outpatients without acute kidney injury, accompanied by largely preserved tubular secretory clearance and greater signs of tubular viability. Within the limitations of the study, this suggests a phenotype of chronic ischemic injury but with initial preservation of tubular function in cirrhosis.

Impact of adverse childhood experiences on risk for internalizing psychiatric disorders in youth at clinical high-risk for psychosis.

INTRODUCTION: Research has established that adverse childhood experiences (ACEs) confer risk for psychiatric diagnoses, and that protective factors moderate this association. Investigation into the effect of protective factors in the relationship between ACEs and internalizing disorders (e.g., depression, anxiety) is limited in high-risk groups. The present study investigated the relationship between ACEs and risk for internalizing disorders in youth at clinical high risk for psychosis (CHR-P) and tests the hypothesis that protective factors moderate this relationship. METHODS: 688 participants aged 12-30 (M = 18; SD = 4.05) meeting criteria for CHR-P were administered measures of child adversity, protective factors (SAVRY), and diagnostic assessment (SCID- 5). Logistic regression tested whether ACEs predicted internalizing disorders. Moderation regression analyses determined whether these associations were weaker in the presence of protective factors. RESULTS & CONCLUSIONS: Higher levels of ACEs predicted history of depressive disorder (ß = 0.26(1.30), p < .001), self-harm/suicide attempts (ß = 0.34(1.40), p < .001), and substance use (ß = 0.14(1.15), p = .04). Childhood sexual abuse (ß = 0.77(2.15), p = .001), emotional neglect (ß = 0.38(1.46), p = .05), and psychological abuse (ß = 0.42(1.52), p = .04), predicted self- harm/suicide attempts. Sexual abuse (ß = 1.00 (2.72), p = .001), and emotional neglect (ß = 0.53(1.71), p = .011), were also linked to depressive disorder. There was no association between ACEs and anxiety disorder, and no moderation effect of protective factors in the relationship between ACEs and psychiatric outcomes. These findings add nuance to a growing literature linking ACEs to psychopathology and highlight the importance of investigation into the mechanisms that may buffer this relationship.

Non-breeding conditions induce carry-over effects on survival of migratory birds.

Identifying the processes that limit populations is a foundational objective of ecology and an urgent need for conservation. For migratory animals, researchers must study individuals throughout their annual cycles to determine how environmental conditions limit demographic rates within each period of the annual cycle and also between periods through carry-over effects and seasonal interactions.1,2,3,4,5,6 Our poor understanding of the rates and causes of avian migration mortality7 hinders the identification of limiting factors and the reversal of widespread avian population declines.8,9 Here, we implement new methods to estimate apparent survival (hereafter survival) during migration directly from automated telemetry data10 in Kirtland's Warblers (Setophaga kirtlandii) and indirectly from mark-recapture data in Black-throated Blue Warblers (S. caerulescens). Previous experimental and observational studies of our focal species and other migratory songbirds have shown strong effects of Caribbean precipitation and habitat quality on food availability,11,12,13,14 body condition,12,13,14,15,16,17,18,19 migration timing,11,12,15,16,20,21,22,23 natal dispersal,24,25 range dynamics,26 reproductive success,20,22,27 and annual survival.18,19,20,23,28,29,30,31 Building on this research, we test the hypotheses that environmental conditions during the non-breeding period affect subsequent survival during spring migration and breeding. We found that reduced precipitation and environmental productivity in the non-breeding period strongly influenced survival in both species, primarily by reducing survival during spring migration. Our results indicate that climate-driven environmental conditions can carry over to affect survival in subsequent periods and thus likely play an important role in year-round population dynamics. These lethal carry-over effects may be widespread and are likely magnified by intensifying climate change.

Disparities in the Utilization of MRI for Prostate Cancer Detection: A Population-Based Study.

BACKGROUND: Racial disparities exist in prostate cancer (PCa) care and outcomes. Ultrasound-guided biopsy may miss a significant portion of clinically significant PCa while magnetic resonance imaging (MRI) improves its detection. This study aims to investigate demographic and SES factors influencing MRI utilization for PCa detection. METHODS: SEER-Medicare data were used to assess use of pre-diagnostic MRI in 90,908 patients diagnosed with primary PCa (2012-2019). Modified Poisson regression models adjusted for socioeconomic factors such as income, education, Medicare buy-in and dual eligibility were used to examine factors associated with MRI use. All statistical tests were two-sided. RESULTS: Pre-diagnostic MRI utilization increased substantially between 2012 (3.8%) and 2019 (32.6%). The disparity in utilization between non-Hispanic Black and non-Hispanic White patients decreased by more than half from 43% (RR = 0.57, 95%CI = 0.48-0.67) in 2012 to 20% (RR = 0.80, 95%CI = 0.74-0.86) in 2019. Rural residents were 35% less likely (RR = 0.65, 95%CI = 0.61-0.69) to undergo MRI, while those in the Central US (vs West) were 49% less likely (RR = 0.49, 95%CI = 0.48-0.51). No significant disparities in MRI use were identified between ages ≥75 and 64-75. SES factors associated with MRI were income, education, Medicare buy-in and dual eligibility. CONCLUSIONS: This study revealed increased MRI utilization over time including among those 75 and older. Racial disparities decreased, while wide urban/rural disparities remained. Targeted public health interventions should focus on geographical factors, as "urban/rural designations" and "US region" were associated with the most prominent disparities. Future research should explore pathways contributing to these disparities, using a multidisciplinary approach, including geographical studies, to help eliminate healthcare inequities.

Heterogeneity of Salmonella enterica lipopolysaccharide counteracts macrophage and antimicrobial peptide defenses.

Salmonella enterica is comprised of over 2,500 serovars, in which non-typhoidal serovars (NTS), Enteritidis (SE), and Typhimurium (STM) are the most clinically associated with human infections. Although NTS have similar genetic elements to cause disease, phenotypic variation including differences in lipopolysaccharide (LPS) composition may control immune evasion. Here, we demonstrate that macrophage host defenses and LL-37 antimicrobial efficacy against SE and STM are substantially altered by LPS heterogeneity. We found that SE evades macrophage killing by inhibiting phagocytosis while STM survives better intracellularly post-phagocytosis. SE-infected macrophages failed to activate the inflammasomes and subsequently produced less interleukin-1ß (IL-1ß), IL-18, and interferon λ. Inactivation of LPS biosynthesis genes altered LPS composition, and the SE LPS-altered mutants could no longer inhibit phagocytosis, inflammasome activation, and type II interferon signaling. In addition, SE and STM showed differential susceptibility to the antimicrobials LL-37 and colistin, and alteration of LPS structure substantially increased susceptibility to these molecules. Collectively, our findings highlight that modification of LPS composition by Salmonella increases resistance to host defenses and antibiotics.

Neurophysiological patterns reflecting vulnerability to delirium subtypes: a resting-state EEG and event-related potential study.

Delirium is a common and acute neurocognitive disorder in older adults associated with increased risk of dementia and death. Understanding the interaction between brain vulnerability and acute stressors is key to delirium pathophysiology, but the neurophysiology of delirium vulnerability is not well defined. This study aimed to identify pre-operative resting-state EEG and event-related potential markers of incident delirium and its subtypes in older adults undergoing elective cardiac procedures. This prospective observational study included 58 older participants (mean age = 75.6 years, SD = 7.1; 46 male/12 female); COVID-19 restrictions limited recruitment. Baseline assessments were conducted in the weeks before elective cardiac procedures and included a 4-min resting-state EEG recording (2-min eyes open and 2-min eyes closed), a 5-min frequency auditory oddball paradigm recording, and cognitive and depression examinations. Periodic peak power, peak frequency and bandwidth measures, and aperiodic offsets and exponents were derived from resting-state EEG data. Event-related potentials were measured as mean component amplitudes (first positive component, first negative component, early third positive component, and mismatch negativity) following standard and deviant auditory stimuli. Incident delirium occurred in 21 participants: 10 hypoactive, 6 mixed, and 5 hyperactive. Incident hyperactive delirium was associated with higher pre-operative eyes open (P = 0.045, d = 1.0) and closed (P = 0.036, d = 1.0) aperiodic offsets. Incident mixed delirium was associated with significantly larger pre-operative first positive component amplitudes to deviants (P = 0.037, d = 1.0) and larger third positive component amplitudes to standards (P = 0.025, d = 1.0) and deviants (P = 0.041, d = 0.9). Other statistically non-significant but moderate-to-large effects were observed in relation to all subtypes. We report evidence of neurophysiological markers of delirium risk weeks prior to elective cardiac procedures in older adults. Despite being underpowered due to COVID-19-related recruitment impacts, these findings indicate pre-operative dysfunction in neural excitation/inhibition balance associated with different delirium subtypes and warrant further investigation on a larger scale.

Beyond the Descriptive: A Comprehensive, Multi-domain Validation of Symptom Trajectories for Individuals at Clinical High Risk for Psychosis.

BACKGROUND: Although the Clinical High-Risk for Psychosis (CHR-P) criteria are widely used to ascertain individuals at heightened risk for imminent onset of psychosis, it remains controversial whether CHR-P status define a diagnostic construct in its own right. In a prior study, CHR-P non-converters were observed to follow three distinct trajectories in symptoms and functioning: remission, partial remission, and maintenance of symptoms and functional impairments at subthreshold levels of intensity. METHODS: Here, we utilized the North American Prodrome Longitudinal Study Phase 3 (NAPLS3) sample (N = 806) to determine whether: 1) the same trajectory groups can be detected when assessing symptoms at 2-month intervals over an 8-month period and 2) the resulting trajectory groups differ from each other and from healthy controls and converting CHR-P cases in terms of risk factors, comorbidities, and functional outcomes. RESULTS: Three distinctive subgroups within the CHR non-converters were identified, largely paralleling those previously observed. Importantly, these extracted groups, along with non-CHR controls and CHR converters, differ from each other significantly with respect to putative etiological risk factors (e.g., predicted risk scores, physiological and self-report measures of stress), affective comorbidities, as well as functional outcomes, providing converging evidence supporting the validity of the identified trajectory groups. CONCLUSIONS: This pattern, along with the fact that even the subgroup of CHR-P nonconverters showing a remission trajectory deviated from healthy controls, supports treating the CHR-P syndrome not just as a status that denotes risk for onset of full psychosis, but also as a marker of ongoing distress for a population in need of interventions.

Psychometric Analysis of the Hip Disability and Osteoarthritis Outcome Score (HOOS).

Hip Disability and Osteoarthritis Outcome Survey (HOOS) was developed as a region- and disease-specific outcome to assess hip disability. Despite the use of the HOOS in clinical practice and research, psychometric analyses of the scale in a large dataset of patients have not been performed. As such, the purposes of this study were to assess the structural validity of the HOOS in patients who underwent a total hip arthroplasty. Data were obtained from the Surgical Outcome System (SOS) global registry. Confirmatory factor analysis (CFA) was conducted to assess the scale structure of the 40-item HOOS and exploratory factor analysis (EFA) was conducted to identify a parsimonious scale structure. The parsimonious model identified was subjected to multi-group and longitudinal invariance testing and LGC modeling. The original five-factor, 40-item HOOS did not meet recommended model fit indices values (CFI = 0.822, TLI = 0.809, IFI = 0.822, RMSEA = 0.085). Alternate model generation identified an alternative model (i.e., HOOS-9). Sound model fit was identified for the HOOS-9 (CFI = 0.974, TLI = 0.961, RMSEA = 0.046). Invariance testing criteria were also met between groups (i.e., age and sex) and across time. Lastly, a nonlinear growth trajectory was identified in responses pertaining to hip disability. The original scale structure of the 40-item HOOS was not supported. The HOOS-9 met contemporary model fit recommendations, along with multi-group and longitudinal invariance testing. Our findings support the preliminary use of the HOOS-9 to assess hip function and disability in research and clinical practice.

Repolarization Injury and Occurrence of Torsades de Pointes During Acute Takotsubo Syndrome.

Background: During takotsubo syndrome (TS), QTc prolongation is common, reflecting repolarization injury and providing the substrate for torsades de pointes (TdP). TdP has been reported sporadically in TS, yet QTc prolongation and TdP risk are often overlooked during management. Objectives: In TS patients, we sought to document TdP incidence, characteristics of patients with TdP, and association of QTc with postdischarge survival. Methods: Among consecutive TS patients at a single institution, we documented admission and discharge QTc, TdP incidence, and postdischarge 1-year mortality from 2006 to 2019. For perspective regarding TdP-TS risk, we characterized all published TdP cases from 2003 to 2022. Results: Of 259 patients, median age was 68 (range: 59-77) years; 92% were female. The QTc interval was prolonged (≥460 ms) on admission in 129 (49.8%) patients and at discharge in 140 (54%) patients. QTc was ≥500 ms either on admission or at discharge in 98 (37.8%) patients. In-hospital TdP incidence was 0.8%. Postdischarge mortality was associated with admission but not discharge, QTc: <460 ms (1.6%); 460-499 ms (12.6%); ≥500 ms (8.8%); P = 0.0056. Among 38 published TdP-TS cases, 80% of TdP events were within 48 hours of hospitalization, 90% of events occurred with QTc ≥500 ms, and 47.5% of events occurred with QTc ≥600 ms. Conditions associated with TdP risk were present in fewer than one-third of patients. Conclusions: During TS, QTc ≥500 ms was frequent. TdP incidence was low, with unpredictable occurrence and observed almost entirely with QTc ≥500 ms. A normal admission QTc was associated with >98% survival at 1-year postdischarge.

Migratory lifestyle carries no added overall energy cost in a partial migratory songbird.

Seasonal bird migration may provide energy benefits associated with moving to areas with less physiologically challenging climates or increased food availability, but migratory movements themselves may carry high costs. However, time-dynamic energy profiles of free-living migrants-especially small-bodied songbirds-are challenging to measure. Here we quantify energy output and thermoregulatory costs in partially migratory common blackbirds using implanted heart rate and temperature loggers paired with automated radio telemetry and energetic modelling. Our results show that blackbirds save considerable energy in preparation for migration by decreasing heart rate and body temperature 28 days before departure, potentially dwarfing the energy costs of migratory flights. Yet, in warmer wintering areas, migrants do not appear to decrease total daily energy expenditure despite a substantially reduced cost of thermoregulation. These findings indicate differential metabolic programmes across different wintering strategies despite equivalent overall energy expenditure, suggesting that the maintenance of migration is associated with differences in energy allocation rather than with total energy expenditure.

Food insecurity and the consumption of plant-centered meals and high sodium foods among students at three large state universities.

Objective: To examine the associations between food insecurity and plant-centered meal consumption and other sodium-related dietary behaviors among university students. Methods: A web-based survey of students at three California state universities was conducted between August 2018 to May 2019. Multivariable logistic regressions examined the associations between food insecurity and four sodium-related dietary behaviors. Interaction terms were introduced to assess if race/ethnicity moderated these associations. Results: High food insecurity was associated with increased odds of reporting 'likely to order' plant-centered meals (AOR = 1.55, 95% CI = 1.16-2.05). Moderate food insecurity was associated with increased odds of frequently eating processed foods (AOR = 1.40, 95% CI = 1.13-1.74). No moderation effects were found for race/ethnicity. Conclusions: University students with high food insecurity appeared receptive to ordering plant-centered meals, whereas those with moderate food insecurity consumed more processed foods. State universities should encourage and offer more low-sodium, plant-centered meal options in their food venues, on- and off-campus, to promote student health.

Serum Cytokine Panels in Pediatric Clinical Practice.

BACKGROUND: Cytokines are soluble signaling proteins that regulate inflammation and coordinate immune responses. Serum cytokine assays are increasingly used in medical practice, yet our understanding of cytokines as biomarkers for disease remains limited. OBJECTIVES: We aimed to analyze real-world single center usage of a multiplexed cytokine panel, correlate its results with diagnosis and severity, and explore its utility in pediatric practice. METHODS: A multiplexed cytokine panel, able to return same-day results, was implemented in April 2020 at our institution and its performance was validated for clinical use. Coded patient data were collected using a REDCap database, and correlations between cytokine levels and outcomes of interest were analyzed retrospectively. RESULTS: Cytokine levels correlate with acuity of care, with patients admitted to the pediatric intensive care unit (PICU) having the highest cytokine values. Patients with familial HLH (fHLH) showed prominent peaks in IFNγ, IL-10, and TNF, while patients with sepsis exhibited high IL-6 and IL-8 with relatively modest IFNγ, and cytokine release syndrome (CRS) post-CAR T cell therapy often demonstrated pan-panel positivity at peak levels, with a similar pattern as that of fHLH. A ratio of [IFNγ]+[IL-10]/[IL-6]+[IL-8] levels was able to distinguish fHLH and CRS from severe sepsis. CONCLUSIONS: Cytokine levels correlate with severity of illness and can help differentiate between syndromes that present similarly, including fHLH and CRS compared to sepsis. Cytokine panels can be used as biomarkers to inform diagnosis and management decisions, but significant work remains to dissect complex clinical patterns of disease.

TGF-ß and RAS jointly unmask primed enhancers to drive metastasis.

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor ß (TGF-ß) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-ß and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-ß. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-ß gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth.

Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.

High ferritin is an important and sensitive biomarker for the various forms of hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system at UPMC Children's Hospital where serum ferritin > 1000 ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells.

Myosin-7A (Myo7A) is a motor protein crucial for the organization and function of stereocilia, specialized actin-rich protrusions on the surface of inner ear hair cells that mediate hearing. Mutations in Myo7A cause several forms of genetic hearing loss, including autosomal dominant DFNA11 deafness. Despite its importance, the structural elements of Myo7A that control its motor activity within cells are not well understood. In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells. Our findings reveal that Myo7A is regulated by specific IQ motifs within its lever arm, and that this regulation can function at least partially independent of its tail sequence. Importantly, we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness.

Multivalent MVA-vectored vaccine elicits EBV neutralizing antibodies in rhesus macaques that reduce EBV infection in humanized mice.

Introduction: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus associated with ~350,000 cases of lymphoid and epithelial malignancies every year, and is etiologically linked to infectious mononucleosis and multiple sclerosis. Despite four decades of research, no EBV vaccine candidate has yet reached licensure. Most previous vaccine attempts focused on a single viral entry glycoprotein, gp350, but recent data from clinical and pre-clinical studies, and the elucidation of viral entry mechanisms, support the inclusion of multiple entry glycoproteins in EBV vaccine design. Methods: Here we generated a modified vaccinia Ankara (MVA)-vectored EBV vaccine, MVA-EBV5-2, that targets five EBV entry glycoproteins, gp350, gB, and the gp42gHgL complex. We characterized the genetic and translational stability of the vaccine, followed by immunogenicity assessment in BALB/c mice and rhesus lymphocryptovirus-negative rhesus macaques as compared to a gp350-based MVA vaccine. Finally, we assessed the efficacy of MVA-EBV5-2-immune rhesus serum at preventing EBV infection in human CD34+ hematopoietic stem cell-reconstituted NSG mice, under two EBV challenge doses. Results: The MVA-EBV5-2 vaccine was genetically and translationally stable over 10 viral passages as shown by genetic and protein expression analysis, and when administered to female and male BALB/c mice, elicited serum EBV-specific IgG of both IgG1 and IgG2a subtypes with neutralizing activity in vitro. In Raji B cells, this neutralizing activity outperformed that of serum from mice immunized with a monovalent MVA-vectored gp350 vaccine. Similarly, MVA-EBV5-2 elicited EBV-specific IgG in rhesus macaques that were detected in both serum and saliva of immunized animals, with serum antibodies demonstrating neutralizing activity in vitro that outperformed serum from MVA-gp350-immunized macaques. Finally, pre-treatment with serum from MVA-EBV5-2-immunized macaques resulted in fewer EBV-infected mice in the two challenge experiments than pretreatment with serum from pre-immune macaques or macaques immunized with the monovalent gp350-based vaccine. Discussion: These results support the inclusion of multiple entry glycoproteins in EBV vaccine design and position our vaccine as a strong candidate for clinical translation.

Global Industry Perspectives on Postgraduate Strength and Conditioning Degrees: An Exploratory Factor Analysis.

PURPOSE: This investigation sought to determine industry perceptions of postgraduate strength and conditioning (S&C) degrees to understand whether graduates are equipped for the demands of sport performance service roles. METHODS: Survey data were collected from 111 participants employed as performance staff or in a role that recruits and supervises performance staff. The survey consisted of 3 main sections: (1) perceptions of career-development opportunities in S&C, (2) perception of S&C postgraduate programs, and (3) perceptions of employability in S&C. Exploratory factor analysis was conducted to identify the key factors considered to be of greatest relevance to career progression in S&C. RESULTS: A 2-factor solution was achieved for each of the 3 sections, resulting in 6 total factors. These factors are Academic and Professional Development, Mentorship and Sport Diversity, Student Preparation, Require Greater Emphasis, Testing and Training, and Personal and Professional Growth. CONCLUSIONS: Postgraduate S&C programs require a broad range of placement/internship opportunities to (1) provide diverse experiences, (2) allow students to build contacts and develop professional networks, (3) gain exposure to working in high-performance environments and multidisciplinary teams, and (4) access high-quality mentors. Alongside the ability to deliver training and testing, graduates should be equipped with strong organizational and relationship-building skills. Improved graduate capabilities can raise the standards of the profession and result in enhanced service provision to athletes.