Real-world experience: a retrospective pediatric chart review to determine why patients and caregivers discontinue oral immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) is an increasingly utilized management strategy for IgE-mediated food allergy. Despite promising efficacy and effectiveness, there is still a lack of data surrounding the reasons for discontinuation of OIT. The primary reason stated in the literature for discontinuation is adverse gastrointestinal effects. Social factors contributing to OIT discontinuation have not been well reported. We hypothesize that social considerations are significant contributors to treatment discontinuation. METHODS: We completed a retrospective chart review of 50 patients treated in community pediatric allergy practices who discontinued OIT out of 507 patients who were started on OIT between October 1, 2017-October 27, 2022. Reasons for discontinuation were identified and classified into five main categories: unsafe care decisions, anxiety, adverse effects of OIT, uncontrolled comorbidity and social factors. Categories were not exclusive. RESULTS: 507 patients were started on OIT, with data available for 50 patients who discontinued OIT, aged 10 months to 18 years and 2 months. The overall discontinuation rate was 9.8%, of which 40 patients (80%) discontinued during buildup, 9 patients (18%) discontinued during maintenance and one patient on two food OIT discontinued one food during buildup and one during maintenance (2%). Thirty-four patients (68%) had multiple reasons for discontinuing OIT. Social factors were the most common reason for discontinuation and were identified in 32 patients (64%). Twenty-four patients (48%) discontinued OIT due to adverse effects. Gastrointestinal symptoms were the most prevalent, while anaphylaxis contributed to discontinuation in 15 patients (30%). Anxiety led to discontinuation in 17 patients (34%). CONCLUSIONS: Our data highlights the importance of social factors and anxiety in the success of OIT completion. Our results support the need to consider not only the patient's medical history, but also their social history and support networks when selecting patients who are good candidates for OIT to optimize the successful completion of OIT.

Supporting early-career military general surgeons: an Eastern Association for the Surgery of Trauma Military Committee position paper.

Early-career surgeons must be exposed to a sufficient number of surgical cases of varying complexity in a mentored environment to allow them to solidify, sustain and build on the skills gained in training. Decreased operative volumes at military treatment facilities and assignments that do not include strong mentoring environments can place military surgeons at a disadvantage relative to their civilian counterparts during this critical time following training. The challenge of lower operative volumes in the current interwar lull has been exacerbated by the decline in beneficiary care conducted within the Military Healthcare System. These challenges must be addressed by ensuring early-career surgeons maintain exposure to a large volume of complex surgical procedures and deliberate mentoring from senior surgeons. The purpose of this position statement is to provide actionable methods to support early-career military surgeons to effectively transition from training to independent practice.

Leveraging HILIC/ERLIC Separations for Online Nanoscale LC-MS/MS Analysis of Phosphopeptide Isoforms from RNA Polymerase II C-terminal Domain.

The eukaryotic RNA polymerase II (Pol II) multi-protein complex transcribes mRNA and coordinates several steps of co-transcriptional mRNA processing and chromatin modification. The largest Pol II subunit, Rpb1, has a C-terminal domain (CTD) comprising dozens of repeated heptad sequences (Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7), each containing five phospho-accepting amino acids. The CTD heptads are dynamically phosphorylated, creating specific patterns correlated with steps of transcription initiation, elongation, and termination. This CTD phosphorylation 'code' choreographs dynamic recruitment of important co-regulatory proteins during gene transcription. Genetic tools were used to engineer protease cleavage sites across the CTD (msCTD), creating tryptic peptides with unique sequences amenable to mass spectrometry analysis. However, phosphorylation isoforms within each msCTD sequence are difficult to resolve by standard reversed phase chromatography typically used for LC-MS/MS applications. Here, we use a panel of synthetic CTD phosphopeptides to explore the potential of hydrophilic interaction and electrostatic repulsion hydrophilic interaction (HILIC and ERLIC) chromatography as alternatives to reversed phase separation for CTD phosphopeptide analysis. Our results demonstrate that ERLIC provides improved performance for separation of singly- and doubly-phosphorylated CTD peptides for sequence analysis by LC-MS/MS. Analysis of native yeast msCTD confirms that phosphorylation on Ser5 and Ser2 represents the major endogenous phosphoisoforms. We expect this methodology will be especially useful in the investigation of pathways where multiple protein phosphorylation events converge in close proximity.

Changes in work and adequacy of financial resources during COVID-19 among people with systemic sclerosis: A Scleroderma Patient-centered Intervention Network study.

Introduction/objective: We investigated (1) work status changes during COVID-19, (2) financial resource adequacy, (3) preferences for work requirements (e.g. remote, workplace, mixed) and (4) work requirements versus preferences, among people with systemic sclerosis. Methods: This was a cross-sectional study of participants in the Scleroderma Patient-centered Intervention Network COVID-19 Cohort, which enrolled participants from the ongoing Scleroderma Patient-centered Intervention Network Cohort and externally in April 2020. In August 2022, participants completed questions on work status, financial well-being using the Consumer Financial Protection Bureau Financial Well-Being Scale, work requirements and work requirement preferences. Results: A total of 298 participants with systemic sclerosis were included. Mean age was 58.6 years (SD = 11.4). There were 101 (34%) participants working at the start of the pandemic and still working in August 2022, 179 (60%) not working at the start of the pandemic and still not working, 10 (3%) who stopped working after April 2020 and 8 (3%) who started working. Mean financial well-being did not change from April 2020 to August 2022 (difference: 0.2 points; 95% confidence interval: -1.1 to 0.7). Working participants (N = 109) preferred flexible work requirements (N = 34, 31%) or working entirely remotely (N = 32, 29%), but most were required to work entirely at a workplace (N = 35, 32%) or combined workplace and remotely with a fixed schedule (N = 31, 28%). Conclusion: Work status and financial well-being did not change substantively among people with systemic sclerosis during the pandemic. Flexible work policies may support people with systemic sclerosis to work.

Ultra-High-k Ferroelectric BaTiO3 Perovskite in the Gate Stack for Two-Dimensional WSe2 p-Type High-Performance Transistors.

The experimental demonstration of a p-type 2D WSe2 transistor with a ferroelectric perovskite BaTiO3 gate oxide is presented. The 30 nm thick BaTiO3 gate stack shows a robust ferroelectric hysteresis with a remanent polarization of 20 µC/cm2 and further enables a capacitance equivalent thickness of 0.5 nm in the hybrid WSe2/BaTiO3 stack due to its high dielectric constant of 323. We demonstrate one of the best ON currents for perovskite gate 2D transistors in the literature. This is enabled by high-quality epitaxial growth of BaTiO3 and a single 2D layer transfer based fabrication method that is shown to be amenable to silicon platforms. This demonstration is an important milestone toward the integration of crystalline complex oxides with 2D channel materials for scaled CMOS and low-voltage ferroelectric logic applications.

Four-dimensional Flow MRI-based Computational Fluid Dynamics Simulation for Noninvasive Portosystemic Pressure Gradient Assessment in Patients with Cirrhosis and Transjugular Intrahepatic Portosystemic Shunt.

Background Transjugular intrahepatic portosystemic shunt (TIPS) dysfunction in patients with liver cirrhosis and recurrent symptoms of portal hypertension is primarily assessed with US and confirmed with invasive catheter venography, which can be used to measure the portosystemic pressure gradient (PSPG) to identify TIPS-refractory portal hypertension. To avoid the risks and costs of invasive catheter venography, noninvasive PSPG evaluation strategies are needed. Purpose To demonstrate the feasibility of the combination of four-dimensional (4D) flow MRI with computational fluid dynamics (CFD) for noninvasive PSPG assessment in participants with cirrhosis and TIPS. Materials and Methods Abdominal 4D flow MRI was performed prospectively in participants with cirrhosis and TIPS between January 2019 and September 2020. Flow rates were measured within the TIPS and inferior vena cava (IVC). The portal vein (PV), TIPS, right hepatic vein, and IVC were segmented on MRI scans to create a CFD mesh. The PV and infrahepatic IVC were defined as inflows for 4D flow MRI-derived flow rates. The suprahepatic IVC was defined as the outflow. CFD simulations were used to noninvasively estimate PSPG as the difference between the simulated pressures in the PV and suprahepatic IVC. Invasive venographic measurements of the PSPG served as the reference standard, and Pearson correlation analysis was conducted to evaluate the relationship between noninvasive estimates and invasive measurements. Results In all 20 participants with cirrhosis (mean age, 58 years ± 9 [SD]; 11 men), 4D flow MRI-based CFD simulations enabled visualization of flow velocities and pressure distributions within the segmented vasculature and TIPS. Noninvasive estimates and invasive measures of PSPG were strongly correlated (r = 0.77; P < .001). The 4D flow MRI-based CFD simulations correctly classified the presence or absence of a post-TIPS PSPG greater than 12 mm Hg in 16 of 20 participants (80%). Conclusion The combination of 4D flow MRI and CFD was feasible for noninvasive PSPG assessment in participants with cirrhosis, portal hypertension, and TIPS. © RSNA, 2024 See also the editorial by Motosugi and Watanabe in this issue.

Relative age effect in male and female elite international amateur boxing.

This study aimed to determine whether the Relative Age Effect (RAE) was present in different sexes and age categories in 12 elite-level international amateur boxing competitions. A total of 4813 athletes competing between 2013 and 2022 were analysed. Athletes were split into four quartiles according to their birth date and compared to the expected (equal) birth date distribution using chi-squared goodness of fit. The results revealed greater RAE prevalence in youth compared to the senior group. RAE was more prominent in males compared to females, with the female group showing an inverse RAE trend. Odds ratio (OR) showed an overrepresentation of male boxers born in Q1 compared to Q4 (OR > 1.19-1.33), while senior female boxers presented an inverse trend (OR < 0.95). Odds Ratios for medallists within the youth group were greater than 1.07 (except Q3 × Q4 = 0.93) highlighting an overrepresentation of boxers born earlier in the year. A shift in strategy to reduce the RAE in young boxers whereby coaches focus less on the short-term pursuit of sporting success is encouraged. Organisations and coaches should increase awareness and provide systematic education around RAE, whilst creating equal competitive opportunities for all young boxers to reduce the extent of RAE in boxing.

Exploratory analysis of the variable response to an intensive lifestyle change program for metabolic syndrome.

BACKGROUND: Substantial variability in response to lifestyle interventions has been recognized for many years, and researchers have begun to disentangle sources of error from inherent differences in individual responsiveness. The objective of this secondary analysis of an intensive lifestyle intervention (diet and exercise) for metabolic syndrome (MetS) was to identify potentially important differences among study completers grouped by treatment response as measured by change in a continuous metabolic syndrome score (Gurka/MetS). METHODS: All study completers from a 12-month primary care study were categorized into one of five groups according to change in the Gurka/MetS score. A change of 0.4 in z-score defined clinically relevant change in line with results of previous studies. Repeated measures analysis of variance was used to examine cardiovascular disease risk and individual clinical indicators of MetS over 12 months, looking for differences in response over time by the five groups. RESULTS: Of 176 participants, 50% (n = 88) had stable scores, 10% (n = 18) had relevant change scores in the first 3 months only and reverted toward baseline, 20% (n = 35) achieved meaningful change over the whole study, 11% (n = 20) had a delayed response at 3-12 months, and 9% (n = 15) demonstrated worsening scores. Significant differential patterns were noted for groups over the duration of the intervention (p < .001). Improvement in diet quality and fitness scores were similar across all groups. Other available variables were tested and did not account for the differences. CONCLUSION: Work is needed to identify key factors that account for differences in responses to lifestyle interventions that can be used to guide treatment decisions for intensive lifestyle interventions for this common condition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01616563; first registered June 12, 2012.

FMNL1 and mDia1 promote efficient T cell migration through complex environments via distinct mechanisms.

Lymphocyte trafficking and migration through tissues is critical for adaptive immune function and, to perform their roles, T cells must be able to navigate through diverse tissue environments that present a range of mechanical challenges. T cells predominantly express two members of the formin family of actin effectors, Formin-like 1 (FMNL1) and mammalian diaphanous-related formin 1 (mDia1). While both FMNL1 and mDia1 have been studied individually, they have not been directly compared to determine functional differences in promoting T cell migration. Through in vivo analysis and the use of in vitro 2D and 3D model environments, we demonstrate that FMNL1 and mDia1 are both required for effective T cell migration, but they have different localization and roles in T cells, with specific environment-dependent functions. We found that mDia1 promotes general motility in 3D environments in conjunction with Myosin-II activity. We also show that, while mDia1 is almost entirely in the cytoplasmic compartment, a portion of FMNL1 physically associates with the nucleus. Furthermore, FMNL1 localizes to the rear of migrating T cells and contributes to efficient migration by promoting deformation of the rigid T cell nucleus in confined environments. Overall, our data indicates that while FMNL1 and mDia1 have similar mechanisms of actin polymerization, they have distinct roles in promoting T cell migration. This suggests that differential modulation of FMNL1 and mDia1 can be an attractive therapeutic route to fine-tune T cell migration behavior.

Relaxivity and In Vivo Human Performance of Brand Name Versus Generic Ferumoxytol.

OBJECTIVES: Ferumoxytol is a superparamagnetic iron-oxide product that is increasingly used off-label for contrast-enhanced magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). With the recent regulatory approval of generic ferumoxytol, there may be an opportunity to reduce cost, so long as generic ferumoxytol has similar imaging performance to brand name ferumoxytol. This study aims to compare the relaxation-concentration dependence and MRI performance of brand name ferumoxytol with generic ferumoxytol through phantom and in vivo experiments. The secondary purpose was to determine the optimal flip angle and optimal weight-based dosing. MATERIALS AND METHODS: Phantom experiments were performed using both brand name (AMAG Pharmaceuticals) and generic (Sandoz Pharmaceuticals) ferumoxytol products. Each ferumoxytol product was diluted in saline, and separately in adult bovine whole blood, at 5 iron concentrations ranging from 0.3 to 2.1 mM. Vials were placed in an MR-compatible water bath at 37°C and imaged at both 1.5 T and 3.0 T. Longitudinal and transverse relaxation rate constants (R1, R2, R2*) were measured for each ferumoxytol concentration, and relaxation-concentration curves were estimated. An in vivo dose accumulation study with flip angle optimization was also implemented using a cross-over design, in healthy volunteers. Cumulative doses of 1, 3, 5, and 7 mg/kg diluted ferumoxytol were administered prior to MRA of the chest on a 3.0 T clinical MRI system. For each incremental dose, the flip angle was varied from 40° to 10° in -10° increments over 5 breath-holds followed by a repeated 40° flip angle acquisition. Regions of interest were drawn in the aortic arch, paraspinous muscles, and a noisy area outside of the patient, free from obvious artifact. Signal-to-noise ratio (SNR) was calculated as the quotient of the average signal in the aortic arch and the standard deviation of the noise, corrected for a Rician noise distribution. Contrast-to-noise ratio was calculated as the difference in SNR between the aorta and paraspinous muscles. Absolute SNR and contrast-to-noise ratio values were compared between products for different flip angles and doses. RESULTS: There were no statistically significant or clinically relevant differences in relaxation-concentration curves between AMAG and Sandoz products in phantom experiments. Six healthy volunteers (38.8 ± 11.5 years, 3 female, 3 male) were successfully recruited and completed both imaging visits. No clinically relevant differences in image quality were observed between ferumoxytol products. The optimal flip angle range and dose for both products was 20°-30° and 5 mg/kg, respectively. CONCLUSIONS: Brand name and generic ferumoxytol products can be used interchangeably for MRA.

Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during skeletal muscle regeneration.

Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. The fusion of satellite cell-derived mononucleated muscle cells (SCMs) is indispensable for the generation of multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain poorly understood. In this study, we uncovered an essential role for branched actin polymerization in SCM fusion. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors, N-WASP and WAVE, we demonstrated that branched actin polymerization is required for the SCM fusion, but not for satellite cell proliferation, differentiation, and migration. We showed that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion. Furthermore, we showed that branched actin polymerization is essential for generating invasive protrusions at the fusogenic synapses in SCMs. Taken together, our study has identified new components of the myoblast fusion machinery in skeletal muscle regeneration and demonstrated a critical role for branched actin-propelled invasive protrusions in this process.

Prediction of MRI R 2 * $$ {\mathrm{R}}_2

To develop Monte Carlo simulations to predict the relationship of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ with liver fat content at 1.5 T and 3.0 T. For various fat fractions (FFs) from 1% to 25%, four types of virtual liver models were developed by incorporating the size and spatial distribution of fat droplets. Magnetic fields were then generated under different fat susceptibilities at 1.5 T and 3.0 T, and proton movement was simulated for phase accrual and MRI signal synthesis. The synthesized signal was fit to single-peak and multi-peak fat signal models for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and proton density fat fraction (PDFF) predictions. In addition, the relationships between R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF predictions were compared with in vivo calibrations and Bland-Altman analysis was performed to quantitatively evaluate the effects of these components (type of virtual liver model, fat susceptibility, and fat signal model) on R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions. A virtual liver model with realistic morphology of fat droplets was demonstrated, and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF values were predicted by Monte Carlo simulations at 1.5 T and 3.0 T. R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions were linearly correlated with PDFF, while the slope was unaffected by the type of virtual liver model and increased as fat susceptibility increased. Compared with in vivo calibrations, the multi-peak fat signal model showed superior performance to the single-peak fat signal model, which yielded an underestimation of liver fat. The R 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF relationships by simulations with fat susceptibility of 0.6 ppm and the multi-peak fat signal model were R 2 * = 0.490 × PDFF + 28.0 $$ {\mathrm{R}}_2^{\ast }=0.490\times \mathrm{PDFF}+28.0 $$ ( R 2 = 0.967 $$ {R}^2=0.967 $$ , p < 0.01 $$ p<0.01 $$ ) at 1.5 T and R 2 * = 0.928 × PDFF + 39.4 $$ {\mathrm{R}}_2^{\ast }=0.928\times \mathrm{PDFF}+39.4 $$ ( R 2 = 0.972 $$ {R}^2=0.972 $$ , p < 0.01 $$ p<0.01 $$ ) at 3.0 T. Monte Carlo simulations provide a new means for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF prediction, which is primarily determined by fat susceptibility, fat signal model, and magnetic field strength. Accurate R 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF calibration has the potential to correct the effect of fat on R 2 * $$ {\mathrm{R}}_2^{\ast } $$ quantification, and may be helpful for accurate R 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements in liver iron overload. In this study, a Monte Carlo simulation of hepatic steatosis was developed to predict the relationship between R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF. Furthermore, the effects of fat droplet morphology, fat susceptibility, fat signal model, and magnetic field strength were evaluated for the R 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF calibration. Our results suggest that Monte Carlo simulations provide a new means for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF prediction and this means can be easily generated for various regimes, such as simulations with higher fields and different echo times, as well as correction of magnetic susceptibility measurements for liver iron quantification.

Screening for depression in patients with epilepsy: same questions but different meaning to different patients.

PURPOSE: Patient-reported outcome measures (PROMs) such as the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E), a 6-item epilepsy-specific PROM, is used to screen for major depressive disorder symptoms for patients with epilepsy (PWE). The validity and interpretation of PROMs can be affected by differential item functioning (DIF), which occurs when subgroups of patients with the same underlying health status respond to and interpret questions about their health status differently. This study aims to determine whether NDDI-E items exhibit DIF and to identify subgroups of PWE that exhibit DIF in NDDI-E items. METHODS: Data were from the Calgary Comprehensive Epilepsy Program database, a clinical registry of adult PWE in Calgary, Canada. A tree-based partial credit model based on recursive partitioning (PCTree) was used to identify subgroups that exhibit DIF on NDDI-E items using patients' characteristics as covariates. Differences in the identified subgroups were characterized using multinomial logistic regression. RESULTS: Of the 1,576 patients in this cohort, 806 (51.1%) were female, and the median age was 38.0 years. PCTree identified four patient subgroups defined by employment status, age, and sex. Subgroup 1 were unemployed patients ≤ 26 years old, subgroup 2 were unemployed patients > 26 years, subgroup 3 were employed females, while subgroup 4 were employed male patients. The subgroups exhibited significant differences on education level, comorbidity index scores, marital status, type of epilepsy, and driving status. CONCLUSION: PWE differed in their interpretation and responses to questions about their depression symptoms, and these differences were a function of sociodemographic and clinical characteristics.

Patient-reported depression screening measures are prone to differential item functioning (DIF), which occurs when patients with the same levels of depression respond to and interpret the questions on the measures differently, as a result of different socio-demographic characteristics. Heterogeneity in how epilepsy patients interpret and respond to depression measures, if not identified, could lead to measurement biases that threaten the validity of inferences from patient-reported outcome measure scores to inform clinical and healthcare decisions for epilepsy management. Using data from a clinical registry of patients with epilepsy, the tree-based item response theory model was used to examine the presence of DIF in the items comprising the patient-reported Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) scale. Four subgroups of epilepsy patients were noted to exhibit DIF on NDDI-E items. These groups were defined by interactions among employment status, age and sex. These characteristics affect the interpretation of NDDI-E item scores. It is recommended that clinicians carefully scrutinize responses to individual items alongside the overall NDDI-E score in different patient groups to inform clinical decisions for epilepsy management.

The Canadian Prospective Cohort Study to understand progression in multiple sclerosis: baseline characteristics.

Background: Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. Objectives: The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. Design: A prospective cohort study. Methods: CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants (n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Results: Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Conclusion: Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo's data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Psychiatric Comorbidity Does Not Enhance Prescription Opioid Use in Inflammatory Bowel Disease as It Does in the General Population.

INTRODUCTION: Little is known about patterns of opioid prescribing in inflammatory bowel disease (IBD), but pain is common in persons with IBD. We estimated the incidence and prevalence of opioid use in adults with IBD and an unaffected reference cohort and assessed factors that modified opioid use. METHODS: Using population-based health administrative data from Manitoba, Canada, we identified 5233 persons with incident IBD and 26 150 persons without IBD matched 5:1 on sex, birth year, and region from 1997 to 2016. New and prevalent opioid prescription dispensations were quantified, and patterns related to duration of use were identified. Generalized linear models were used to test the association between IBD, psychiatric comorbidity, and opioid use adjusting for sociodemographic characteristics, physical comorbidities, and healthcare use. RESULTS: Opioids were dispensed to 27% of persons with IBD and to 12.9% of the unaffected reference cohort. The unadjusted crude incidence per 1000 person-years of opioid use was nearly twice as high for the IBD cohort (88.63; 95% CI, 82.73-91.99) vs the reference cohort (45.02; 95% CI, 43.49-45.82; relative risk 1.97; 95% CI, 1.86-2.08). The incidence rate per 1000 person-years was highest in those 18-44 years at diagnosis (98.01; 95% CI, 91.45-104.57). The relative increase in opioid use by persons with IBD compared to reference cohort was lower among persons with psychiatric comorbidity relative to the increased opioid use among persons with IBD and reference cohort without psychiatric comorbidity. DISCUSSION: The use of opioids is more common in people with IBD than in people without IBD. This does not appear to be driven by psychiatric comorbidity.

The use of opioids is more common in people with inflammatory bowel disease (IBD) than in people without IBD. Psychiatric comorbidity does not significantly impact chronic opioid use in persons with IBD as it does in unaffected controls.

Foundry manufacturing of octave-spanning microcombs.

Soliton microcombs provide a chip-based, octave-spanning source for self-referencing and optical metrology. We use a silicon nitride integrated photonics foundry to manufacture 280 single-chip solutions of octave-spanning microcombs on a wafer. By group-velocity dispersion (GVD) engineering with the waveguide cross section, we shape the soliton spectrum for dispersive-wave spectral enhancements at the frequencies for f-2f self-referencing. Moreover, we demonstrate the other considerations, including models for soliton spectrum design, ultra-broadband resonator external coupling, low-loss edge couplers, and the nonlinear self-interactions of few-cycle solitons. To cover the fabrication tolerance, we systematically scan 336 parameter sets of resonator width and radius, ensuring at least one device on each chip can yield an octave-spanning comb with an electronically detectable carrier-envelope offset frequency, which has been supported by our experiment. Our design and testing process permit highly repeatable creation of single-chip solutions of soliton microcombs optimized for pump operation ∼100 mW and high comb mode power for f-2f detection, which is the central component of a compact microsystem for optical metrology.

Multicenter, multivendor validation of liver quantitative susceptibility mapping in patients with iron overload at 1.5 T and 3 T.

PURPOSE: To evaluate the repeatability and reproducibility of QSM of the liver via single breath-hold chemical shift-encoded MRI at both 1.5 T and 3 T in a multicenter, multivendor study in subjects with iron overload. METHODS: This prospective study included four academic medical centers with three different MRI vendors at 1.5 T and 3 T. Subjects with known or suspected liver iron overload underwent multi-echo spoiled gradient-recalled-echo scans at each field strength. A subset received repeatability testing at either 1.5 T or 3 T. Susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed from the multi-echo images and analyzed at a single center. QSM-measured susceptibility was compared with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and a commercial R2-based liver iron concentration method across centers and field strengths using linear regression and F-tests on the intercept and slope. Field-strength reproducibility and test/retest repeatability were evaluated using Bland-Altman analysis. RESULTS: A total of 155/80 data sets (test/retest) were available at 1.5 T, and 159/70 data sets (test/retest) were available at 3 T. Calibrations across sites were reproducible, with some variability (e.g., susceptibility slope with liver iron concentration ranged from 0.102 to 0.123 g/[mg · $$ \cdotp $$ ppm] across centers at 1.5 T). Field strength reproducibility was good (concordance correlation coefficient = 0.862), and test/retest repeatability was excellent (intraclass correlation coefficient = 0.951). CONCLUSION: QSM as an imaging biomarker of liver iron overload is feasible and repeatable across centers and MR vendors. It may be complementary with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ as they are obtained from the same acquisition. Although good reproducibility was observed, liver QSM may benefit from standardization of acquisition parameters. Overall, QSM is a promising method for liver iron quantification.

The ApoA1-mimetic peptide 4F blocks flavivirus NS1-triggered endothelial dysfunction and protects against lethal dengue virus challenge.

Flavivirus infections result in a variety of outcomes, from clinically inapparent infections to severe, sometimes fatal cases characterized by hemorrhagic manifestations and vascular leakage leading to shock (dengue), meningomyeloencephalitis (West Nile), and congenital abnormalities (Zika). Although there are approved vaccines against several flaviviruses, potentially enhancing cross-reactive immune responses have complicated the development and implementation of vaccines against dengue and Zika viruses, and no specific therapeutics currently exist. The flavivirus nonstructural protein 1 (NS1) is a promising antiviral target because it is a conserved multifunctional virulence factor that directly triggers vascular leak. We previously showed that interactions between NS1 and the ApoA1 lipoprotein modulate DENV infection. Here, we evaluated the potential of the ApoA1-mimetic peptide, 4F, to interfere with endothelial dysfunction mediated by the NS1 protein of dengue, Zika, and West Nile flaviviruses. In an in vitro model consisting of human endothelial cell monolayers, 4F inhibited NS1-induced hyperpermeability, as measured by a transendothelial electrical resistance assay, and prevented NS1-triggered disruption of the endothelial glycocalyx layer. We also demonstrate that treatment with 4F inhibited NS1 interaction with endothelial cells. Finally, we show that 4F protects against lethal DENV challenge in a mouse model, reducing morbidity and mortality in a dose-dependent manner. Our data demonstrate the potential of 4F to inhibit flavivirus NS1-mediated pathology and severe dengue disease in mice and suggest that 4F can also serve as a molecular tool to probe different NS1 functions in vitro and in vivo.

Postdischarge Mortality in a Cohort Hospitalized With Anorexia Nervosa.

OBJECTIVE: To characterize mortality after hospital discharge in cohorts with and without anorexia nervosa (AN). METHODS: We obtained data for all hospitalizations for psychiatric reasons in Canada (except Quebec) between April 1, 2006, and March 31, 2021 (n = 1.3 million admissions). Cases of AN were identified using ICD-10 (F50.0 and F50.1) codes. First admissions during this interval for AN and other psychiatric conditions were linked to vital statistics data. Mortality was characterized through cross-tabulation, Cox proportional hazards models, and competing cause regression. RESULTS: After adjustment for age and sex, there was no significant difference in mortality between AN and those with other psychiatric conditions (HR = 1.04; p = 0.644). Among AN admissions, 25% (95% CI 18.6-31.4) of deaths were attributed to psychiatric conditions (ICD-F codes), with 88% of these (comprising 22% of all deaths in the AN group) having AN itself identified as the underlying cause of death. In contrast, only 8% of deaths among non-AN admissions were attributed to a mental disorder. DISCUSSION: Prevention of premature mortality in the general psychiatric population emphasizes modification of metabolic (e.g., hyperlipidemia) and lifestyle-related (e.g., sedentary behavior) risk factors. However, as AN itself makes a major contribution to mortality, specialized preventive strategies may be required.

The association between neighborhood socioeconomic deprivation and mental health in low- and middle-income countries: A scoping review.

BACKGROUND: Environmental research on mental health primarily originates from high-income countries, while information about the rest of the world remains limited. AIMS: This study examined: (1) the available published research evidence regarding the association between neighborhood-level deprivation and indicators of mental health and illness in low- and middle-income countries (LMICs), and (2) the gaps in the relevant research in LMIC settings that should be addressed in future studies. METHOD: First, we systematically searched for relevant primary studies in electronic databases (Ovid Medline, Scopus, Socindex, and PsycINFO) and citations in the reference lists. Then, a two-stage screening procedure was employed to select the relevant studies by screening the titles and abstracts and reviewing the selected full texts by independent researchers. After charting the data from the selected study reports, we collated, summarized, and discussed the results. RESULTS: We retrieved 51 studies across 19 LMICs, with only one study originating from a low-income country. Most studies focused on adult mental health topics and few explored children's mental health. Notably, a significant majority of these studies (N = 37) reported a positive association between neighborhood deprivation and mental health/disorder. However, the research methods used varied significantly, and there were several methodological limitations. CONCLUSIONS: This review highlights the need for more original studies in LMICs on the association between neighborhood deprivation and mental health, employing stronger methodologies.