Rosai-Dorfman-Destombes disease in adults: a single center experience.

Recent advances in Rosai-Dorfman-Destombes disease (RDD), notably molecular testing, targeted therapy, and PET-CT imaging, hold promise for better recognition and improved outcomes. This study presents patients diagnosed and treated in a "real world" setting, where navigating limited resources must be considered. This retrospective single-center review includes 15 adult patients diagnosed with RDD at Vancouver General Hospital between November 2015 and October 2023. The cohort comprised five males and ten females with a median age 53 years (range 19-80 years). All 15 patients had extra-nodal disease; 11 patients exclusively had extra-nodal disease, and four patients also had lymph node involvement. Seven patients had tissue next-generation sequencing, identifying MAP2K1 mutations in four cases and a KRAS p.K117N mutation in one case that was treated with targeted therapy using trametinib. PET-CT was used for disease staging in four cases. Six patients with refractory disease tolerated lenalidomide and dexamethasone without significant toxicity; three patients achieved complete response, and three had partial response. This study highlights RDD's diverse extra-nodal manifestations. Lenalidomide combined with dexamethasone is an effective and well-tolerated treatment option for select patients, especially those with refractory disease. Broad utilization of NGS and PET-CT can positively influence management decisions.

Femoral head decentration on hip MRI: comparison between imaging planes, methods of contrast administration, and hip deformities.

OBJECTIVES: To compare the prevalence of femoral head decentration (FHD) on different MR imaging planes in patients undergoing direct/indirect hip MR arthrography (MRA) with asymptomatic controls and to evaluate its association with osseous deformities. METHODS: IRB-approved retrospective single-center study of symptomatic hips undergoing direct or indirect hip MRA at 3 T. Asymptomatic participants underwent non-contrast hip MRI at 3 T. FHD was defined as a continuous fluid layer between the acetabulum and femoral head and assessed on axial, sagittal and radial images. The association of intra-articular/intra-venous contrast agents and the prevalence of FHD was evaluated. The association of FHD with osseous deformities and joint damage was assessed using multiple logistic regression analysis. RESULTS: Three-hundred ninety-four patients (447 hips, mean age 31 ± 9 years, 247 females) were included and compared to 43 asymptomatic controls (43 hips, mean age 31 ± 6 years, 26 females). FHD was most prevalent on radial images and more frequent in symptomatic hips (30% versus 2%, p < 0.001). FHD prevalence was not associated with the presence/absence of intra-articular contrast agents (30% versus 22%, OR = 1.5 (95% CI 0.9-2.5), p = 0.125). FHD was associated with hip dysplasia (OR = 6.1 (3.3-11.1), p < 0.001), excessive femoral torsion (OR = 3.0 (1.3-6.8), p = 0.010), and severe cartilage damage (OR = 3.6 (2.0-6.7), p < 0.001). CONCLUSION: While rare in asymptomatic patients, femoral head decentration in symptomatic patients is associated with osseous deformities predisposing to hip instability, as well as with extensive cartilage damage. CRITICAL RELEVANCE STATEMENT: Decentration of the femoral head on radial MRA may be interpreted as a sign of hip instability in symptomatic hips without extensive cartilage defects. Its presence could unmask hip instability and yield promise in surgical decision-making. KEY POINTS: The best method of identifying femoral head decentration is radial MRI. The presence/absence of intra-articular contrast is not associated with femoral head decentration. Femoral head decentration is associated with hip deformities predisposing to hip instability.

Functional reorganization of North American wintering avifauna.

Wintering birds serve as vital climate sentinels, yet they are often overlooked in studies of avian diversity change. Here, we provide a continental-scale characterization of change in multifaceted wintering avifauna and examine the effects of climate change on these dynamics. We reveal a strong functional reorganization of wintering bird communities marked by a north-south gradient in functional diversity change, along with a superimposed mild east-west gradient in trait composition change. Assemblages in the northern United States saw contractions of the functional space and increases in functional evenness and originality, while the southern United States saw smaller contractions of the functional space and stasis in evenness and originality. Shifts in functional diversity were underlined by significant reshuffling in trait composition, particularly pronounced in the western and northern United States. Finally, we find strong contributions of climate change to this functional reorganization, underscoring the importance of wintering birds in tracking climate change impacts on biodiversity.

Evaluating User Experience and DNA Yield from Self-Collection Devices.

BACKGROUND: The COVID-19 pandemic emphasized an urgent need for devices used in the self-collection of biospecimens in an evolving patient care system. The mailing of biospecimen self-collection kits to patients, with samples returned via mail, provides a more convenient testing regimen, but could also impart patient sampling variabilities. User compliance with device directions is central to downstream testing of collected biospecimens and clear instructions are central to this goal. METHODS: Here, we performed an evaluation of 10 oral DNA collection devices involving either swab or saliva self-collection and analyzed ease of use and comfort level with a device, as well as DNA recovery quantity/quality and sample stability. RESULTS: We show that while these DNA quality/quantity metrics are comparable between devices, users prefer direct saliva collection over swab-based devices. CONCLUSIONS: This information is useful in guiding future experiments including their use in human RNA, microbial, or viral sample collection/recovery and their use in clinical testing.

Underwhelming pleasures: Toward a self-regulatory account of hedonic compensation and overconsumption.

Hedonic overconsumption (e.g., overconsumption of gratifying behaviors, e.g., eating, gaming) is common in daily life and often problematic, pointing to the need for adequate behavioral models. In this article, we develop a self-regulatory framework proposing that when an actual consumption experience falls short of hedonic expectations-such as when being distracted-people will want to consume more to compensate for the shortfall. In a preliminary meta-analysis, a small-scale field experiment on distraction during lunch and subsequent afternoon snacking (Study 1), and a preregistered experience sampling study (Study 2) involving more than 6,000 consumption episodes in everyday life across multiple consumption domains, we investigated the predictions from our hedonic compensation model. There was clear and consistent evidence across studies and analyses for the prediction that distraction during consumption compromises the actual enjoyment of a given consumption experience. Both empirical studies yielded consistent evidence for a positive association between actual enjoyment and consumption satisfaction but inconsistent and weaker evidence for the expected role of actual-expected enjoyment discrepancies for this part of the model. There was also consistent evidence for the expected negative association between consumption satisfaction and the need for further gratification. Finally, there was moderate and inconsistent support linking the need for further gratification to subsequent consumption across Study 1 (amount and frequency of snacking in the afternoon) and Study 2 (shorter duration to subsequent consumption). Taken together, the present framework provides initial support for the proposed link among compromising consumption contexts, consumption enjoyment, and subsequent hedonic compensation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Syndesmotic injury with ankle fracture: A systematic review of screw vs dynamic fixation.

Cortical screw fixation across the tibiofibular joint is the mainstay of treatment for syndesmotic injury. Dynamic fixation devices have been developed offering similar advantages to screw fixation in terms of reduction and stability of the syndesmosis. Dynamic fixation may also facilitate a more physiological movement between the tibiofibular joint and thus incur less morbidity. Patient's rehabilitation potential is enhanced and reduces the need for hardware removal. Our systematic review aims to analyse the relevant current literature and compare screw fixation to dynamic fixation in the treatment of syndesmotic injury associated with acute ankle fractures. A literature search was performed on Pubmed and Ovid Medline to find scientific papers relating to syndesmotic fixation in acute ankle fractures. Papers were screened and included dependent on predetermined criteria. Risk of bias was assessed after screening full papers by two independent reviewers. Tables and analysis were made using Microsoft excel. A total of 8 papers with 673 patients were included. We found no functional difference between screw fixation or dynamic fixation groups at final follow-up. Three papers showed statistically significant lower rates of reoperation in the dynamic fixation group. Dynamic fixation may offer lower post operative complications and reoperation rates. Therefore, dynamic fixation may be a beneficial alternative treatment compared to traditionally used syndesmotic screws.

Assessing the state of antibacterial drug discovery through patent analysis.

Patent filings suggest increasing intensity of antibacterial drug discovery in recent years, but the share of patents published by commercial companies has declined.

Efficacy of Targeted Mast Cell Inhibition Therapy in Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

OBJECTIVE: To identify a subgroup of patients with mast cell dysfunction in chronic prostatitis/chronic pelvic pain syndrome and evaluate efficacy of mast cell-directed therapy. MATERIALS AND METHODS: Men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) were recruited and evaluated in an open-label, interventional uncontrolled trial after therapy with cromolyn sodium and cetirizine hydrochloride. The primary endpoint was a change in mast cell tryptase concentrations after treatment while secondary endpoints were changes in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and AUA-SI. Isolated cells from postprostatic massage urine were evaluated for immune changes using mRNA expression analysis. RESULTS: 31 patients with a diagnoses of Category III CP/CPPS were consented, 25 patients qualified and 20 completed the study after meeting a prespecified threshold for active tryptase in expressed prostatic secretions. After treatment with cromolyn sodium and cetirizine dihydrochloride for 3-week, active tryptase concentrations were significantly reduced from 49.03±14.05 ug/mL to 25.49±5.48 ug/mL (P<.05). The NIH-CPSI total score was reduced with a mean difference of 5.2±1 along with reduction in the pain, urinary and quality of life subscores (P<.001). A reduction in the AUA-SI was observed following treatment (P<.05). NanoString mRNA analysis of isolated cells revealed downregulation of immune-related pathways including Th1 and Th17 T cell differentiation and TLR signaling. Marked reduction in CD45+ cells and specifically macrophages and neutrophil abundance was observed. CONCLUSION: Identification of CP/CPPS patients with mast cell dysfunction may be achieved using tryptase as a discriminating biomarker. Mast cell-directed therapy in this targeted subgroup may be effective in reducing symptoms and modulating the immune inflammatory environment.

Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI. METHODS: We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. RESULTS: We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases. CONCLUSIONS: We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.

Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer.

This work examines differences in chromatin accessibility, methylation, and response to DNA hypomethylating agents between mismatch repair-deficient and non-mismatch repair-deficient endometrial cancer. Next-generation sequencing of a stage 1B, grade 2 endometrioid endometrial cancer tumor revealed microsatellite instability and a variant of unknown significance in POLE along with global and MLH1 hypermethylation. Inhibition of viability by decitabine in the study and comparison tumors was minimal, as shown by an inhibitory effect of 0 and 17.9, respectively. Conversely, the inhibitory effect of azacitidine on the study tumor was more pronounced, at 72.8 versus 41.2. In vitro, mismatch repair-deficient endometrial cancer with MLH1 hypermethylation respond better to DNA methyltransferase inhibition by azacytidine (DNA/RNA inhibition), than to decitabine (DNA-only inhibition). Additional large studies are needed to substantiate our findings.

Fatal drug use in the COVID-19 pandemic response: Changing trends in drug-involved deaths before and after stay-at-home orders in Louisiana.

The effect of disaster events on increasing drug-involved deaths has been clearly shown in previous literature. As the COVID-19 pandemic led to stay-at-home orders throughout the United States, there was a simultaneous spike in drug-involved deaths around the country. The landscape of a preexisting epidemic of drug-involved deaths in the United States is one which is not geographically homogenous. Given this unequal distribution of mortality, state-specific analysis of changing trends in drug use and drug-involved deaths is vital to inform both care for people who use drugs and local policy. An analysis of public health surveillance data from the state of Louisiana, both before and after the initial stay-at-home order of the COVID-19 pandemic, was used to determine the effect the pandemic may have had on the drug-involved deaths within this state. Using the linear regression analysis of total drug-involved deaths, as well as drug-specific subgroups, trends were measured based on quarterly (Qly) deaths. With the initial stay-at-home order as the change point, trends measured through quarter 1 (Q1) of 2020 were compared to trends measured from quarter 2 (Q2) of 2020 through quarter 3 (Q3) of 2021. The significantly increased rate of change in Qly drug-involved deaths, synthetic opioid-involved deaths, stimulant-involved deaths, and psychostimulant-involved deaths indicates a long-term change following the initial response to the COVID-19 pandemic. Changes in the delivery of mental health services, harm reduction services, medication for opioid use disorder (MOUD), treatment services, withdrawal management services, addiction counseling, shelters, housing, and food supplies further limited drug-involved prevention support, all of which were exacerbated by the new stress of living in a pandemic and economic uncertainty.

Frequency of inter-specialty consensus decisions and adherence to advice following discussion at a weekly neurovascular multidisciplinary meeting.

BACKGROUND/AIMS: Data are limited on the frequency of 'consensus decisions' between sub-specialists attending a neurovascular multidisciplinary meeting (MDM) regarding management of patients with extracranial carotid/vertebral stenoses and post-MDM 'adherence' to such advice. METHODS: This prospective audit/quality improvement project collated prospectively-recorded data from a weekly Neurovascular/Stroke Centre MDM documenting the proportion of extracranial carotid/vertebral stenosis patients in whom 'consensus management decisions' were reached by neurologists, vascular surgeons, stroke physicians-geriatricians and neuroradiologists. Adherence to MDM advice was analysed in asymptomatic carotid stenosis (ACS), symptomatic carotid stenosis (SCS), 'indeterminate symptomatic status stenosis' (ISS) and vertebral artery stenosis (VAS) patients, including intervals between index event to MDM + / - intervention. RESULTS: One hundred fifteen patients were discussed: 108 with carotid stenosis and 7 with VAS. Consensus regarding management was noted in 96.5% (111/115): 100% with ACS and VAS, 96.2% with SCS and 92.9% with ISS. Adherence to MDM management advice was 96.4% (107/111): 100% in ACS, ISS and VAS patients; 92% (46/50) in SCS patients. The median interval from index symptoms to revascularisation in 50-99% SCS patients was 12.5 days (IQR: 9-18.3 days; N = 26), with a median interval from MDM to revascularisation of 5.5 days (IQR: 1-7 days). Thirty patients underwent revascularisation. Two out of twenty-nine patients (6.9%) with either SCS or ISS had a peri-procedural ipsilateral ischaemic stroke, with no further strokes/deaths during 3-months follow-up. CONCLUSIONS: The high frequency of inter-specialty consensus regarding management and adherence to proposed treatment supports a collaborative/multidisciplinary model of care in patients with extracranial arterial stenoses. Service development should aim to shorten times between MDM discussion-intervention and optimise prevention of stroke/death.

Validation of a Novel Method of Measuring Cup Orientation Using BiPlanar Simultaneous Radiographic Images.

BACKGROUND: Accurate acetabular component positioning is paramount to the success of total hip arthroplasty (THA). Two-dimensional imaging alone remains a popular tool for implant position assessment despite known limitations. We investigated the accuracy of a novel method for assessing acetabular component position based upon orthogonal simultaneous biplanar X-ray images. METHODS: There were forty consecutive patients who had a preexisting THA on the contralateral side who underwent both computed tomography (CT) and simultaneous orthogonal biplanar radiographic scans for preoperative planning of THA. The operative inclination (OI) and operative anteversion (OA) of the acetabular cup were calculated by a new measurement method using the biplanar simultaneous scans. Those measurements were compared to measurement of the cup orientation on CT. The measurements were made by 2 independent observers. Interobserver correlation coefficients were calculated between the 2 observers to measure reliability. RESULTS: The mean error in OA measurement of the acetabular cup between simultaneous orthogonal biplanar radiographic and CT imaging was 0.5° (SD: 1.9°, minimum -4.0°, maximum 5.0°), the mean error in OI was 0.0° (SD: 1.7°, minimum -5.0°, maximum 4.0°). The average absolute error was 1.5° for OA and 1.2° for OI. Interobserver correlation coefficient was 0.83 for OA and 0.93 for OI. CONCLUSION: The novel method of measuring cup orientation using simultaneous biplanar radiographic scans utilized in this study was accurate and reproducible between observers compared to CT measurements.

Spatial and temporal non-stationarity in long-term population dynamics of over-wintering birds of North America.

Understanding population changes across long time scales and at fine spatiotemporal resolutions is important for confronting a broad suite of conservation challenges. However, this task is hampered by a lack of quality long-term census data for multiple species collected across large geographic regions. Here, we used century-long (1919-2018) data from the Audubon Christmas Bird Count (CBC) survey to assess population changes in over 300 avian species in North America and evaluate their temporal non-stationarity. To estimate population sizes across the entire century, we employed a Bayesian hierarchical model that accounts for species detection probabilities, variable sampling effort, and missing data. We evaluated population trends using generalized additive models (GAMs) and assessed temporal non-stationarity in the rate of population change by extracting the first derivatives from the fitted GAM functions. We then summarized the population dynamics across species, space, and time using a non-parametric clustering algorithm that categorized individual population trends into four distinct trend clusters. We found that species varied widely in their population trajectories, with over 90% of species showing a considerable degree of spatial and/or temporal non-stationarity, and many showing strong shifts in the direction and magnitude of population trends throughout the past century. Species were roughly equally distributed across the four clusters of population trajectories, although grassland, forest, and desert specialists more commonly showed declining trends. Interestingly, for many species, region-wide population trends often differed from those observed at individual sites, suggesting that conservation decisions need to be tailored to fine spatial scales. Together, our results highlight the importance of considering spatial and temporal non-stationarity when assessing long-term population changes. More generally, we demonstrate the promise of novel statistical techniques for improving the utility and extending the temporal scope of existing citizen science datasets.

Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a Series of PRMT5 Inhibitors.

An imidazolone → triazolone replacement addressed the limited passive permeability of a series of protein arginine methyl transferase 5 (PRMT5) inhibitors. This increase in passive permeability was unexpected given the increase in the hydrogen bond acceptor (HBA) count and topological polar surface area (TPSA), two descriptors that are typically inversely correlated with permeability. Quantum mechanics (QM) calculations revealed that this unusual effect was due to an electronically driven disconnect between TPSA and 3D-PSA, which manifests in a reduction in overall HBA strength as indicated by the HBA moment descriptor from COSMO-RS (conductor-like screening model for real solvation). HBA moment was subsequently deployed as a design parameter leading to the discovery of inhibitors with not only improved passive permeability but also reduced P-glycoprotein (P-gp) transport. Our case study suggests that hidden polarity as quantified by TPSA-3DPSA can be rationally designed through QM calculations.

Projected US savings from biosimilars, 2021-2025.

OBJECTIVES: Biologics account for an increasing share of US prescription drug spending. Biosimilars could lower biologic prices through competition, but barriers to increasing both supply and uptake remain. We projected US biosimilar savings from 2021 to 2025 under different scenarios. STUDY DESIGN: We projected US spending on biologics over a 5-year period under 3 scenarios: (1) a baseline scenario holding quarter 4 (Q4) of 2020 market conditions constant; (2) under main assumptions allowing for biosimilar market growth and entry; and (3) an upper-bound scenario assuming greater biosimilar uptake, more robust price competition, and quicker biosimilar entry. METHODS: We first analyzed 2014-2020 US volume and price data from IQVIA's MIDAS database for biologics already facing biosimilar competition to inform model parameter values. We used these inputs to project biosimilar entry, biosimilar volume shares, biosimilar prices, and reference biologic prices. We calculated 2021-2025 new savings from biosimilar competition vs the Q4 2020 baseline. RESULTS: Estimated biosimilar savings from 2021 to 2025 under our main approach were $38.4 billion, or 5.9% of projected spending on biologics over the same period. Biologics first facing biosimilar competition from 2021 to 2025 accounted for $26.1 billion of savings, with $12.2 billion from evolving market conditions for already-marketed biosimilars. Furthermore, $24.6 billion of savings under our main approach were from downward pressure on reference biologic prices rather than lower biosimilar prices. Savings were substantially higher ($124.5 billion) under the upper-bound scenario. CONCLUSIONS: Biosimilar savings from 2021 to 2025 were $38.4 billion under our main assumptions. Greater savings may be feasible if managed care and other settings increase biosimilar utilization and promote competition.