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).

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.

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.

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.

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.

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.

Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults.

Importance: Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking. Objective: To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics. Design, Setting, and Participants: This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months. Exposures: Diagnosis of iRMD. Main Outcomes and Measures: Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features. Results: Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change. Conclusions and Relevance: The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

A juxtamembrane basolateral targeting motif regulates signaling through a TGF-ß pathway receptor in Drosophila.

In polarized epithelial cells, receptor-ligand interactions can be restricted by different spatial distributions of the 2 interacting components, giving rise to an underappreciated layer of regulatory complexity. We explored whether such regulation occurs in the Drosophila wing disc, an epithelial tissue featuring the TGF-ß family member Decapentaplegic (Dpp) as a morphogen controlling growth and patterning. Dpp protein has been observed in an extracellular gradient within the columnar cell layer of the disc, but also uniformly in the disc lumen, leading to the question of how graded signaling is achieved in the face of 2 distinctly localized ligand pools. We find the Dpp Type II receptor Punt, but not the Type I receptor Tkv, is enriched at the basolateral membrane and depleted at the junctions and apical surface. Wit, a second Type II receptor, shows a markedly different behavior, with the protein detected on all membrane regions but enriched at the apical side. Mutational studies identified a short juxtamembrane sequence required for basolateral restriction of Punt in both wing discs and mammalian Madin-Darby canine kidney (MDCK) cells. This basolateral targeting (BLT) determinant can dominantly confer basolateral localization on an otherwise apical receptor. Rescue of punt mutants with transgenes altered in the targeting motif showed that flies expressing apicalized Punt due to the lack of a functional BLT displayed developmental defects, female sterility, and significant lethality. We also show that apicalized Punt does not produce an ectopic signal, indicating that the apical pool of Dpp is not a significant signaling source even when presented with Punt. Instead, we find that basolateral presentation of Punt is required for optimal signaling. Finally, we present evidence that the BLT acts through polarized sorting machinery that differs between types of epithelia. This suggests a code whereby each epithelial cell type may differentially traffic common receptors to enable distinctive responses to spatially localized pools of extracellular ligands.