Mathematical model of intestinal lipolysis of a long-chain triglyceride.

Lipids are an important component of food and oral drug formulations. Upon release into gastrointestinal fluids, triglycerides, common components of foods and drug delivery systems, form emulsions and are digested into simpler amphiphilic lipids (e.g., fatty acids) that can associate with intestinal bile micelles and impact their drug solubilization capacity. Digestion of triglycerides is dynamic and dependent on lipid quantity and type, and quantities of other components in the intestinal environment (e.g., bile salts, lipases). The ability to predict lipid digestion kinetics in the intestine could enhance understanding of lipid impact on the fate of co-administered compounds (e.g., drugs, nutrients). In this study, we present a kinetic model that can predict the lipolysis of emulsions of triolein, a model long-chain triglyceride, as a function of triglyceride amount, droplet size, and quantity of pancreatic lipase in an intestinal environment containing bile micelles. The model is based on a Ping Pong Bi Bi mechanism coupled with quantitative analysis of partitioning of lipolysis products in colloids, including bile micelles, in solution. The agreement of lipolysis model predictions with experimental data suggests that the mechanism and proposed assumptions adequately represent triglyceride digestion in a simulated intestinal environment. In addition, we demonstrate the value of such a model over simpler, semi-mechanistic models reported in the literature. This lipolysis framework can serve as a basis for modeling digestion kinetics of different classes of triglycerides and other complex lipids as relevant in food and drug delivery systems.

Acceptance of disability in stroke: A qualitative metasynthesis.

Disability acceptance has been conceptualized as an internalization of oneself as a person experiencing disability and associated with better coping and motivation for rehabilitation. This is particularly pertinent to individuals experiencing stroke because many are initially not fully aware of their stroke-related impairments, which affects the acceptance process. This qualitative metasynthesis aimed to synthesize qualitative findings regarding disability acceptance in stroke and identify barriers and facilitators associated with it. Eighteen studies published from 2003 to 2022, conducted in Asia, Europe, and Australasia, were included in our review. A thematic synthesis was carried out through line-by-line coding and identification of descriptive and analytical themes. Three analytical themes emerged from the analysis: "understanding impairments," "flexibility and active engagement," and "disability acceptance as a non-linear process." Healthcare professionals may facilitate this process by guiding individuals experiencing stroke to recognize that they can manage their limitations and still lead meaningful lives.

IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model.

ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

Power to Detect What? Considerations for Planning and Evaluating Sample Size.

ACADEMIC ABSTRACT: In the wake of the replication crisis, social and personality psychologists have increased attention to power analysis and the adequacy of sample sizes. In this article, we analyze current controversies in this area, including choosing effect sizes, why and whether power analyses should be conducted on already-collected data, how to mitigate the negative effects of sample size criteria on specific kinds of research, and which power criterion to use. For novel research questions, we advocate that researchers base sample sizes on effects that are likely to be cost-effective for other people to implement (in applied settings) or to study (in basic research settings), given the limitations of interest-based minimums or field-wide effect sizes. We discuss two alternatives to power analysis, precision analysis and sequential analysis, and end with recommendations for improving the practices of researchers, reviewers, and journal editors in social-personality psychology. PUBLIC ABSTRACT: Recently, social-personality psychology has been criticized for basing some of its conclusions on studies with low numbers of participants. As a result, power analysis, a mathematical way to ensure that a study has enough participants to reliably "detect" a given size of psychological effect, has become popular. This article describes power analysis and discusses some controversies about it, including how researchers should derive assumptions about effect size, and how the requirements of power analysis can be applied without harming research on hard-to-reach and marginalized communities. For novel research questions, we advocate that researchers base sample sizes on effects that are likely to be cost-effective for other people to implement (in applied settings) or to study (in basic research settings). We discuss two alternatives to power analysis, precision analysis and sequential analysis, and end with recommendations for improving the practices of researchers, reviewers, and journal editors in social-personality psychology.

Acceptance of disability in stroke: a systematic review.

BACKGROUND: Evidence for the association between acceptance of disability (AOD) and positive rehabilitation outcomes, as well as for the use of AOD measurements in stroke rehabilitation practice, has increased in the international literature in the last decade. However, measurement tools for AOD are heterogenous and there has not been a systematic review summarizing the current evidence on the use of AOD measures and factors associated with AOD. OBJECTIVE: This study aimed to summarize current evidence on measurement tools used, present existing AOD scores in people with stroke and identify risk factors for and protective factors against poor AOD in people with stroke. METHODS: The original design and protocol of this systematic review were registered with PROSPERO. The included studies were published from 2008 to 2020 and identified from 5 databases-PubMed, EMBASE, CINAHL Plus, PsycInfo, and the Cochrane Library-using the following inclusion criteria: participants diagnosed with stroke and aged ≥16 years, measurement of AOD, and published in English in a peer-reviewed scientific journal. Review articles were excluded. RESULTS: Five measurement tools for AOD were reported. The Revised Acceptance of Disability Scale (ADS-R) and the acceptance subscale of the Illness Cognition Questionnaire (ICQ) had the highest internal consistency. Scores ranged from 71.7 to 74.2 on the ADS-R, 16.9-18.3 on the ICQ, 16.5-26.9 on the Acceptance of Illness Scale, and 87.8-93.2 on the Attitudes towards Disabled Persons Form A. Poorer function and depressive symptoms were associated with poor AOD, whereas religious beliefs, support from others, and an understanding of stroke were associated with better AOD. CONCLUSIONS: The ADS-R and the acceptance subscale of the ICQ are currently the most reliable measurement tools for measuring AOD in people with stroke. Further research to validate the measurement tools is required. This may help to identify people who require additional support. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42017077063; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=77063.

Experiencing Pain Invalidation is Associated with Under-Reporting of Pain: A Social Psychological Perspective on Acute Pain Communication.

Pain invalidation involves the dismissal or lack of understanding of another's pain, undermining their subjective experience. Frequent exposure to invalidation negatively impacts mental and physical health as well as pain-related behaviors, potentially leading people to conceal their pain from others in the future and/or withdraw from potential sources of support. It is therefore possible that experiencing pain invalidation may also impact pain-reporting behavior in clinical settings. Across 2 separate samples of emerging adults, we examined whether exposure to invalidation of one's pain was associated with cognizant modulation of one's subjective acute pain ratings within routine medical and dental settings. Drawing upon social psychological theories of impression management and self-presentation, we hypothesized that exposure to pain invalidation would be associated with the under-rating of one's pain. In Study 1, previous experiences of invalidation were associated with under-rating of one's pain when visiting the doctor and the dentist. Study 2 found that invalidation from family and medical professionals-but not from friends-was associated with under-rating pain in both settings. Findings provide further evidence for the harmful effects of pain invalidation, particularly for emerging adults, as the dismissal of one's subjective experience may sow self-doubt while reinforcing cultural stigmas against pain, leading to alterations in pain communication that ultimately creates barriers to efficacious clinical treatment and care and increase pain-related suffering. PERSPECTIVE: Pain invalidation imparts harm to those who already suffer from pain, be it mentally, physically, and/or behaviorally. We show that people who have encountered invalidation are more likely to under-rate their pain when seeking care, impeding assessment and treatment, and further highlighting the importance of clinical validation of pain experiences.

Acceleration-Based Estimation of Vertical Ground Reaction Forces during Running: A Comparison of Methods across Running Speeds, Surfaces, and Foot Strike Patterns.

Twenty-seven methods of estimating vertical ground reaction force first peak, loading rate, second peak, average, and/or time series from a single wearable accelerometer worn on the shank or approximate center of mass during running were compared. Force estimation errors were quantified for 74 participants across different running surfaces, speeds, and foot strike angles and biases, repeatability coefficients, and limits of agreement were modeled with linear mixed effects to quantify the accuracy, reliability, and precision. Several methods accurately and reliably estimated the first peak and loading rate, however, none could do so precisely (the limits of agreement exceeded ±65% of target values). Thus, we do not recommend first peak or loading rate estimation from accelerometers with the methods currently available. In contrast, the second peak, average, and time series could all be estimated accurately, reliably, and precisely with several different methods. Of these, we recommend the 'Pogson' methods due to their accuracy, reliability, and precision as well as their stability across surfaces, speeds, and foot strike angles.

Delivery of Therapeutic RNA to the Bone Marrow in Multiple Myeloma Using CD38-Targeted Lipid Nanoparticles.

Multiple myeloma (MM) is a cancer of differentiated plasma cells that occurs in the bone marrow (BM). Despite the recent advancements in drug development, most patients with MM eventually relapse and the disease remains incurable. RNA therapy delivered via lipid nanoparticles (LNPs) has the potential to be a promising cancer treatment, however, its clinical implementation is limited due to inefficient delivery to non-hepatic tissues. Here, targeted (t)LNPs designed for delivery of RNA payload to MM cells are presented. The tLNPs consist of a novel ionizable lipid and are coated with an anti-CD38 antibody (αCD38-tLNPs). To explore their therapeutic potential, it is demonstrated that LNPs encapsulating small interference RNA (siRNA) against cytoskeleton-associated protein 5 (CKAP5) lead to a ≈90% decrease in cell viability of MM cells in vitro. Next, a new xenograft MM mouse model is employed, which clinically resembles the human disease and demonstrates efficient homing of MM cells to the BM. Specific delivery of αCD38-tLNPs to BM-residing and disseminated MM cells and the improvement in therapeutic outcome of MM-bearing mice treated with αCD38-tLNPs-siRNA-CKAP5 are shown. These results underscore the potential of RNA therapeutics for treatment of MM and the importance of developing effective targeted delivery systems and reliable preclinical models.

Clinical variables for predicting type-1 and type-2 non-ST segment elevation myocardial infarction in those presenting with ischemic symptoms.

Introduction: The accuracy of detecting myocardial infarction (MI) has greatly improved with the advent of more sensitive assays, and this has led to etiologic subtyping. Distinguishing between type 1 and type 2 non-ST-segment elevation myocardial infarction (NSTEMI) early in the clinical course allows for the most appropriate advanced diagnostic procedures and most efficacious treatments. The purpose of this study was to investigate the predictive effect of demographic and clinical variables on predicting NSTEMI subtypes in patients presenting with ischemic symptoms. Material and methods: We performed a single institution retrospective cohort study of patients who presented to the emergency department (ED) with ischemic signs and symptoms consistent with non-ST-segment myocardial infarction, for whom results of coronary angiography were available. We analyzed demographic, laboratory, echocardiography and angiography data to determine predictors of NSTEMI sub-types. Results: Five hundred and forty-six patients were enrolled; 426 patients were found on coronary angiography to have type 1 acute MI (T1AMI), whereas 120 patients had type 2 acute MI (T2AMI). Age (OR per year = 1.03 (1.00, 1.05), p = 0.03), prior MI (OR = 3.50 (1.68, 7.22), p = 0.001), L/H > 2.0 (OR = 1.55 (1.12, 2.13), p = 0.007), percentage change in troponin I > 25% (OR = 2.54 (1.38, 4.69), p = 0.003), and regional wall motion abnormalities (RWMA) (OR = 3.53 (1.46, 8.54), p = 0.004) were independent predictors of T1AMI, whereas sex, race, body mass index, hypertension, end-stage renal disease (ESRD), heart failure, family history (FH) of coronary artery disease (CAD), HbA1c, and left ventricular ejection fraction (LVEF) were not. Conclusions: Key clinical variables such as age, prior MI, L/H ratio, percentage change in troponin I, and presence of RWMA on echocardiogram may be utilized as significant predictors of T1AMI in patients presenting with ischemic symptoms to the ED.

Over-Rating Pain is Overrated: A Fundamental Self-Other Bias in Pain Reporting Behavior.

Wide-spread cultural beliefs influence personal experiences and clinical treatment of pain, yet are often unexamined and unchallenged in the pain literature. The common cultural belief that people generally over-report or exaggerate pain is familiar, reflected in discordant patient-provider pain assessments, and compounded in the context of disparities in pain treatment. However, no studies have directly measured the prevalence of this belief among the general population, nor challenged the validity of this assumption by assessing normative pain reporting in clinical settings. Results of an initial and replication study suggest that reporting pain accurately "as-is" is the norm, yet most people still believe that others normatively over-report pain. We refer to the phenomenon by which most people report their pain as they experience it while paradoxically believing that others over-report their pain as the fundamental pain bias, and suggest this false perception may contribute to larger scale pain stigma and poor outcomes for people in pain. We also identify counter-stereotypical patterns of pain reporting among groups (ie, women, Latinx Americans) that face more disparate care. Results reinforce the need for respecting patient pain reports, and suggest that distrust surrounding others' pain experiences is prevalent in society. PERSPECTIVE: Most people claim to report their pain as accurately as possible, while simultaneously perpetuating common cultural beliefs that others over-report their pain. This fundamental pain bias highlights a pervasive misconception that likely contributes to patient-provider mistrust and broader cultural pain stigma.

Discovery proteomics defines androgen-regulated glycoprotein networks in prostate cancer cells, as well as putative biomarkers of prostatic diseases.

Supraphysiologic androgen (SPA) inhibits cell proliferation in prostate cancer (PCa) cells by transcriptional repression of DNA replication and cell-cycle genes. In this study, quantitative glycoprotein profiling identified androgen-regulated glycoprotein networks associated with SPA-mediated inhibition of PCa cell proliferation, and androgen-regulated glycoproteins in clinical prostate tissues. SPA-regulated glycoprotein networks were enriched for translation factors and ribosomal proteins, proteins that are known to be O-GlcNAcylated in response to various cellular stresses. Thus, androgen-regulated glycoproteins are likely to be targeted for O-GlcNAcylation. Comparative analysis of glycosylated proteins in PCa cells and clinical prostate tissue identified androgen-regulated glycoproteins that are differentially expressed prostate tissues at various stages of cancer. Notably, the enzyme ectonucleoside triphosphate diphosphohydrolase 5 was found to be an androgen-regulated glycoprotein in PCa cells, with higher expression in cancerous versus non-cancerous prostate tissue. Our glycoproteomics study provides an experimental framework for characterizing androgen-regulated proteins and glycoprotein networks, toward better understanding how this subproteome leads to physiologic and supraphysiologic proliferation responses in PCa cells, and their potential use as druggable biomarkers of dysregulated AR-dependent signaling in PCa cells.

How and Why Patient Concerns Influence Pain Reporting: A Qualitative Analysis of Personal Accounts and Perceptions of Others' Use of Numerical Pain Scales.

Complex factors influence how people report and interpret numerical pain ratings. Such variability can introduce noise and systematic bias into clinical pain assessment. Identification of factors that influence self-rated pain and its interpretation by others may bolster utility of these scales. In this qualitative study, 338 participants described motivations for modulating their own pain reports relative to a numerical pain scale (0-10), as well as perceptions of others' pain reporting modulation. Responses indicated that people over-report pain to enhance provider belief/responsiveness or the likelihood of pain relief, and out of fear of future pain or potential illness. Concerns of how one's pain affects and is perceived by others, and financial concerns motivated pain under-reporting. Unprompted, many participants reported never modulating their pain ratings, citing trust in providers and personal ethics. Similar reasons were assumed to motivate others' pain ratings. However, participants often attributed others' over-reporting to internal causes, and their own to external. This bias may underlie common assumptions that patients over-report pain for nefarious reasons, distort interpretation of pain reports, and contribute to pain invalidation. Recognition of patient concerns and one's own personal biases toward others' pain reporting may improve patient-provider trust and support precision of numerical pain ratings.

A simulated patient experience to improve pharmacy student empathy for patients on hemodialysis.

INTRODUCTION: The aim of this study was to increase student empathy towards hemodialysis patients through an educational intervention that simulates a hemodialysis patient experience. METHODS: Second-year pharmacy students (n = 83) in a required therapeutic module were asked to follow key lifestyle modifications of a hemodialysis patient for two weeks. Students' self-perceived empathy level was assessed using the Kiersma-Chen Empathy Scale (KCES) pre- and post-intervention and post-reflection questions captured students' perceptions of the experience. Data were analyzed using frequencies and Wilcoxon signed ranks tests to assess pre-post changes. Reflection questions were assessed using a grounded analysis to identify themes. RESULTS: Significant differences were found on 13 of 15 KCES items and KCES composite scores. Of the 13 significant KCES items, nine were related to the cognitive domain and four were related to the affective domain. When asked how the experience impacted the student personally, 38 responded that it provided them with a better understanding of the challenges associated with managing hemodialysis treatments. In response to how this experience would change their professional interactions with a hemodialysis patient, students explained that they felt more equipped to empathize with patients (n = 22). CONCLUSIONS: This intervention improved students' cognitive and affective empathy towards hemodialysis patients, which may prepare them to be more compassionate healthcare professionals. Experiencing first-hand some of the quality-of-life challenges hemodialysis patients face significantly influenced student empathy levels towards this population.

Publisher Correction: A Simplified, Graded, Electrodiagnostic Criterion for Guillain-Barré Syndrome That Incorporates Sensory Nerve Conduction Studies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Happiness, Meaning, and Psychological Richness.

What kind of life do people want? In psychology, a good life has typically been conceptualized in terms of either hedonic or eudaimonic well-being. We propose that psychological richness is another neglected aspect of what people consider a good life. In study 1 (9-nation cross-cultural study), we asked participants whether they ideally wanted a happy, a meaningful, or a psychologically rich life. Roughly 7 to 17% of participants chose the psychologically rich life. In study 2, we asked 1611 Americans and 680 Koreans what they regret most in their lives; then, if they could undo or reverse the regretful event, whether their lives would have been happier, more meaningful, or psychologically richer as a result. Roughly 28% of Americans and 35% of Koreans reported their lives would have been psychologically richer. Together, this work provides a foundation for the study of psychological richness as another dimension of a good life.

Biocompatibility and Durability of Diazonium Adhesives on Dental Alloys.

PURPOSE: A new type of diazonium-based adhesive has been recently developed by our team to bind dental alloys (Titanium, stainless steel, and cobalt chromium) to dental polymers. Here, we explored the endurance of the resulting adhesive after thermal-cycling and autoclave aging. MATERIALS AND METHODS: Polished samples of titanium (Ti), stainless steel (SS) and cobalt chromium (Co-Cr) were coated with a diazonium-based adhesive. Untreated samples served as controls (n = 12 per each condition). X-ray photoelectron spectroscopy (XPS) was performed to characterize the elemental compositions of the different surfaces. Biocompatibility of the coated alloys was assessed with human gingival fibroblasts (HGF). Inductively coupled plasma (ICP) and total organic carbon (TOC) analyses were used to quantify the ions and organic matters released from the diazonium coated alloys. Endurance of the adhesives was assessed by exposing the samples to autoclaving and thermal-cycling. The tensile strength of the poly(methylmethacrylate) (PMMA)-alloy bond was also tested. RESULTS: Results of mechanical testing demonstrated a higher endurance of the coated CoCr, Ti, and SS compared to the uncoated alloys. The human fibroblasts cultured on the substrates remained alive and metabolically active, and the coatings did not release significant amounts of toxic chemicals in solutions. CONCLUSIONS: The results further support the use of diazonium-based adhesives as new coupling agents for dental applications.

The influence of Latinx American identity on pain perception and treatment seeking.

INTRODUCTION: Latinx-Americans are underserved across healthcare contexts, and racial disparities in pain management are pervasive. One potential contributor is racial bias in pain perception - including low-level implicit biases and explicitly held lay-beliefs. Delays in seeking pain treatment may compound these disparities. However, experiments testing these factors in the context of Latinx-American pain are limited, and mechanisms by which Latinx-American group-membership influences pain perception and treatment are not understood. METHODS: Here, Latinx-American and White-American participants read vignettes including a Latinx or White patient's pain description and numerical pain rating. Participants then rated how much pain they thought each patient was in using the same numerical scale. Participants also reported how much pain they themselves would need to experience to prompt treatment-seeking. RESULTS: In contrast to prior work identifying lay beliefs that Latinx-Americans feel less pain than White-Americans, participants in the current study revealed a bias in the opposite direction. This was largely driven, however, by Latinx-American participants, who have been under-represented in previous studies of empathy and pain perception. Latinx-Americans ascribed more pain to patients overall - irrespective of patient race - relative to White-Americans. Latinx-American participants also reported that their own pain would need to be significantly more intense before seeing a doctor. CONCLUSION: These results suggest that, relative to White-Americans, Latinx-Americans may be more likely to believe people are in more pain than they report - or may be more perceptive of others' pain - and that they may be in more pain upon presenting to medical settings.

A Simplified, Graded, Electrodiagnostic Criterion for Guillain-Barré Syndrome That Incorporates Sensory Nerve Conduction Studies.

Traditional electrodiagnostic (EDX) criteria for Guillain-Barré Syndrome (GBS), e.g. those delineated by Ho et al. and Hadden et al., rely on motor nerve conduction studies (NCS), and focus on differentiating GBS subtypes instead of the accurate diagnosis of GBS. Sensory studies, including the sural-sparing pattern, are not routinely used in GBS EDX. We studied the utility of a simplified criterion that utilizes sensory NCS. Motor and sensory NCS abnormalities were defined by comparing against age and height adjusted norms derived from 245 controls. We considered the sural-sparing pattern a positive diagnostic feature. We analyzed 109 prospectively validated GBS patients and graded them as "Definite", "Probable" and "Possible" based on the number of motor and sensory abnormalities detected. Using proposed EDX criteria, 35.8%, 43.1%, 11.9% of all GBS patients were considered "Definite", "Probable" or "Possible" respectively; whereas traditional EDX criteria only diagnosed 49.5% of cases. 27.5%, 35.3% and 21.6% of patients with the Miller-Fisher Syndrome (MFS) subtype of GBS were considered "Definite", "Probable" or "Possible" respectively. In comparison, traditional criteria only detected 15.7% of cases. Our proposed EDX criterion, that includes sensory NCS, improves and grades the diagnostic certainty of GBS, especially MFS.