Trypanosoma brucei Invariant Surface Glycoprotein 75 Is an Immunoglobulin Fc Receptor Inhibiting Complement Activation and Antibody-Mediated Cellular Phagocytosis.

Various subspecies of the unicellular parasite Trypanosoma brucei cause sleeping sickness, a neglected tropical disease affecting millions of individuals and domestic animals. Immune evasion mechanisms play a pivotal role in parasite survival within the host and enable the parasite to establish a chronic infection. In particular, the rapid switching of variant surface glycoproteins covering a large proportion of the parasite's surface enables the parasite to avoid clearance by the adaptive immune system of the host. In this article, we present the crystal structure and discover an immune-evasive function of the extracellular region of the T. brucei invariant surface gp75 (ISG75). Structural analysis determined that the ISG75 ectodomain is organized as a globular head domain and a long slender coiled-coil domain. Subsequent ligand screening and binding analysis determined that the head domain of ISG75 confers interaction with the Fc region of all subclasses of human IgG. Importantly, the ISG75-IgG interaction strongly inhibits both activation of the classical complement pathway and Ab-dependent cellular phagocytosis by competing with C1q and host cell FcγR CD32. Our data reveal a novel immune evasion mechanism of T. brucei, with ISG75 able to inactivate the activities of Abs recognizing the parasite surface proteins.

A simulation study on the sensitivity of transcranial ray-tracing ultrasound modeling to skull properties.

In transcranial focused ultrasound therapies, such as treating essential tremor via thermal ablation in the thalamus, acoustic energy is focused through the skull using a phased-array transducer. Ray tracing is a computationally efficient method that can correct skull-induced phase aberrations via per-element phase delay calculations using patient-specific computed tomography (CT) data. However, recent studies show that variations in CT-derived Hounsfield unit may account for only 50% of the speed of sound variability in human skull specimens, potentially limiting clinical transcranial ultrasound applications. Therefore, understanding the sensitivity of treatment planning methods to material parameter variations is essential. The present work uses a ray-tracing simulation model to explore how imprecision in model inputs, arising from clinically significant uncertainties in skull properties or considerations of acoustic phenomena, affects acoustic focusing quality through the skull. We propose and validate new methods to optimize ray-tracing skull simulations for clinical treatment planning, relevant for predicting intracranial target's thermal rise, using experimental data from ex-vivo human skulls.

How Do Colorado Public Libraries Respond to Patron Queries about Opioid Use Disorder? A Secret Shopper Study.

Background: Colorado's age-adjusted fatal opioid overdose rate increased over 400% from 2000 to 2020. Public libraries are increasingly valuable community resources for accessing health-related information. We sought to evaluate the availability and types of opioid use disorder (OUD)-related resources offered through Colorado Public Library branches using secret shoppers to collect data. Methods: This was a cross sectional study of 197 Colorado Public Libraries in 2021. Anonymous auditors posed as library patrons asking a brief standardized script about availability of OUD-related resources over the phone. We conducted descriptive analyses of the libraries contacted, the response types of OUD resources provided, and information about naloxone availability. Outcomes were compared between urban/rural and libraries within/outside the Denver Public Library (DPL) system via means comparison tests. Results: Approximately 50% of libraries were classified as urban. Most (81%) of the libraries offered a valid OUD-resource, and over half (51%) provided a referral to a treatment center offering at least one medication for OUD. Over a third (36%) of librarians referenced the statewide naloxone standing order allowing patients to obtain naloxone from a pharmacy without prescription. One in ten libraries provided at least one invalid referral resource. Libraries within the DPL system referenced Colorado's naloxone standing order at higher rates than non-DPL libraries. Conclusions: Public libraries may benefit from the development of a standard for OUD-related resource training/education that can be distributed across the state to create a space for community members to obtain resources related to substance use.

Models of gene-culture evolution are incomplete without incorporating epigenetic effects.

Epigenetics impacts gene-culture coevolution by amplifying phenotypic variation, including clustering, and bridging the difference in timescales between genetic and cultural evolution. The dual inheritance model described by Uchiyama et al. could be modified to provide greater explanatory power by incorporating epigenetic effects.

Clinical context for cancer risk of immunosuppressive agents used in dermatology.

Dermatologic care of inflammatory skin conditions has been transformed over recent decades through the use of small molecules disease-modifying anti-rheumatic drugs and targeted biologic therapies. Alongside the tremendous benefit of these agents, concerns remain regarding possible side effects, particularly cancer risk. To improve guidance and counseling of patients with skin diseases who are considering treatment with such agents, this article reviews available information on the risk of malignancies in patients treated with these agents. When possible, this article adds clinical context to risk through a number needed to harm that estimates the number of patients a provider would need to treat with a given agent in 1 year to cause a single adverse outcome over time.

Modulation of the Hippo pathway and organ growth by RNA processing proteins.

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors-Yorkie (Yki) in Drosophila and YAP/TAZ in mammals-result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.

Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide.

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the cis-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding trans-system can be fulfilled by several competing helical structures.

The Role of Conformational Dynamics in the Recognition and Regulation of Ubiquitination.

The ubiquitination pathway is central to many cell signaling and regulatory events. One of the intriguing aspects of the pathway is the combinatorial sophistication of substrate recognition and ubiquitin chain building determinations. The abundant structural and biological data portray several characteristic protein folds among E2 and E3 proteins, and the understanding of the combinatorial complexity that enables interaction with much of the human proteome is a major goal to developing targeted and selective manipulation of the pathway. With the commonality of some folds, there are likely other aspects that can provide differentiation and recognition. These aspects involve allosteric effects and conformational dynamics that can direct recognition and chain building processes. In this review, we will describe the current state of the knowledge for conformational dynamics across a wide timescale, address the limitations of present approaches, and illustrate the potential to make new advances in connecting dynamics with ubiquitination regulation.

Integrated Effects of Neonatal Ventral Hippocampal Lesions and Impoverished Social-Environmental Rearing on Endophenotypes of Mental Illness and Addiction Vulnerability.

A wide range of mental illnesses show high rates of addiction comorbidities regardless of their genetic, neurodevelopmental, and/or adverse-environmental etiologies. Understanding how the spectrum of mental illnesses produce addiction vulnerability will be key to discovering more effective preventions and integrated treatments for adults with addiction and dual diagnosis comorbidities. A population of 131 rats containing a spectrum of etiological mental illness models and degrees of severity was experimentally generated by crossing neonatal ventral hippocampal lesions (NVHL; n = 68) or controls (SHAM-operated; n = 63) with adolescent rearing in environmentally/socially enriched (ENR; n = 66) or impoverished (IMP; n = 65) conditions. This population was divided into 2 experiments: first, examining NVHL and IMP effects on novelty and mild stress-induced locomotion across 3 adolescent ages; second, looking at initial cocaine reactivity and long-term cocaine behavioral sensitization in adulthood. NVHL and IMP-environmental conditions independently produced remarkably similar and robustly significant abnormalities of hyperreactivity to novelty, mild stress, and long-term cocaine sensitization. The combined NVHL-IMP groups showed the most severe phenotypes across the board, so that the mental illness and addiction vulnerability phenotypes increased together in severity in a consistent stepwise progression from the healthiest rats to those with the greatest loading of etiological models. These findings add weight to our understanding of mental illness and addiction vulnerability as brain disorders that are biologically and developmentally unified in ways that transcend etiological causes, and yet co-intensify with increased loading of etiological conditions. Combining neurodevelopmental and adverse-environmental models of mental illness may provide an approach to identifying and therapeutically targeting cortical-striatal-limbic network mechanisms that generate addiction and dual diagnosis diseases.

Predicting opioid use disorder in patients with chronic pain who present to the emergency department.

BACKGROUND: Emergency department (ED) patients with chronic pain challenge providers to make quick and accurate assessments without an in-depth pain management consultation. Emergency physicians need reliable means to determine which patients may receive opioid therapy without exacerbating opioid use disorder (OUD). METHODS: Eighty-nine ED patients with a chief complaint of chronic pain were enrolled. Researchers administered questionnaires and reviewed medical and state prescription monitoring database information. Participants were classified as either OUD or non-OUD. Statistical analysis included a bivariate analysis comparing differences between groups and multivariate logistic regression evaluating ORs. RESULTS: The 45 participants categorised as OUD had a higher proportion of documented or reported psychiatric diagnoses (p=0.049), preference of opioid treatment (p=0.005), current oxycodone prescription (p=0.043), borrowed pain medicine (p=0.004) and non-authorised dose increase (p<0.001). The state prescription monitoring database revealed the OUD group to have an increased number of opioid prescriptions (p=0.005) and pills (p=0.010). Participants who borrowed pain medicine and engaged in non-authorised dose increase were 5.2 (p=0.025, 95% CI 1.24 to 21.9) and 6.1 times (p=0.001, 95% CI 1.55 to 24.1) more likely to have OUD, respectively. LIMITATIONS: Major limitations of our study include a small sample size, self-reported measures and convenience sample which may introduce selection bias. CONCLUSION: Patients with chronic pain with OUD have distinguishable characteristics. Emergency physicians should consider such evidence-based variables prior to opioid therapy to ameliorate the opioid crisis and limit implicit bias.

Superposition method for modelling boundaries between media in viscoelastic finite difference time domain simulations.

Finite-difference time domain (FDTD) techniques are widely used to model the propagation of viscoelastic waves through complex and heterogeneous structures. However, in the specific case of media mixing liquid and solid, attempts to model continuous media onto a Cartesian grid produces errors when the liquid-solid interface between different media do not align precisely with the Cartesian grid. The increase in spatial resolution required to eliminate this grid staircasing effect can be computationally prohibitive. Here, a modification to the Virieux staggered-grid FDTD scheme called the superposition method is presented. This method is intended to reduce this staircasing effect while keeping a manageable computational time. The method was validated by comparing low-spatial-resolution simulations against simulations with sufficiently high resolution to provide reasonably accurate results at any incident angle. The comparison of the root-mean-square of the stress amplitude maps showed that the amplitude of artifactual waves could be reduced by several orders of magnitude when compared to the Virieux staggered-grid FDTD method and that the superposition method helped to significantly reduce the staircasing effect in FDTD simulations.

Impact of Co-Morbidities on the Cost of Care in Primary Elective Joint Arthroplasty.

BACKGROUND: The Comprehensive Care for Joint Replacement model is the newest iteration of the bundled payment methodology introduced by the Centers for Medicare and Medicaid Services. Comprehensive Care for Joint Replacement model, while incentivizing providers to deliver care at a lower cost, does not incorporate any patient-level risk stratification. Our study evaluated the impact of specific medical co-morbidities on the cost of care in total joint arthroplasty (TJA) patients. METHODS: A retrospective study was conducted on 1258 Medicare patients who underwent primary elective TJA between January 2015 and July 2016 at a single institution. There were 488 males, 552 hips, and the mean age was 71 years. Cost data were obtained from the Centers for Medicare and Medicaid Services. Co-morbidity information was obtained from a manual review of patient records. Fourteen co-morbidities were included in our final multiple linear regression models. RESULTS: The regression models significantly predicted cost variation (P < .001). For index hospital costs, a history of cardiac arrhythmias (P < .001), valvular heart disease (P = .014), and anemia (P = .020) significantly increased costs. For post-acute care costs, a history of neurological conditions like Parkinson's disease or seizures (P < .001), malignancy (P = .001), hypertension (P = .012), depression (P = .014), and hypothyroidism (P = .044) were associated with increases in cost. Similarly, for total episode cost, a history of neurological conditions (P < .001), hypertension (P = .012), malignancy (P = .023), and diabetes (P = .029) were predictors for increased costs. CONCLUSION: The cost of care in primary elective TJA increases with greater patient co-morbidity. Our data provide insight into the relative impact of specific medical conditions on cost of care and may be used in risk stratification in future reimbursement methodologies.

Adolescent flourishing in relation to having asthma: Results from a population-based cross-sectional study.

OBJECTIVE: This study investigated parent report of adolescent behaviors and flourishing of adolescents with asthma from a nationwide sample. METHODS: A secondary analysis of the 2011-2012 National Survey of Children's Health was conducted. There were 2,880 youth with asthma in our sample and 25,841 without asthma between 13 and 17 years of age. Analyses examined flourishing among adolescents with and without asthma and the impact of adolescent arguing, bullying, and mood difficulties on adolescent flourishing for adolescents with asthma, while controlling for sex, age, and race. RESULTS: Findings indicated lower flourishing for youth with asthma compared to youth without asthma. Moreover, adolescents with asthma who experienced negative behaviors, such as arguing and bullying, and adolescents who were experiencing sad feelings had lower flourishing. CONCLUSIONS: The results were consistent with literature, indicating that relatively poorer behavioral and emotional functioning is related to lower flourishing in adolescents with asthma. The results highlight the importance of screening for emotional functioning in adolescents and the need for further research to understand characteristics of adolescents related to their positive functioning.

ICS Use May Modify FEV1 Decline in α1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils.

BACKGROUND: α1-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. OBJECTIVES: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV1 decline in patients with AATD. METHODS: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 × 109/L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted. RESULTS: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. CONCLUSIONS: Blood eosinophil levels persistently >0.2 × 109/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV1 decline.

Assessment of risk behaviors in patients with opioid prescriptions: A study of indiana's inspect data.

BACKGROUND AND OBJECTIVES: Prescription Drug Monitoring Programs (PDMPs) can serve as screening tools and support the clinical decision-making process in patients receiving opioids. The objective of the study was to utilize 2014 INSPECT (Indiana's PDMP) data to identify factors that increase patients' likelihood to engage in opioid-related risk behaviors. METHODS: Based on a literature review, four risk behaviors were identified: Receiving >90 morphine milligram equivalents (MME), having >4 opioid prescribers, obtaining opioids from >4 pharmacies, and concurrent use of opioids and benzodiazepines. Two binary logistic regression analyses (engaging in at least one risk behaviors; engaging in all four risk behaviors) and an ordinal regression analysis (engaging in 0-4 risk behaviors) were conducted to identify factors associated with these opioid-related risk behaviors. RESULTS: Of the 1,538,120 unique opioid patients included in the study, 18.4% engaged in one, 5.3% in two, 1.6% in three, and .4% in all four risk behaviors. Depending on the model, prescribing a second monthly opioid increased patients' odds to engage in risk behaviors by a factor of 10 or more and prescribing two or more benzodiazepines annually increased the odds at least 13-fold. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: About one-fourth of all patients consuming opioids engaged in one or more risk behaviors; higher number of opioid prescriptions and addition of even a small number of benzodiazepine prescriptions dramatically increased these odds. PDMPs can be helpful in identifying opioid users at high-risk for misuse. This information could be used to target efforts to reduce the prescription drug epidemic. (Am J Addict 2017;26:822-829).

Lung Transplantation in Alpha-1-Antitrypsin Deficiency.

BACKGROUND: Lung transplantation is a therapeutic option for patients with end-stage lung disease and a survival benefit has been described in patients with alpha-1-antitrypsin deficiency (A1ATD). The aims of the current study were to determine the survival and health benefits of lung transplantation in UK patients with A1ATD compared to carefully matched non-transplant patients. METHODS: Patients with the PiZZ (alpha-1-antitrypsin deficiency) genotype who had undergone lung transplantation between 1996 and 2011 were identified from the UK A1ATD registry. Lung physiology, health status and survival were compared pre- and post-transplant using carefully matched non-transplant patients. RESULTS: Thirty-two A1ATD patients who had undergone lung transplant were identified. Lung function decline pre-transplant was not different to the closely matched non-transplanted cohort. The transplant group pre-transplant, although matched for FEV1, had lower gas transfer measurements, (mean KCO% predicted 41.0% SE ± 3.86 vs 55.6% SE ± 3.10 p < 0.001) and worse health status (SGRQ mean score 64.2 SE ± 2.5 vs 55.3 SE ± 2.0, p < 0.001). Post-transplant, physiology and health status improved significantly (p < 0.002). However, the post-operative mortality over 5 years was no better than for a second group of non-transplant patients further matched for gas transfer or a third group also matched for SGRQ. CONCLUSION: Patients who underwent lung transplant had lower gas transfer and quality-of-life pre-transplant compared to non-transplant patients matched for FEV1, age and sex, suggesting that these parameters provide extra information helpful in decision making. Lung transplantation for A1ATD patients significantly improves quality-of-life but not survival.

Structural basis for cell surface patterning through NetrinG-NGL interactions.

Brain wiring depends on cells making highly localized and selective connections through surface protein-protein interactions, including those between NetrinGs and NetrinG ligands (NGLs). The NetrinGs are members of the structurally uncharacterized netrin family. We present a comprehensive crystallographic analysis comprising NetrinG1-NGL1 and NetrinG2-NGL2 complexes, unliganded NetrinG2 and NGL3. Cognate NetrinG-NGL interactions depend on three specificity-conferring NetrinG loops, clasped tightly by matching NGL surfaces. We engineered these NGL surfaces to implant custom-made affinities for NetrinG1 and NetrinG2. In a cellular patterning assay, we demonstrate that NetrinG-binding selectivity can direct the sorting of a mixed population of NGLs into discrete cell surface subdomains. These results provide a molecular model for selectivity-based patterning in a neuronal recognition system, dysregulation of which is associated with severe neuropsychological disorders.

Effects of food on pharmacokinetics of immediate release oral formulations of aspirin, dipyrone, paracetamol and NSAIDs - a systematic review.

AIMS: It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states. METHODS: A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (tmax ), and its extent (Cmax ) was conducted. Delayed-release formulations were not included. RESULTS: Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting tmax was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed tmax was 1.30 to 2.80 times longer than fasted tmax . Cmax was typically reduced, with greater reduction seen with more rapid absorption (fed Cmax only 44-85% of the fasted Cmax for aspirin, diclofenac, ibuprofen and paracetamol). CONCLUSION: There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public.

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote.

BACKGROUND: Inheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes. METHODS: Second order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied. RESULTS: The F variant had a reduced association rate constant with neutrophil elastase (5.60 ± 0.83 × 106 M-1 s-1) compared to the normal M variant (1.45 ± 0.02 × 107 M-1 s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34 ± 0.03 × 106 M-1 s-1). The association rate constant for the F variant and proteinase 3 (1.06 ± 0.22 × 106 M-1 s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease. CONCLUSIONS: The F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin.