Outcomes of a Fatigue Management Intervention for People With Post COVID-19 Condition.

OBJECTIVE: Fatigue is identified as one of the most prevalent and persistent problems reported by people with post COVID-19 condition that negatively impacts on everyday living and resumption of pre-COVID-19 lifestyle. A pilot occupational therapy fatigue management intervention was designed for patients presenting with post COVID-19 condition fatigue. DESIGN: A retrospective analysis was carried out after the delivery of the fatigue management intervention. Self-reported measures of fatigue, well-being, and health status were taken at baseline and repeated at 2 wks after intervention. Baseline and postintervention scores were compared using nonparametric analysis. RESULTS: Sixty participants (73% female), median age 50.5 yrs (range, 17-74), 93% reporting symptoms persisting for 12 wks or longer, completed the fatigue management intervention. All participants reported moderate to severe fatigue impacting on everyday activity at baseline. The greatest impact of fatigue was on engagement in leisure and work activity. Statistically significant improvement in fatigue ( P < 0.001), well-being ( P < 0.001), and health status ( P < 0.001) were noted after the intervention. CONCLUSIONS: Findings indicate the potential of occupational therapy fatigue management interventions to enable self-management strategies and reduce the negative impact of fatigue among people with post COVID-19 condition.

Penile Evaluation: An Illustrated Review.

ABSTRACT: High-frequency ultrasound is the imaging modality of choice for evaluating penile pathology because of its easy access, low cost, and patient tolerance ( The Penis, Diagnostic Ultrasound, second edtion . Boca Raton: CRC Press; 2007:957-978). This pictorial review will illustrate the sonographic features of emergent and nonemergent penile conditions such as penile fracture, spongial tear, urethral injury, various types of priapism, erectile dysfunction, penile abscess, and Mondor disease.

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

Thermal Traits Vary with Mass and across Populations of the Marsh Periwinkle, Littoraria irrorata.

AbstractPhysiological processes influence how individuals perform in various environmental contexts. The basis of such processes, metabolism, scales allometrically with body mass and nonlinearly with temperature, as described by a thermal performance curve. Past studies of thermal performance curves tend to focus on effects of temperature on a single body size or population, rather than variation in the thermal performance curve across sizes and populations. Here, we estimate intraspecific variation in parameters of the thermal performance curve in the salt marsh gastropod Littoraria irrorata. First, we quantify the thermal performance curve for respiration rate as a function of both temperature and body size in Littoraria and evaluate whether the thermal parameters and body size scaling are interdependent. Next, we quantify how parameters in the thermal performance curve for feeding rate vary between three Littoraria populations that occur along a latitudinal gradient. Our work suggests that the thermal traits describing Littoraria respiration are dependent on body mass and that both the thermal traits and the mass scaling of feeding vary across sites. We found limited evidence to suggest that mass scaling of Littoraria feeding or respiration rates depends on temperature. Variation in the thermal performance curves interacts with the size structure of the Littoraria population to generate divergent population-level responses to temperature. These results highlight the importance of considering variation in population size structure and physiological allometry when attempting to predict how temperature change will affect physiological responses and consumer-resource interactions.

Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription.

Posttranslational modifications of histone tails are a key contributor to epigenetic regulation. Histone H3 Arg26 and Lys27 are both modified by multiple enzymes, and their modifications have profound effects on gene expression. Citrullination of H3R26 by PAD2 and methylation of H3K27 by PRC2 have opposing downstream impacts on gene regulation; H3R26 citrullination activates gene expression, and H3K27 methylation represses gene expression. Both of these modifications are drivers of a variety of cancers, and their writer enzymes, PAD2 and EZH2, are the targets of drug therapies. After biochemical and cell-based analysis of these modifications, a negative crosstalk interaction is observed. Methylation of H3K27 slows citrullination of H3R26 30-fold, whereas citrullination of H3R26 slows methylation 30,000-fold. Examination of the mechanism of this crosstalk interaction uncovered a change in structure of the histone tail upon citrullination which prevents methylation by the PRC2 complex. This mechanism of crosstalk is reiterated in cell lines using knockdowns and inhibitors of both enzymes. Based our data, we propose a model in which, after H3 Cit26 formation, H3K27 demethylases are recruited to the chromatin to activate transcription. In total, our studies support the existence of crosstalk between citrullination of H3R26 and methylation of H3K27.

Development of a Selective Inhibitor of Protein Arginine Deiminase 2.

Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.

Detection and identification of protein citrullination in complex biological systems.

Protein citrullination is a post-translational modification of arginine that is catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Aberrantly increased citrullination is associated with a host of inflammatory diseases and cancer and PAD inhibitors have shown remarkable efficacy in a range of diseases including rheumatoid arthritis, lupus, atherosclerosis, and ulcerative colitis. In rheumatoid arthritis, citrullinated proteins serve as key antigens for rheumatoid arthritis-associated autoantibodies. These data suggest that citrullinated proteins may serve more generally as biomarkers of specific disease states, however, the identification of citrullinated residues remains challenging due to the small 1Da mass change that occurs upon citrullination. Herein, we highlight the available techniques to identify citrullinated proteins/residues focusing on advanced MS techniques as well as chemical derivatization strategies that are currently being employed to identify citrullinated proteins as well as the specific residues modified within those proteins.

Public Health Climate Change Adaptation Planning Using Stakeholder Feedback.

CONTEXT: Public health climate change adaptation planning is an urgent priority requiring stakeholder feedback. The 10 Essential Public Health Services can be applied to adaptation activities. OBJECTIVE: To develop a state health department climate and health adaptation plan as informed by stakeholder feedback. DESIGN: With Centers for Disease Control and Prevention (CDC) funding, the New York State Department of Health (NYSDOH) implemented a 2010-2013 climate and health planning process, including 7 surveys on perceptions and adaptation priorities. PARTICIPANTS: New York State Department of Health program managers participated in initial (n = 41, denominator unknown) and follow-up (72.2%) needs assessments. Surveillance system information was collected from 98.1% of surveillance system managers. For adaptation prioritization surveys, participants included 75.4% of NYSDOH leaders; 60.3% of local health departments (LHDs); and 53.7% of other stakeholders representing environmental, governmental, health, community, policy, academic, and business organizations. Interviews were also completed with 38.9% of other stakeholders. RESULTS: In 2011 surveys, 34.1% of state health program directors believed that climate change would impact their program priorities. However, 84.6% of state health surveillance system managers provided ideas for using databases for climate and health monitoring/surveillance. In 2012 surveys, 46.5% of state health leaders agreed they had sufficient information about climate and health compared to 17.1% of LHDs (P = .0046) and 40.9% of other stakeholders (nonsignificant difference). Significantly fewer (P < .0001) LHDs (22.9%) were incorporating or considering incorporating climate and health into planning compared to state health leaders (55.8%) and other stakeholders (68.2%). Stakeholder groups agreed on the 4 highest priority adaptation categories including core public health activities such as surveillance, coordination/collaboration, education, and policy development. CONCLUSIONS: Feedback from diverse stakeholders was utilized by NYSDOH to develop its Climate and Health Strategic Map in 2013. The CDC Building Resilience Against Climate Effects (BRACE) framework and funding provides a collaborative model for state climate and health adaptation planning.

An exploration of strategies used by older people to obtain information about health- and social care services in the community.

PURPOSE: To explore the strategies used by older people living in Ireland to obtain information about community health and social services. METHODS: A qualitative exploratory design was used. Focus groups (n = 3) were conducted with community dwelling older people (n = 17). A series of vignettes were used to guide discussion regarding hypothetical situations that approximated real-life scenarios for older people. Data were transcribed verbatim and analysed using content analysis. RESULTS: Obtaining information about community health and social services is an ongoing process that requires continuous commitment by older adults. Key strategies which emerged from the data included (i) taking a proactive stance towards accessing health information, (ii) making use of personal networks in your community and (iii) developing 'insider' knowledge. CONCLUSION: Older people in this study had a proactive approach to obtaining health information and identified the importance of taking responsibility for managing their own needs. Despite this, obtaining basic information about community health and social services was a challenging and time-consuming process. Future research should focus on developing health literacy interventions that build upon and expand the strategies currently used by older people.

Chemical Proteomic Platform To Identify Citrullinated Proteins.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination is also increased in cancer and other autoimmune disorders, suggesting that citrullinated proteins may serve as biomarkers for diseases beyond RA. To identify these citrullinated proteins, we developed biotin-conjugated phenylglyoxal (biotin-PG). Using this probe and our platform technology, we identified >50 intracellular citrullinated proteins. More than 20 of these are involved in RNA splicing, suggesting, for the first time, that citrullination modulates RNA biology. Overall, this chemical proteomic platform will play a key role in furthering our understanding of protein citrullination in rheumatoid arthritis and potentially a wider spectrum of inflammatory diseases.

Ready for our children? Results from a survey of upstate New York hospitals' utilization of Pediatric Emergency Preparedness Toolkit guidance.

OBJECTIVE: This project evaluated New York (NY) hospitals outside of New York City (upstate) for their awareness and utilization of the NY State Department of Health Pediatric and Obstetric Emergency Preparedness Toolkit (toolkit) and presence of pediatric emergency preparedness planning elements. METHODS: A survey assessing toolkit awareness and utilization was distributed to all 145 upstate NY hospitals. Quantitative survey data were analyzed using summary statistics, χ(2) analysis, and odds ratios (OR) in aggregate, by hospital size, and by presence of pediatric medicine/surgery, pediatric intensive care unit (PICU), and/or neonatal ICU (NICU) beds (pediatric beds). RESULTS: Of the 145 hospitals, 116 (80%) completed the survey; 86% of these had reviewed the toolkit. Most had staff clinicians with pediatric expertise, but fewer had appointed pediatric clinical (physician or nurse) coordinators. Hospitals with at least one pediatric bed were more than 2.5 times more likely to have an emergency management plan (EMP) for pediatric patients (P = .0223) and nearly 8 times more likely to have appointed a pediatric physician coordinator (P < .0001) than were hospitals without pediatric beds. Appointment of a pediatric clinical coordinator was significantly associated (P < .001) with presence of various pediatric emergency plan elements (OR range: 3.06-15.13), while staff pediatric clinical expertise or toolkit review were not. CONCLUSIONS: Appointment of at least one pediatric clinical coordinator and the presence of one or more pediatric beds were significantly associated with having developed key EMP pediatric elements. Further research should examine barriers to pediatric clinical coordinator appointment and explore the awareness that pediatric patients may arrive at nonpediatric hospitals during a disaster with no option for transfer.

Autocatalytic intramolecular isopeptide bond formation in gram-positive bacterial pili: a QM/MM simulation.

Many gram-positive pathogens possess external pili or fimbriae with which they adhere to host cells during the infection process. Unusual dual intramolecular isopeptide bonds between Asn and Lys side chains within the N-terminal and C-terminal domains of the pilus subunits have been observed initially in the Streptococcus pyogenes pilin subunit Spy0128 and subsequently in GBS52 from Streptococcus agalactiae, in the BcpA major pilin of Bacillus cereus and in the RrgB pilin of Streptococcus pneumoniae, among others. Within each pilin subunit, intramolecular isopeptide bonds serve to stabilize the protein. These bonds provide a means to withstand large external mechanical forces, as well as possibly assisting in supporting a conformation favored for pilin subunit polymerization via sortase transpeptidases. Genome-wide analyses of pili-containing gram-positive bacteria are known or suspected to contain isopeptide bonds in pilin subunits. For the autocatalytic formation of isopeptide cross-links, a conservation of three amino acids including Asn, Lys, and a catalytically important acidic Glu (or Asp) residue are responsible. However, the chemical mechanism of how isopeptide bonds form within pilin remains poorly understood. Although it is possible that several mechanistic paths could lead to isopeptide bond formation in pili, the requirement of a conserved glutamate and highly organized positioning of residues within the hydrophobic environment of the active site were found in numerous pilin crystal structures such as Spy0128 and RrgB. This suggests a mechanism involving direct coupling of lysine side chain amine to the asparagine carboxamide mediated by critical acid/base or hydrogen bonding interactions with the catalytic glutamate residue. From this mechanistic perspective, we used the QM/MM minimum free-energy path method to examine the reaction details of forming the isopeptide bonds with Spy0128 as a model pilin, specifically focusing on the role of the glutamate in catalysis. It was determined that the reaction mechanism likely consists of two major steps: the nucleophilic attack on Cγ by nitrogen in the unprotonated Lys ε-amino group and, then two concerted proton transfers occur during the formation of the intramolecular isopeptide bond to subsequently release ammonia. More importantly, within the dual active sites of Spy0128, Glu(117), and Glu(258) residues function as crucial catalysts for each isopeptide bond formation, respectively, by relaying two proton transfers. This work also suggests that domain-domain interactions within Spy0128 may modulate the reactivity of residues within each active site. Our results may hopefully shed light on the molecular mechanisms of pilin biogenesis in gram-positive bacteria.

Sortase transpeptidases: insights into mechanism, substrate specificity, and inhibition.

Gram-positive bacteria pose a serious healthcare threat. The growing antibiotic resistance epidemic creates a dire need for new antibiotic targets. The sortase family of enzymes is a promising target for antimicrobial therapy. This review covers the current knowledge of the mechanism, substrate specificity, and inhibitory studies of the Gram-positive bacterial [corrected] enzyme sortase.

NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1.

Dexras1 is a 30 kDa G protein in the Ras subfamily whose discovery was based on its pronounced inducibility by the glucocorticoid dexamethasone. It binds to neuronal nitric oxide synthase (nNOS) via the adaptor protein CAPON, eliciting S-nitrosylation and activation of Dexras1. We report that Dexras1 binds to the peripheral benzodiazepine receptor-associated protein (PAP7), a protein of unknown function that binds to cyclic AMP-dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 in turn binds to the divalent metal transporter (DMT1), an iron import channel. We have identified a signaling cascade in neurons whereby stimulation of NMDA receptors activates nNOS, leading to S-nitrosylation and activation of Dexras1, which, via PAP7 and DMT1, physiologically induces iron uptake. As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity.