Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis.

Message-specific translational control is required for gametogenesis. In yeast, the RNA-binding protein Rim4 mediates translational repression of numerous mRNAs, including the B-type cyclin CLB3, which is essential for establishing the meiotic chromosome segregation pattern. Here, we show that Rim4 forms amyloid-like aggregates and that it is the amyloid-like form of Rim4 that is the active, translationally repressive form of the protein. Our data further show that Rim4 aggregation is a developmentally regulated process. Starvation induces the conversion of monomeric Rim4 into amyloid-like aggregates, thereby activating the protein to bring about repression of translation. At the onset of meiosis II, Rim4 aggregates are abruptly degraded allowing translation to commence. Although amyloids are best known for their role in the etiology of diseases such as Alzheimer's, Parkinson's, and diabetes by forming toxic protein aggregates, our findings show that cells can utilize amyloid-like protein aggregates to function as central regulators of gametogenesis.

Colon Cancer Survival Among South Asian Americans: A Cross-Sectional Analysis of a National Dataset.

INTRODUCTION: Colon cancer (CC) is one of the most common cancers among South Asian Americans (SAAs). The objective of this study was to measure differences in risk-adjusted survival among SAAs with CC compared to non-Hispanic Whites (NHWs) using a representative national dataset from the United States. METHODS: A retrospective analysis of patients with CC in the National Cancer Database (2004-2020) was performed. Differences in presentation, management, median overall survival (OS), three-year survival, and five-year survival between SAAs and NHWs were compared. Kaplan-Meier analysis and multivariable Cox regression were used to assess differences in survival outcomes, adjusting for demographics, presentation, and treatments received. RESULTS: Data from 2873 SAA and 639,488 NHW patients with CC were analyzed. SAAs were younger at diagnosis (62.2 versus 69.5 y, P < 0.001), higher stage (stage III [29.0% versus 26.2%, P = 0.001] or Stage IV [21.4% versus 20.0%, P = 0.001]), and experienced delays to first treatment (SAA 5.9% versus 4.9%, P = 0.003). SAAs with CC had higher OS (median not achieved versus 68.1 mo for NHWs), three-year survival (76.3% versus 63.4%), and five-year survival (69.1% versus 52.9%). On multivariable Cox regression, SAAs with CC had a lower risk of death across all stages (hazard ratio: 0.64, P < 0.001). CONCLUSIONS: In this national study, SAA patients with CC presented earlier in life with more advanced disease, and a higher proportion experienced treatment delay compared to NHW patients. Despite these differences, SAAs had better adjusted OS than NHW, warranting further exploration of tumor biology and socioeconomic determinants of cancer outcomes in SAAs.

European violence risk and mental disorders (EU-VIORMED): a multi-centre prospective cohort study protocol.

BACKGROUND: The link between schizophrenia spectrum disorders (SSD) and violence is a core issue for most forensic psychiatric services. However, the drivers of violence in this population remain unclear, and, to date tools to predict violence risk have a range of limitations. Perhaps because of this uncertainty about the nature of violence risk, treatment programmes and care pathways for mentally disordered offenders vary substantially across the European Union, and differences in legal and policy frameworks are highly relevant. METHODS: The three-year EU-VIORMED project (Grant Number PP-2-3-2016, November 2017-October 2020) involves forensic centres in Italy, Austria, Germany, Poland, and the U.K. It aims to: (a) identify and compare violence risk factors, clinical needs, and decision making capacity in violent (N = 200, "cases") and nonviolent patients with SSD (N = 200; "controls") using a case-control design; (b) test the predictive validity of the HCR-20v3, OxMIS and FoVOx among cases alone (N = 200), using a prospective cohort study; and (c) compare forensic-psychiatric care pathways across the EU, in a continent wide service mapping study. DISCUSSION: Data collection started in September 2018 and continues. By September 2019, 333 participants have been enrolled (201 cases and 132 controls were recruited). Experts from 23 countries provided data for the service mapping exercise. TRIAL REGISTRATION: Retrospectively registered on January 2, 2019 as researchregistry4604 January 2, 2019.

Predicting and preventing alcohol relapse in alcohol-related liver disease.

BACKGROUND: despite a 450% increase in UK alcohol-related liver disease mortality over the past 30 years, little evidence-based guidance exists regarding preventing recidivism post-liver transplant for alcohol-related liver disease. METHOD: a systematic literature review was conducted to identify demographic variables predictive of alcohol relapse and effective psychosocial interventions for alcohol-related liver disease patients post-liver transplant. RESULTS: variables most significantly predictive of alcohol relapse post-transplant were-less than 12 months pre-liver transplant abstinence; patients with children; poor pre-liver transplant psychosomatic evaluation; non-compliance with post-liver transplant treatment plan; and patients with active insurance policies. Structured management was the most effective psychosocial intervention in preventing alcohol relapse. CONCLUSION: findings should be interpreted cautiously, due to limited and poor-quality evidence. Rigorously designed further research of the psychosocial interventions targeting predictive demographic variables is recommended.

Understanding alcohol-related liver disease patients' illness beliefs and views about their medicine.

BACKGROUND: people with alcohol-related liver disease require complex treatment plans that often include the need for medication for the rest of their lives. Between 30% and 50% of all patients do not take their treatment as prescribed, leading to a significantly increased risk of morbidity and mortality. AIM: to consider the factors which influence beliefs held by patients with alcohol-related liver disease about their medication to provide an evidence base to support interventions to reduce medication non-adherence. METHOD: an observational cross-sectional patient survey. RESULTS: statistically significant associations were found between positive attitudes towards medication and the illness representation dimensions of 'illness identity' and 'illness comprehension'. CONCLUSIONS: medication adherence in patients with alcohol-related liver disease is likely to be improved by an intervention that strives to improve the patient's understanding of their illness condition and their perception of their illness symptoms.

Nurses' perceptions and experiences of work role transitions: a mixed methods systematic review of the literature.

AIM: To understand nurses' perceptions and experiences of work role transitions. BACKGROUND: Globally an uncertain healthcare landscape exists and when changing work roles nurses experience periods of transition when they may not cope well. A greater understanding of work role transitions may help facilitate workforce retention and successful careers. DESIGN: Mixed methods systematic review. DATA SOURCES: Six data bases were searched for peer reviewed primary empirical research, published in English language between January 1990 and December 2014, supplemented by hand and citation searching. REVIEW METHODS: Evidence for Policy and Practice Information and Co-ordinating Centre methods for systematic reviews principles were followed. Analysis and synthesis of the qualitative and quantitative papers was conducted separately using thematic analysis. A third synthesis combined the narrative findings and a narrative synthesis of results is presented. RESULTS: Twenty-six papers were included. Across nurses' work role transitions two pathways were found: Novice and Experienced. 'Novice' comprises pre-registration and newly qualified nurses. 'Experienced' comprises, Enrolled/Licensed Practical Nurse to Registered Nurse, experienced to specialist nurse and clinical role changes. Each pathway results in different emphasizes of two themes; 'Striving for a new professional self' includes emotional upheaval and identity while 'Know how' includes competence and boundaries. Novice nurses are more susceptible to the extremes of emotional upheaval while experienced nurses' competence eases aspects of transitions while boundary issues pervade. CONCLUSION: Informed work and educational environments are required for all groups of nurses. Using existing models of transition can facilitate successful individual transitions and develop the workplace.

Patients with alcohol-related liver disease--beliefs about their illness and factors that influence their self-management.

AIM: To determine the association between illness belief and self-efficacy to provide the evidence-base to develop a personalized framework to support self-management in patients with alcohol-related liver disease. BACKGROUND: Research in a variety of long-term illnesses suggests patients' illness beliefs are a more influential factor for patient recovery than the severity of the illness. However, research into illness belief and self-efficacy of patients with alcohol-related liver disease is sparse. DESIGN: A cross-sectional survey. METHODS: A cohort of 159 patients with alcohol-related liver disease who attended the Liver Outpatient Clinics at a London Hospital (October 2012-November 2013) completed a set of validated instruments measuring illness beliefs, self-efficacy, emotional states and quality of life. FINDINGS: The mean age of enrolled patients was 52 years, 67% male, 26% live on their own, 61% had no previous history of other chronic illness and average Model for End-Stage Liver Disease and The AUDIT Alcohol Consumption Questions scores were 11·0 and 3·5 respectively. After adjusting for demographic and illness characteristic components, multiple regression analysis shows that the three illness belief components 'Symptoms', 'Understanding' and 'Concerns' made a significant contribution to their confidence to self-manage their liver condition and the 'Symptoms' component makes a signification contribution across to all outcome measures: Anxiety, Depression, Quality of Life and Self-Efficacy. CONCLUSION: Interventions designed to improve these patients' understanding of their illness and strategies to manage their symptoms are likely to improve their self-management, quality of life and reduce anxiety and depression.

Personalised discharge care planning for postmyocardial infarction patients through the use of the Personalised Patient Education Protocol - implementing theory into practice.

AIMS AND OBJECTIVES: This study aims to evaluate the service impact of the integration of an evidence-based instrument - the Personalised Patient Education Protocol - into an existing postmyocardial infarction care pathway. BACKGROUND: Recent research indicates that while better patient health outcomes can be achieved when care planning is personalised, delivery staff feel less satisfied and less confident in its provision. To achieve a shift to personalised care, innovations are needed to enable an effective transition for staff. DESIGN: A service evaluation using a patient survey and nurse interviews. METHOD: A longitudinal patient survey measured changes in patient illness beliefs, cardiac diet and exercise self-efficacy, anxiety, depression and quality of life study of a patient cohort of 74. Paired t-tests analysed the effects before and after the implementation of the Personalised Patient Education Protocol. Cardiac rehabilitation nurses who implemented the Personalised Patient Education Protocol were interviewed and a patient survey identified perceptions of the usefulness of the service innovation. RESULTS: Analysis of change from baseline to three months results showed statistically significant changes in Illness Belief component 'Understanding' and the Dartmouth Quality of Life 'General Health'. The integration of the Personalised Patient Education Protocol into the existing discharge process identified service improvements for cardiac nurse training and care pathway delivery, while patients identified the level and frequency of their use of the protocol following discharge. CONCLUSION: The introduction of the Personalised Patient Education Protocol succeeded in increasing patient engagement, facilitated a more patient-centred service by enabling practitioners to systematically provide personalised patient education, and gave patients a postdischarge structure to better follow-up their illness concerns with health professionals in the community. RELEVANCE TO CLINICAL PRACTICE: Integration of the Personalised Patient Education Protocol into an existing postmyocardial infarction care pathway enabled nurses to systematically respond to individual patients' illness beliefs and expectations.

MicroRNA circulating in the early aftermath of motor vehicle collision predict persistent pain development and suggest a role for microRNA in sex-specific pain differences.

BACKGROUND: Molecular mediators influencing the transition from acute to persistent musculoskeletal pain following common stress exposures such as motor vehicle collision (MVC) remain poorly understood. In this exploratory, proof of concept study, we compared circulating microRNA (miRNA) expression profiles in the early aftermath of MVC among individuals who did and did not subsequently develop persistent pain. Blood RNA samples were obtained from African American individuals (n = 53) who presented to the emergency department after MVC and were discharged to home after evaluation. The presence or absence of severe pain in the axial region, the most common and morbid region in which post-MVC pain occurs, was assessed 6 weeks following MVC via standardized questionnaire. miRNA expression was determined using miRNA-sequencing; nonparametric analyses were used to compare miRNA expression levels among individuals with and without persistent pain. RESULTS: Thirty-two mature miRNA were differentially expressed (p < 0.05) in those with and without severe axial pain at 6 weeks. miR-135a-5p, a regulator of the serotonin receptor that is known to be stress-responsive, differed most significantly between groups (p = 3 × 10(-4)). This miRNA, and miR-3613-3p (p = 0.001) survived correction for multiple testing (FDR = 0.15) in this small sample. Interestingly, differentially expressed miRNA were enriched for X chromosome location. In secondary analyses, the eight X chromosome miRNA were (a) more significantly associated with axial pain in women than men, (b) expressed more highly in the peripheral blood of women than men, and (c) predicted in pathway analyses (DIANA miRPath v 2.0) to regulate neuronal and neuroendocrine pathways previously implicated in various pain pathologies. CONCLUSIONS: These results show that circulating miRNA predict persistent severe axial pain after MVC and suggest that they may be involved in the pathogenesis of post-traumatic musculoskeletal pain. However, further studies are needed to determine if these miRNA play a direct causal role.

Survival of the Hmong population diagnosed with colon and rectal cancers in the United States.

BACKGROUND: The Hmong population constitutes an independent ethnic group historically dispersed throughout Southeast Asia; fallout from the Vietnam War led to their forced migration to the United States as refugees. This study seeks to investigate characteristics of the Hmong population diagnosed with in colorectal cancer (CRC) as well as survival within this population. METHODS: Cases of colon and rectal adenocarcinoma diagnosed between 2004 and 2017 were identified from the National Cancer Database (NCDB). Summary statistics of demographic, clinical, socioeconomic, and treatment variables were generated with emphasis on age and stage at the time of diagnosis. Cox-proportional hazard models were constructed for survival analysis. RESULTS: Of 881,243 total CRC cases within the NCDB, 120 were classified as Hmong. The average age of Hmong individuals at diagnosis was 58.9 years compared 68.7 years for Non-Hispanic White (NHW) individuals (p < 0.01). The distribution of analytic stage differed between the Hmong population and the reference NHW population, with 61.8% of Hmong individuals compared to 45.8% of NHW individuals with known stage being diagnosed at stage III or IV CRC compared to 0, I, or II (p = 0.001). However, there was no difference in OS when adjusting for potential confounders (HR 1.00 [0.77-1.33]; p = 0.998). CONCLUSIONS: Hmong individuals are nearly a decade younger at the time of diagnosis of CRC compared to the NHW individuals. However, these data do not suggest an association between Hmong ethnicity and overall survival, when compared to the NHW population.

New insights into the role of mast cells in autoimmunity: evidence for a common mechanism of action?

Mast cells are classically considered innate immune cells that act as first responders in many microbial infections and have long been appreciated as potent contributors to allergic reactions. However, recent advances in the realm of autoimmunity have made it clear that these cells are also involved in the pathogenic responses that exacerbate disease. In the murine models of multiple sclerosis, rheumatoid arthritis and bullous pemphigoid, both the pathogenic role of mast cells and some of their mechanisms of action are shared. Similar to their role in infection and a subset of allergic responses, mast cells are required for the efficient recruitment of neutrophils to sites of inflammation. Although this mast cell-dependent neutrophil response is protective in infection settings, it is postulated that neutrophils promote local vascular permeability and facilitate the entry of inflammatory cells that enhance tissue destruction at target sites. However, there is still much to learn. There is little information regarding mechanisms of mast cell activation in disease. Nor is it known how many mast cell-derived mediators are relevant and whether interactions with other cells are implicated in these diseases including T cells, B cells and astrocytes. Here we review the current state of knowledge about mast cells in autoimmune disease. We also discuss findings regarding newly discovered mast cell actions and factors that modulate mast cell function. We speculate that much of this new information will ultimately contribute to a greater understanding of the full range of mast cell actions in autoimmunity. This article is part of a Special Issue entitled: Mast cells in inflammation.

Mast cell activation and neutrophil recruitment promotes early and robust inflammation in the meninges in EAE.

The meninges are often considered inert tissues that house the CSF and provide protection for the brain and spinal cord. Yet emerging data demonstrates that they are also active sites of immune responses. Furthermore, the blood-CSF barrier surrounding meningeal blood vessels, together with the blood-brain barrier (BBB), is postulated to serve as a gateway for the pathological infiltration of immune cells into the CNS in multiple sclerosis (MS). Our previous studies using mast cell-deficient (Kit(W/Wv)) mice demonstrated that mast cells resident in the dura mater and pia mater exacerbate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by facilitating CNS inflammatory cell influx. Here we examined the underlying mechanisms that mediate these effects. We demonstrate that there are dramatic alterations in immune associated gene expression in the meninges in pre-clinical disease, including those associated with mast cell and neutrophil function. Meningeal mast cells are activated within 24 h of disease induction, but do not directly compromise CNS vascular integrity. Rather, through production of TNF, mast cells elicit an early influx of neutrophils, cells known to alter vascular permeability, into the meninges. These data add to the growing evidence that inflammation in the meninges precedes CNS immune cell infiltration and establish that mast cells are among the earliest participants in these disease-initiating events. We hypothesize that mast cell-dependent neutrophil recruitment and activation in the meninges promotes early breakdown of the local BBB and CSF-blood barrier allowing initial immune cell access to the CNS.

Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis.

Mast cells (MCs) exert a significant pathologic influence on disease severity in C57BL/6 (B6) strain-dependent experimental allergic encephalomyelitis (EAE), a model of primary progressive multiple sclerosis (MS). However, relapsing-remitting MS, which is modeled in SJL mice, is the more prevalent form. Given genetically determined heterogeneity in numbers and responsiveness of MCs from various strains of mice, we asked whether these cells also influence this more clinically relevant MS model using SJL-Kit(W/W-v) mice. Similar to the commercially available WBB6F(1)-Kit(W/W-v) mice, SJL-Kit(W/W-v) mice are MC-deficient, anemic, and neutropenic and have normal T cell compartments. They exhibit significantly reduced disease severity, but retain the relapsing-remitting course, a phenotype reversed by selective MC reconstitution. These data confirm that MC influence is not confined to an isolated model of EAE and reveal a new system to study the effects of MC heterogeneity on relapsing-remitting EAE and other SJL strain-specific diseases.

Non-classical Non-covalent σ-Hole Interactions in Protein Structure and Function: Concepts for Potential Protein Engineering Applications.

The structures and associated functions of biological molecules are driven by noncovalent interactions, which have classically been dominated by the hydrogen bond (H-bond). Introduction of the σ-hole concept to describe the anisotropic distribution of electrostatic potential of covalently bonded elements from across the periodic table has opened a broad range of nonclassical noncovalent (ncNC) interactions for applications in chemistry and biochemistry. Here, we review how halogen bonds, chalcogen bonds and tetrel bonds, as they are found naturally or introduced synthetically, affect the structures, assemblies, and potential functions of peptides and proteins. This review intentionally focuses on examples that introduce or support principles of stability, assembly and catalysis that can potentially guide the design of new functional proteins. These three types of ncNC interactions have energies that are comparable to the H-bond and, therefore, are now significant concepts in molecular recognition and design. However, the recently described H-bond enhanced X-bond shows how synergism among ncNC interactions can be exploited as potential means to broaden the range of their applications to affect protein structures and functions.

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Education and support needs of the older adult with congenital heart disease.

AIM: This article is a report of a study exploring health-related quality of life in adults with congenital heart disease and the extent to which it is associated with patients' illness beliefs and emotional health. BACKGROUND: A reduction in mortality in patients with congenital heart disease has led to an increasingly older population that faces new challenges. Studies in a younger adult population have reported inconsistent findings regarding health-related quality of life. Factors such as, the complexity of the congenital heart defect, have not been found to be associated with quality of life. The association between illness beliefs and health-related quality of life has not previously been reported. METHOD: A cross-sectional questionnaire study of adults with congenital heart disease attending an outpatient clinic in a specialist centre in the United Kingdom between October 2007 and May 2008. RESULTS: The mean age of the study population was 37·2 years. Participants reported poorer physical functioning, role functioning and general health than a general population. High levels of anxiety were reported in 38% and high levels of depression in 17%. In multivariate analysis, higher levels of anxiety and depression were associated with poorer mental functioning and higher levels of depression with poorer physical quality of life. CONCLUSION: We have reported that high levels of anxiety and depression in an older population of patients with congenital heart disease are associated with poorer quality of life. This highlights the need to routinely assess anxiety and depression in this patient group and to provide psychological support appropriately.

A Case of Isolated Myeloid Sarcoma Associated With Germline EGFR T790M Variant: The Importance of Recognizing Potential Germline Variants on Somatic Tumor Sequencing Panels.

Isolated myeloid sarcoma is an uncommon subtype of acute myeloid leukemia associated with variable prognosis. We present the case of a previously healthy 30-year-old man presenting with chest pain and weight loss who was found to have a large mediastinal mass. Biopsy of the mass was consistent with isolated myeloid sarcoma. A somatic tumor sequencing panel revealed an EGFR T790M variant, which was later confirmed to be of germline origin. Germline EGFR T790M variants are associated with a hereditary predisposition to lung cancer, though myeloid malignancies have not yet been described. To our knowledge, this is the first reported case of myeloid sarcoma in a patient with an underlying germline EGFR T790M mutation. As somatic tumor sequencing panels become more commonplace, it is important to recognize potential germline variants in order to facilitate appropriate referral for genetic counseling, perform confirmatory genetic testing, and to develop a personalized treatment and surveillance plan for patients and their families.

Care of patients following liver transplantation.

This article provides an overview of the care of patients following liver transplantation. It focuses on the immediate post-operative care, the role of the transplant co-ordinator in providing support and education and the long-term follow up required to promote health and quality of life in this specific patient group.

A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease.

INTRODUCTION: We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. METHODS: Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. RESULTS: Gamma flicker was safe, tolerable, and adherable. Participants' neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. DISCUSSION: These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

Genetic determination of essential residues of the Vibrio cholerae actin cross-linking domain reveals functional similarity with glutamine synthetases.

Actin cross-linking domains (ACDs) are distinct domains found in several bacterial toxins, including the Vibrio cholerae MARTX toxin. The ACD of V. cholerae (ACD(Vc)) catalyses the formation of an irreversible iso-peptide bond between lysine 50 and glutamic acid 270 on two actin molecules in an ATP- and Mg/Mn(2+)-dependent manner. In vivo, cross-linking depletes the cellular pool of G-actin leading to actin cytoskeleton depolymerization. While the actin cross-linking reaction performed by these effector domains has been significantly characterized, the ACD(Vc) catalytic site has remained elusive due to lack of significant homology to known proteins. Using multiple genetic approaches, we have identified regions and amino acids of ACD(Vc) required for full actin cross-linking activity. Then, using these functional data and structural homology predictions, it was determined that several residues demonstrated to be important for ACD(Vc) activity are conserved with active-site residues of the glutamine synthetase family of enzymes. Thus, the ACDs are a family of bacterial toxin effectors that may be evolutionarily related to ligases involved in amino acid biosynthesis.