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.

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.

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.

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.

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.

Using in situ simulation to improve care of the acutely ill patient by enhancing interprofessional working: a qualitative proof of concept study in primary care in England.

OBJECTIVE: Acutely unwell patients in the primary care setting are uncommon, but their successful management requires involvement from staff (clinical and non-clinical) working as a cohesive team. Despite the advantages of interprofessional education being well documented, there is little research evidence of this within primary care. Enhancing interprofessional working could ultimately improve care of the acutely ill patient. This proof of concept study aimed to develop an in situ simulation of a medical emergency to use within primary care, and assess its acceptability and utility through participants' reported experiences. SETTING: Three research-active General Practices in south east England. Nine staff members per practice consented to participate, representing clinical and non-clinical professions. METHODS: The intervention of an in situ simulation scenario of a cardiac arrest was developed by the research team. For the evaluation, staff participated in individual qualitative semistructured interviews following the in situ simulation: these focused on their experiences of participating, with particular attention on interdisciplinary training and potential future developments of the in situ simulation. RESULTS: The in situ simulation was appropriate for use within the participating General Practices. Qualitative thematic analysis of the interviews identified four themes: (1) apprehension and (un)willing participation, (2) reflection on the simulation design, (3) experiences of the scenario and (4) training. CONCLUSIONS: This study suggests in situ simulation can be an acceptable approach for interdisciplinary team training within primary care, being well-received by practices and staff. This contributes to a fuller understanding of how in situ simulation can benefit both workforce and patients. Future research is needed to further refine the in situ simulation training session.

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.

Biomarker-Based Metabolic Labeling for Redirected and Enhanced Immune Response.

Installation of an antibody-recruiting moiety on the surface of disease-relevant cells can lead to the selective destruction of targets by the immune system. Such an approach can be an alternative strategy to traditional chemotherapeutics in cancer therapy and possibly other diseases. Herein we describe the development of a new strategy to selectively label targets with an antibody-recruiting moiety through its covalent and stable installation, complementing existing methods of employing reversible binding. This is achieved through selective delivery of 1,3,4- O-acetyl- N-azidoacetylmannosamine (Ac3ManNAz) to folate receptor-overexpressing cells using an Ac3ManNAz-folate conjugate via a cleavable linker. As such, Ac3ManNAz is converted to cell surface glycan bearing an azido group, which serves as an anchor to introduce l-rhamnose (Rha), a hapten, via a click reaction with aza-dibenzocyclooctyne (DBCO)-Rha. We tested this method in several cell lines including KB, HEK-293, and MCF7 and were able to demonstrate the following: 1) Rha can be selectively installed to the folate receptor overexpressing cell surface and 2) the Rha installed on the target surface can recruit anti-rhamnose (anti-Rha) antibodies, leading to the destruction of target cells via complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).

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.

Genetic variant rs3750625 in the 3'UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site.

α2A adrenergic receptor (α2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs facilitation after both physical and psychological stress. To our knowledge, the influence of genetic variants in the gene encoding α2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3'UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased musculoskeletal pain in distressed individuals (stress*rs3750625 P = 0.043 for MVC cohort and P = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3'UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together, these results suggest that ADRA2A rs3750625 contributes to poststress musculoskeletal pain severity by modulating miR-34a regulation.

MicroRNA 320a Predicts Chronic Axial and Widespread Pain Development Following Motor Vehicle Collision in a Stress-Dependent Manner.

Study Design Prospective human cohort study combined with molecular studies. Background A microRNA is a small, noncoding RNA molecule that can play a role in disease onset. Recent studies found that circulating levels of microRNA 320a (miR-320a) are associated with musculoskeletal pain conditions and that miR-320a is stress responsive. Objectives To investigate whether circulating expression levels of miR-320a in the peritraumatic period predict persistent axial musculoskeletal pain 6 months after motor vehicle collision (MVC). Methods We evaluated whether (1) circulating miR-320a and related members of the miR-320a family predict axial musculoskeletal pain and other musculoskeletal pain outcomes 6 months following MVC, and (2) miR-320a regulates stress system and pain-related transcripts in cell culture. Given the wealth of data suggesting that biological mechanisms influencing pain outcomes are often sex and/or stress dependent, interactions between miR-320a, stress, and sex were evaluated. Results In primary analyses (n = 69), a significant crossover interaction was observed between the influence of circulating miR-320a and peritraumatic distress (ß = -0.01, P = .002) on post-MVC axial musculoskeletal pain. Reduced peritraumatic miR-320a expression levels predicted axial musculoskeletal pain in distressed individuals (ß = -0.12, P = .006) but not nondistressed individuals. In secondary analyses, miR-320a predicted widespread musculoskeletal pain, and related members of the miR-320a family also predicted axial and widespread musculoskeletal pain. In cell culture, miR-320a bound stress and pain-associated 3'UTR transcripts (FKBP5, ADCYAP1, PER2, and NR3C1). Conclusion These data suggest that miR-320a may help mediate regional and widespread changes in pain sensitivity after MVC. J Orthop Sports Phys Ther 2016;46(10):911-919. doi:10.2519/jospt.2016.6944.

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.

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.

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.

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.

The Pla protease of Yersinia pestis degrades fas ligand to manipulate host cell death and inflammation.

Pneumonic plague is a deadly respiratory disease caused by Yersinia pestis. The bacterial protease Pla contributes to disease progression and manipulation of host immunity, but the mechanisms by which this occurs are largely unknown. Here we show that Pla degrades the apoptotic signaling molecule Fas ligand (FasL) to prevent host cell apoptosis and inflammation. Wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection. Consistent with a role for FasL in regulating immune responses, Δpla infection results in aberrant proinflammatory cytokine levels. The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs. Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection.