Intraphagosomal Free Ca2+ Changes during Phagocytosis.

Phagocytosis (and endocytosis) is an unusual cellular process that results in the formation of a novel subcellular organelle, the phagosome. This phagosome contains not only the internalised target of phagocytosis but also the external medium, creating a new border between extracellular and intracellular environments. The boundary at the plasma membrane is, of course, tightly controlled and exploited in ionic cell signalling events. Although there has been much work on the control of phagocytosis by ions, notably, Ca2+ ions influxing across the plasma membrane, increasing our understanding of the mechanism enormously, very little work has been done exploring the phagosome/cytosol boundary. In this paper, we explored the changes in the intra-phagosomal Ca2+ ion content that occur during phagocytosis and phagosome formation in human neutrophils. Measuring Ca2+ ion concentration in the phagosome is potentially prone to artefacts as the intra-phagosomal environment experiences changes in pH and oxidation. However, by excluding such artefacts, we conclude that there are open Ca2+ channels on the phagosome that allow Ca2+ ions to "drain" into the surrounding cytosol. This conclusion was confirmed by monitoring the translocation of the intracellularly expressed YFP-tagged C2 domain of PKC-γ. This approach marked regions of membrane at which Ca2+ influx occurred, the earliest being the phagocytic cup, and then the whole cell. This paper therefore presents data that have novel implications for understanding phagocytic Ca2+ signalling events, such as peri-phagosomal Ca2+ hotspots, and other phenomena.

MicroRNAs Associated with Metformin Treatment in the Diabetes Prevention Program.

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision health strategies.

Ca2+-activated cleavage of ezrin visualised dynamically in living myeloid cells during cell surface area expansion.

The intracellular events underlying phagocytosis, a crucial event for innate immunity, are still unresolved. In order to test whether the reservoir of membrane required for the formation of the phagocytic pseudopodia is maintained by cortical ezrin, and that its cleavage is a key step in releasing this membrane, the cleavage of cortical ezrin was monitored within living phagocytes (the phagocytically competent cell line RAW264.7) through expressing two ezrin constructs with fluorescent protein tags located either inside the FERM or at the actin-binding domains. When ezrin is cleaved in the linker region by the Ca2+-activated protease calpain, separation of the two fluorophores would result. Experimentally induced Ca2+ influx triggered cleavage of peripherally located ezrin, which was temporally associated with cell expansion. Ezrin cleavage was also observed in the phagocytic pseudopodia during phagocytosis. Thus, our data demonstrates that peripheral ezrin is cleaved during Ca2+-influx-induced membrane expansion and locally within the extending pseudopodia during phagocytosis. This is consistent with a role for intact ezrin in maintaining folded membrane on the cell surface, which then becomes available for cell spreading and phagocytosis.

Pandemic perspectives from the frontline-The nursing stories.

AIM: To describe the experiences of registered nurses working in a US healthcare system during the COVID-19 pandemic. DESIGN: This qualitative thematic analysis study is a secondary analysis of stories submitted by nurses to a repository established by the parent study. METHODS: Registered nurses working in various roles in a healthcare system submitted stories (N = 45) to open-ended prompts via an online repository between June 2020 and February 2021. A team of three nurse scientists coded the stories using Dedoose software. Initial codes were then reviewed by the team to synthesize initial coding into themes. The COREQ checklist was used to ensure research reporting guidelines were met. RESULTS: Thematic analysis revealed three themes in a global theme of COVID-19 pandemic-related personal and professional evolution: (1) The art and science of pandemic nursing, (2) Persisting despite challenges; and (3) Learning as we went. Each of the three organizing themes were supported by basic themes. CONCLUSIONS: Identified themes affirm some of nursing's long-standing core values, such as the central role of human connectedness in restoring health, but findings also reflect new evolutionary processes of moral identity formation that occurred among nurses and the nursing profession during the COVID-19 pandemic. IMPACT: Findings from this study describe the processes by which nurses' moral identity evolved during a segment of the COVID-19 pandemic. Collectively, these evolutions represent important shifts in the nursing profession. Using findings from this study, nurse educators, nurse managers and healthcare administrators will be able to implement effective, sustainable policies and processes that meet the needs of both the community and the workforce. NO PATIENT OR PUBLIC CONTRIBUTION: This study was designed to capture the experiences of nurses employed by one healthcare organization. However, it was not conducted using input or suggestions from the public or the patient population served by the organization.

Caring for sick kids: An integrative review of the evidence about the prevalence of compassion fatigue and effects on pediatric nurse retention.

PROBLEM: Compassion Fatigue (CF) in healthcare professionals has been explored in multiple studies, but few focused on hospital-based pediatric nurses. The purpose of this integrative review is to synthesize the evidence about CF prevalence in nurses caring for pediatric patients, and to describe its effects on retention and job satisfaction. ELIGIBILITY CRITERIA: Included studies were in English from any date describing research or quality improvement studies about CF in pediatric nurses. SAMPLE: An integrative review of nine electronic databases yielded 13 articles about 1921 nurses. Data were synthesized from four qualitative and nine quantitative studies separately before integrating results. A risk of bias analysis was included for evidence level and quality. RESULTS: Overall CF prevalence was low, but 14% of nurses were at high risk of burnout and 10% were at high risk for secondary traumatic stress. Studies examining the effects of CF on retention found no significant relationship. Most studies were about critical care or oncology nurses. CONCLUSIONS: A subset of pediatric nurses is highly vulnerable to CF, but more high-quality evidence is needed to fully address this topic. Leaders should study CF prevalence, protective and exacerbating factors, relationships between CF and retention, and targeted strategies to resolve CF in high-risk nurses.

Pediatric Patient Surge: Evaluation of an Alternate Care Site Quality Improvement Initiative.

BACKGROUND: Pediatric Level I trauma centers often experience patient volume surges. The increase stresses the emergency department, and usual patient care areas become inadequate. The purpose of this quality improvement study is to describe the implementation and analysis of an alternate care site to facilitate patient flow during seasonal patient volume surges. METHODS: This initiative used a nonequivalent historical control group posttest-only design. An alternate care site was selected because of its size, temporary nature, low cost, and proximity to the emergency department. The alternate care site was activated between January and March 2019 using the following criteria: the total number of patients in waiting room 30 or more and wait times 2.5 hr or more. Outcome metrics include total census, length of stay-admissions, length of stay-discharges, left without being seen, hours per patient visit, patient satisfaction scores, and process metrics. Descriptive statistics and t tests were used to determine differences between groups. RESULTS: A total of 180 patients were analyzed with n = 90 from 2018 and n = 90 from 2019. The alternate care site was activated five times over one season. The alternate care site decreased median waiting times, length of stay-admissions, length of stay-discharges, and left without being seen as compared with the previous year. Hours per patient visit and patient satisfaction scores remained constant as compared with the previous year. CONCLUSIONS: The creation of an alternate care site within the emergency department allowed quick mobilization, response, and treatment of patients. The alternate care site decreased median length of stay for admissions, discharges, and who left without being seen while keeping hours per patient visit and patient satisfaction constant. Future studies should confirm findings by testing the alternate care site in other hospitals and settings and should consider formally evaluating staff satisfaction.

Does Simulation Training for Acute Care Nurses Improve Patient Safety Outcomes: A Systematic Review to Inform Evidence-Based Practice.

BACKGROUND: Simulation is increasingly used as a training tool for acute care medical-surgical nurses to improve patient safety outcomes. A synthesis of the evidence is needed to describe the characteristics of research studies about acute care nurse simulation trainings and patient safety. An additional purpose is to examine the effects of acute care registered nurse (RN) simulation trainings on patient safety outcomes. METHODS: Five Internet databases were searched for articles published on any date through October 2018 examining the effect of RN simulation trainings on patient safety outcomes in the adult acute care setting. SAMPLE: N = 12 articles represented 844 RNs of varying experience levels and 271 interprofessional participants. RESULTS: Nine studies (75%) used high-fidelity scenarios developed locally about high risk but infrequent events. Five studies (42%) incorporated interdisciplinary team members in the scenarios and/or outcome evaluations. Outcome measures were self-reported, direct observation, or clinical indicators. All studies in this review achieved improved patient safety outcomes. It is unknown how outcomes vary for different groups of RNs because of insufficient gender, ethnicity/race, and age reporting. LINKING EVIDENCE TO ACTION: Findings support the design of simulation training research studies for patient safety outcomes and use of simulation training and research in acute care RNs. Additional high-quality research is needed to support this field. Future studies should include descriptors that characterize the sample (i.e., age, gender, education level, type of nursing degree, ethnicity or race, or years of experience); incorporate interdisciplinary teams; evaluate a combination of outcome measure types (i.e., self-report, direct observation, and clinical outcomes) both proximal and distal to the simulation; and that utilize standardized scenarios, validated outcome measure instruments, and standardized debriefing tools.

Oral Health Intervention for Low-Income African American Men in Atlanta, Georgia.

OBJECTIVES: To describe the Minority Men's Oral Health Dental Access Program (MOHDAP) intervention and report participants' outcomes and satisfaction. METHODS: MOHDAP was designed to increase the oral health knowledge of low-income, African American men in Atlanta, GA, in 2013. A community-based participatory approach and needs assessment guided the intervention development, which consisted of 3 educational modules delivered over a 2-day period. All participants (n = 45; mean age = 50 years) were African American men. We assessed changes in oral health knowledge and attitudes at baseline and postintervention via survey. RESULTS: After the intervention, the percentage of correct responses to questions about gingivitis increased by 24.2% (P = .01), about use of a hard (instead of a soft) toothbrush increased by 42.2% (P < .01), and knowledge of ways to prevent gum diseases increased by 16.0% (P = .03). The percentage agreeing with erroneous statements decreased 11.3% (P = .02) regarding oral health-related fatalism and oral health self-care and 17.4% (P = .05) regarding saving front versus back teeth. CONCLUSIONS: Community-based oral health educational interventions designed for African American men may reduce oral health disparities among this population.

Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient.

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.

Testing the health promotion model for adherence and quality of life in individuals with multiple sclerosis.

The nature of multiple sclerosis (MS) presents challenges to health-promoting behaviors (e.g. adherence) and quality of life. The Health Promotion Model (HPM) proposes that these outcomes are explained by individual characteristics (i.e. biological, social, psychological) and behavior-specific cognitions (e.g. self-efficacy). The current study sought to test the HPM in explaining self-reported adherence and MS quality of life among 121 MS patients receiving care in an MS clinic in the southeastern United States. Hierarchical regression models partially supported the HPM for adherence (R2 = .27) and more fully for quality of life (QoL) (R2 = .64). Depression and stigma were among the variables most strongly related to both adherence and QoL; contrary to HPM theory, self-efficacy was not significantly related to adherence but was to QoL. Thus, the HPM may help to guide strategies used to improve QoL among individuals living with MS; however, the model may need further refinement to be used with adherence.

Sociocultural Considerations in Juvenile Arthritis: A Review.

PROBLEM: Juvenile Arthritis (JA) is one of the most common autoimmune diseases in children. A variety of sociocultural factors that influence health outcomes in children with JA have been examined in previous research. However, clinical guidelines to guide the care of these children lack support because this research has not been systematically examined and synthesized. ELIGIBILITY CRITERIA: Primary research articles from five internet databases were included if they were peer-reviewed articles in English of studies conducted in the U.S. or Canada and referenced one or more determinants of health, quality of life, socioeconomic status, or health disparities in children with JA. SAMPLE: The final sample included 16 articles representing 2139 children and 939 parents. RESULTS: Topics covered in the studies included medication compliance, electronic medical records, environmental risk factors, economic hardship, parental coping, leisure activities, and their effects on patient outcomes including disability and quality of life. Patients with Medicaid experienced more severe outcomes than patients with private insurance despite equivalent levels of healthcare utilization. Other important topics, such as effects of the physical environment and alcohol use, were missing from the literature. CONCLUSIONS: Five categories of health determinants were found to influence outcomes: biology, individual behaviors, social environment, physical environment, and health services. Disparities continue to exist for racial and ethnic minority children with JA and those of low socioeconomic status. IMPLICATIONS: Sociocultural factors should be taken into consideration when developing care plans, research studies, and policies in order to remove barriers and promote the best outcomes for this vulnerable population.

Substance abuse screening in adolescents.

Substance abuse among adolescents is a significant public health challenge. This article reviews changes to the American Academy of Pediatrics' policy statement recommending the use of SBIRT (screening, brief intervention, and referral for treatment) to screen adolescents for substance abuse.

Specific electrophysiological components disentangle affective sharing and empathic concern in psychopathy.

Empathic impairment is one of the hallmarks of psychopathy, a personality dimension associated with poverty in affective reactions, lack of attachment to others, and a callous disregard for the feelings, rights, and welfare of others. Neuroscience research on the relation between empathy and psychopathy has predominately focused on the affective sharing and cognitive components of empathy in forensic populations, and much less on empathic concern. The current study used high-density electroencephalography in a community sample to examine the spatiotemporal neurodynamic responses when viewing people in physical distress under two subjective contexts: one evoking affective sharing, the other, empathic concern. Results indicate that early automatic (175-275 ms) and later controlled responses (LPP 400-1,000 ms) were differentially modulated by engagement in affective sharing or empathic concern. Importantly, the late event-related potentials (ERP) component was significantly impacted by dispositional empathy and psychopathy, but the early component was not. Individual differences in dispositional empathic concern directly predicted gamma coherence (25-40 Hz), whereas psychopathy was inversely modulatory. Interestingly, significant suppression in the mu/alpha band (8-13 Hz) when perceiving others in distress was positively associated with higher trait psychopathy, which argues against the assumption that sensorimotor resonance underpins empathy. Greater scores on trait psychopathy were inversely related to subjective ratings of both empathic concern and affective sharing. Overall, the study demonstrates that neural markers of affective sharing and empathic concern to the same cues of another's distress can be distinguished at an electrophysiological level, and that psychopathy alters later time-locked differentiations and spectral coherence associated with empathic concern.

The impact of supervision training on genetic counselor supervisory identity development.

Supervision is critical to the training of genetic counselors. Limited research exists on the influence of supervision training and experience on the development of genetic counseling supervisors. The purpose of this study was to investigate the impact of supervision training in addition to supervisory and clinical experience on supervisory identity development, and the perceived confidence and competence supervisors have in their own supervisory skills. In addition, we explored genetic counselors' (N = 291) interest in and barriers to training as well as perspectives on requirements for supervisors. Results indicated clinical experience, supervision experience, and formal supervision training are positively associated with genetic counselors' supervisory identity development as measured by the Psychotherapy Supervisory Development Scale (PSDS) (p < 0.05). Despite a moderate correlation between supervision experience and formal training (ρ = 0.42, p < 0.001), both had independent effects on PSDS scores (p < 0.04). A majority of genetic counselors were interested in receiving supervision training but noted lack of available training as a barrier. The majority of participants indicated that supervisors should be certified as genetic counselors, but there was no consensus on training requirements. Development of additional supervision training opportunities for genetic counselors should be considered.

An Exploratory Analysis of Contributors to Cognitive Functioning Among Sexual and Gender Minority Individuals Who Had COVID-19.

Sexual and gender minority (SGM) individuals face mental health disparities. However, research analyzing SGM people's mental health after a COVID-19 diagnosis is scarce. In this secondary analysis of a remote study, we 1) examined associations between cognitive and psychosocial health and 2) explored differences between these health outcomes among SGM (n = 14) and heterosexual cisgender (n = 64) U.S. adults who had COVID-19. We used the Patient Reported Outcome Measures Information System (PROMIS) v2.0 to assess subjective cognition and the BrainCheck cognitive test to analyze objective cognition. We administered the Perceived Stress Scale and PROMIS 57 Profile V.2.0 to measure psychosocial health. SGM COVID-19 survivors had worse scores in depression, anxiety, sleep disturbance, pain, stress, and objective cognition than heterosexual cisgender participants (p-values < .05). Objective cognition was associated with age, SGM classification, racial or ethnic minority classification, income, comorbidities, COVID-19 severity, number of symptoms, and pain (|0.137| < r < |0.373|, p-values < .05). Subjective cognition was associated with comorbidities, number of symptoms, depression, anxiety, sleep disturbance, pain, and stress (|0.158| < r < |0.537|, p-values < .05). Additional studies are needed to expand what is known about post-COVID-19 health disparities and to guide policies and interventions that promote cognitive functioning.

MicroRNAs Associated with Metformin Treatment in the Diabetes Prevention Program.

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman's correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision-health strategies.

Longitudinal Associations Between MicroRNAs and Weight in the Diabetes Prevention Program.

OBJECTIVE: Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. RESEARCH DESIGN AND METHODS: A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. RESULTS: In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. DISCUSSION: This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.

Longitudinal associations between microRNAs and weight in the diabetes prevention program.

Objective: Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. Research design and methods: A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. Results: In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. Discussion: This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.

A sum of its parts: A systematic review evaluating biopsychosocial and behavioral determinants of perinatal depression.

INTRODUCTION: Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied. METHODS: Four databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. RESULTS: Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. CONCLUSIONS: Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.