MINocyclinE to Reduce inflammation and blood-brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double-blind, placebo-controlled experimental medicine trial.

INTRODUCTION: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. METHODS: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using 11C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). RESULTS: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on 11C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. DISCUSSION: 11C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. INTERNATIONAL CLINICAL TRIALS REGISTRY PORTAL IDENTIFIER: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Do Regions of Increased Inflammation Progress to New White Matter Hyperintensities?: A Longitudinal Positron Emission Tomography-Magnetic Resonance Imaging Study.

BACKGROUND: Recent studies have demonstrated increased microglial activation using 11C-PK11195 positron emission tomography imaging, indicating central nervous system inflammation, in cerebral small vessel disease. However, whether such areas of neuroinflammation progress to tissue damage is uncertain. We determined whether white matter destined to become white matter hyperintensities (WMH) at 1 year had evidence of altered inflammation at baseline. METHODS: Forty subjects with small vessel disease (20 sporadic and 20 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and 20 controls were recruited to this case-control observational study from in- and out-patient clinics at Addenbrooke's Hospital, Cambridge, UK and imaged at baseline with both 11C-PK11195 positron emission tomography and magnetic resonance imaging; and magnetic resonance imaging including diffusion tensor imaging was repeated at 1 year. WMH were segmented at baseline and 1 year, and areas of new lesion identified. Baseline 11C-PK11195 binding potential and diffusion tensor imaging parameters in these voxels, and normal appearing white matter, was measured. RESULTS: Complete positron emission tomography-magnetic resonance imaging data was available for 17 controls, 16 sporadic small vessel disease, and 14 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy participants. 11C-PK11195 binding in voxels destined to become new WMH was lower than in normal appearing white matter, which did not progress to WMH (-0.133[±0.081] versus -0.045 [±0.044]; P<0.001). Mean diffusivity was higher and mean fractional anisotropy lower in new WMH voxels than in normal appearing white matter (900 [±80]×10-6 versus 1045 [±149]×10-6 mm2/s and 0.37±0.05 versus 0.29±0.06, both P<0.001) consistent with new WMH showing tissue damage on diffusion tensor imaging a year prior to developing into new WMH; similar results were seen across the 3 groups. CONCLUSIONS: White matter tissue destined to develop into new WMH over the subsequent year is associated with both lower neuroinflammation, and white matter ultrastructural damage at baseline. Our results suggest that this tissue is already damaged 1 year prior to lesion formation. This may reflect that the role of neuroinflammation in the lesion development process occurs at an early stage, although more studies over a longer period would be needed to investigate this further.

Intravital Microscopy Reveals Unforeseen Biodistribution Within the Liver and Kidney Mechanistically Connected to the Clearance of a Bifunctional Antibody.

Bifunctional antibody (BfAb) therapeutics offer the potential for novel functionalities beyond those of the individual monospecific entities. However, combining these entities into a single molecule can have unpredictable effects, including changes in pharmacokinetics that limit the compound's therapeutic profile. A better understanding of how molecular modifications affect in vivo tissue interactions could help inform BfAb design. The present studies were predicated on the observation that a BfAb designed to have minimal off-target interactions cleared from the circulation twice as fast as the monoclonal antibody (mAb) from which it was derived. The present study leverages the spatial and temporal resolution of intravital microscopy (IVM) to identify cellular interactions that may explain the different pharmacokinetics of the two compounds. Disposition studies of mice demonstrated that radiolabeled compounds distributed similarly over the first 24 hours, except that BfAb accumulated approximately two- to -three times more than mAb in the liver. IVM studies of mice demonstrated that both distributed to endosomes of liver endothelia but with different kinetics. Whereas mAb accumulated rapidly within the first hour of administration, BfAb accumulated only modestly during the first hour but continued to accumulate over 24 hours, ultimately reaching levels similar to those of the mAb. Although neither compound was freely filtered by the mouse or rat kidney, BfAb, but not mAb, was found to accumulate over 24 hours in endosomes of proximal tubule cells. These studies demonstrate how IVM can be used as a tool in drug design, revealing unpredicted cellular interactions that are undetectable by conventional analyses. SIGNIFICANCE STATEMENT: Bifunctional antibodies offer novel therapeutic functionalities beyond those of the individual monospecific entities. However, combining these entities into a single molecule can have unpredictable effects, including undesirable changes in pharmacokinetics. Studies of the dynamic distribution of a bifunctional antibody and its parent monoclonal antibody presented here demonstrate how intravital microscopy can expand our understanding of the in vivo disposition of therapeutics, detecting off-target interactions that could not be detected by conventional pharmacokinetics approaches or predicted by conventional physicochemical analyses.

Nursing Students' Self-Efficacy and Performance in Self-Management Support for Patients in Rural Primary Care.

ABSTRACT: There is currently no evidence of undergraduate nursing students' self-efficacy and performance in self-management support for chronic diseases in rural primary care. Using the Self-Efficacy and Performance in Self-Management Support instrument, this quasi-experimental study assessed students' self-efficacy and performance in self-management support before and after implementation of a primary care enhanced curriculum. Nursing students (n = 140) reported a significant increase in total mean scores (pretest, M = 268.01; posttest, M = 289.51), p = .0001. Providing a primary care enhanced curriculum increased nursing students' self-efficacy and performance in self-management support.

Evaluating Knowledge of Public Health Nursing Competencies in Baccalaureate Nursing Students.

ABSTRACT: Community health workers are projected to grow in number by 17 percent by 2030. A baccalaureate degree in nursing (BSN) provides a foundation for public health nursing practice. The Competencies for Public Health Nursing Practice instrument was distributed to BSN students at a Midwestern university before and after an educational intervention. Students completed a pretest ( n = 269) and posttest ( n = 154). All four subscales and total score indicated a significant increase in competence ( p < .001). There is a need to develop interactive public health nursing simulations with an interprofessional venue to help students improve teamwork and communication competencies.

Factors associated with changes in nurses' emotional distress during the COVID-19 pandemic.

PURPOSE: The purpose of this study was twofold: to assess if nurses experienced changes in emotional distress (stress, depression, and anxiety) as the number of patients infected with coronavirus disease 2019 (COVID-19) increased and if there were any sociodemographic, psychosocial, and work environmental influence on the change. METHODS: Using a repeated cross-sectional study design, we collected survey data among 198 South Dakota (SD) nurses. Data were collected in two waves, during the first 12 months of the COVID-19 pandemic in the United States (July and December 2020). Participants completed two online surveys: (a) The Depression, Anxiety, and Stress Scale (DASS-21); and (b) Change Fatigue Scale. Predictive factors were divided into three groups: sociodemographic, psychosocial, and work environment variables. Multiple linear regression models were run to estimate the factors associated with the change in DASS-21 subscale score. RESULTS: Total DASS-21 score and scores for all subscales significantly increased from Survey 1 to Survey 2. Significant positive associations were found between change fatigue and workplace barriers with change in depression, anxiety, and stress scores. A linear relationship was identified between self-worry about COVID-19 risk and depression and stress and being male and young were associated with changes in depression. CONCLUSIONS: Increase in emotional distress of nurses as the pandemic progresses is consistent with other studies. It is vital for healthcare organizations to recognize the factors associated with the changes in emotional distress and their role in decreasing the stress levels of nurses.

Preclinical Characterization of LY3209590, a Novel Weekly Basal Insulin Fc-Fusion Protein.

The benefit of once-weekly basal insulin is less frequent dosing, which has the potential to reduce the barrier to injection therapy and impact patient activation, adherence and compliance, quality of life, and outcomes. Basal Insulin Fc (BIF, LY3209590, or insulin efsitora alfa) is a once-weekly basal insulin in clinical testing for type 1 and type 2 diabetes mellitus. BIF is comprised of a novel single-chain variant of insulin fused to a human IgG2 fragment crystallizable region of an antibody domain using a peptide linker. The in vitro binding affinity of BIF for the human insulin receptor (IR) was two orders of magnitude weaker relative to human insulin. BIF stimulated IR phosphorylation in cells with reduced potency, yet full agonism, and exhibited a significantly faster dephosphorylation kinetic profile than human insulin or AspB10 insulin. BIF stimulated de novo lipogenesis in 3T3-L1 adipocytes and cell proliferation in SAOS-2 and H4IIE cells with ≥70-fold reduction in in vitro potency compared with human insulin. BIF possessed markedly reduced binding to hIGF-1R, making definitive measurements unattainable. In vivo pharmacology studies using streptozotocin-treated diabetic rats demonstrated a significant decrease in blood glucose compared with vehicle-treated animals 24 hours post-injection, persisting through 336 hours following subcutaneous administration. In streptozotocin-treated rats, BIF reached time at maximum concentration at 48 hours and possessed a clearance rate of ∼0.85 ml/h per kg, with a terminal half-life of ∼120 hours following subcutaneous administration. These results demonstrate BIF has an in vitro pharmacological profile similar to native insulin, with significantly reduced potency and an extended time-action profile in vivo that supports once-weekly dosing in humans. SIGNIFICANCE STATEMENT: BIF is a novel basal insulin Fc-fusion protein designed for once-weekly dosing. In this study, we demonstrate that BIF has an in vitro pharmacological profile similar to human insulin, but with weaker potency across assays for IR binding and activity. BIF has a PD and PK profile in STZ-treated rats supportive of weekly dosing in humans.

Rate of, and risk factors for, white matter hyperintensity growth: a systematic review and meta-analysis with implications for clinical trial design.

BACKGROUND: White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood. METHODS: We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint. RESULTS: WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided. CONCLUSIONS: WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure. PROSPERO REGISTRATION NUMBER: CRD42020191781.

Influence of FcRn binding properties on the gastrointestinal absorption and exposure profile of Fc molecules.

The neonatal Fc receptor (FcRn) represents a transport system with the potential to facilitate absorption of biologics across the gastrointestinal barrier. How biologics interact with FcRn to enable their gastrointestinal absorption, and how these interactions might be optimized in a biological therapeutic are not well understood. Thus, we studied the absorption of Fc molecules from the intestine using three IgG4-derived Fc variants with different, pH-dependent FcRn binding and release profiles. Using several different intestinal models, we consistently observed that FcRn binding affinity correlated with transcytosis. Our findings support targeting FcRn to enable intestinal absorption of biologics and highlight additional strategic considerations for future work.

Parenting stress, self-efficacy and COVID-19 health risks as predictors of general stress among nurses.

AIM: The purpose of the study was to examine the influence of parenting stress, self-efficacy and COVID-19 health risks on general stress among nurses in the Midwest, United States, during the pandemic. BACKGROUND: As frontline workers amidst the coronavirus disease 2019 (COVID-19) pandemic, nurses have been subject to stressors at home and at work. METHOD: This quantitative, cross-sectional study included 896 nurses with at least one child below 18 years of age. Using purposive sampling, participants answered an online survey composed of demographic questions, perception of COVID-19 health risks, measures of self-efficacy, general stress and parenting stress. Bivariate correlation and multiple regression were conducted. Data were collected from July 13 to August 13, 2020. RESULTS: The four predictors, along with eight demographic covariates, accounted for 40% of the variance in general stress. Parenting stress and COVID-19 health risks were positively related to general stress, while self-efficacy was negatively associated with general stress. CONCLUSIONS: Results highlight the negative influence of parenting stress on nurses' general stress and the importance of self-efficacy in reducing stress. Findings suggest that support services for nurses should focus not only on work-related stressors but also consider parenting stressors, work-home imbalances and self-efficacy.

Factors associated with nurses emotional distress during the COVID-19 pandemic.

BACKGROUND: Nurses are among the frontline healthcare workers directly impacted by the burden of the coronavirus disease of 2019 (COVID-19) pandemic. This study aimed to examine the prevalence of emotional distress and the associated factors among nurses practicing in South Dakota during the COVID-19 pandemic. METHODS: An online survey was conducted among practicing, licensed nurses in South Dakota during the pandemic (July 2020 - August 2020). Emotional distress was measured using the Depression, Anxiety, and Stress Scale (DASS-21). Logistic regression models were performed to examine the association of emotional distress and the three DASS-21 subscales with: sociodemographic and work environment factors (e.g., work setting, job satisfaction, number of COVID-19 cases seen at the facility, preparedness, concerns with worsening pre-exiting mental health conditions due to the pandemic, and contracting the illness). RESULTS: Among 1505 participants, overall emotional distress was reported by 22.2%, while anxiety, depression and stress were 15.8%, 14.5% and 11.9%, respectively. Factors associated with moderate to severe emotional distress, depression, anxiety, and stress were as follows: concerns for worsening of pre-existing mental health conditions, job dissatisfaction, encountering higher number of COVID-19 cases at one's work facility, feeling unprepared for the pandemic, and concern for contracting the illness (all p < 0.05). CONCLUSIONS: Our study suggests a high prevalence of emotional distress among nurses and highlights the factors associated with emotional distress during the COVID-19 pandemic. Promoting appropriate support is imperative to reduce nurses' emotional distress and promote psychological well-being during the COVID-19 world health crisis and in future pandemics.

High COVID-19 Attack Rate Among Attendees at Events at a Church - Arkansas, March 2020.

On March 16, 2020, the day that national social distancing guidelines were released (1), the Arkansas Department of Health (ADH) was notified of two cases of coronavirus disease 2019 (COVID-19) from a rural county of approximately 25,000 persons; these cases were the first identified in this county. The two cases occurred in a husband and wife; the husband is the pastor at a local church (church A). The couple (the index cases) attended church-related events during March 6-8, and developed nonspecific respiratory symptoms and fever on March 10 (wife) and 11 (husband). Before his symptoms had developed, the husband attended a Bible study group on March 11. Including the index cases, 35 confirmed COVID-19 cases occurred among 92 (38%) persons who attended events held at church A during March 6-11; three patients died. The age-specific attack rates among persons aged ≤18 years, 19-64 years, and ≥65 years were 6.3%, 59.4%, and 50.0%, respectively. During contact tracing, at least 26 additional persons with confirmed COVID-19 cases were identified among community members who reported contact with church A attendees and likely were infected by them; one of the additional persons was hospitalized and subsequently died. This outbreak highlights the potential for widespread transmission of SARS-CoV-2, the virus that causes COVID-19, both at group gatherings during church events and within the broader community. These findings underscore the opportunity for faith-based organizations to prevent COVID-19 by following local authorities' guidance and the U.S. Government's Guidelines: Opening Up America Again (2) regarding modification of activities to prevent virus transmission during the COVID-19 pandemic.

Modulation of the Biophysical Properties of Bifunctional Antibodies as a Strategy for Mitigating Poor Pharmacokinetics.

Interest in the development of bi- or multispecific antibody (BsAbs)-based biotherapeutics is growing rapidly due to their inherent ability to interact with many targets simultaneously, thereby potentially protracting their functionality relative to monoclonal antibodies (mAbs). Biophysical property assays have been used to improve the probability of clinical success for various mAb therapeutics; however, there is a paucity of such data for BsAbs. This work evaluates a fusion of an IgG with an isolated protein domain (deemed ECD) and serves to understand how molecular architecture influences biophysical and biochemical properties and, in turn, how these relate to drug disposition. The biophysical characteristics of the molecules (charge, nonspecific binding, FcRn and Fcγ receptor interactions, thermal stability, structure-dynamics, and hydrophobic properties) indicated preferred orientations of ECD and IgG, which supported better pharmacokinetic outcomes. In certain instances, in which ECD-IgG configurations led to suboptimal biophysical behavior in the form of increased hydrophobicity and global ECD instability, drug clearance was found to be increased by ≥2-fold, driven by endothelial cell-based association/clearance mechanisms in the liver, kidneys, and spleen. Improvements in the pharmacokinetic properties were afforded by positional modulation of ECD that was able to bring the disposition characteristics in line with those of the parental mAb. The findings provide some pragmatic, broadly applicable strategies and guidance for the design considerations and evaluation of ECD-BsAb constructs. Additional studies, delineating the precise interactions involved in the clearance of the ECD-BsAb constructs, remain an opportunistic area for improving their in vivo kinetic properties.

Do Cerebral Small Vessel Disease and Multiple Sclerosis Share Common Mechanisms of White Matter Injury?

Background and Purpose- The role of inflammation in ischemic white matter disease is increasingly recognized, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis (MS) is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesized that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically elevated white matter hyperintensity (WMH) volume was associated with increased MS risk. Methods- We investigated the genetic association in 2 cohorts with magnetic resonance imaging-quantified ischemic white matter lesion volume (WMH in stroke; n=2797 and UK Biobank; n=8353) and 14 802 cases of MS and 26 703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual-level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally, we looked for evidence of overlapping risk across the whole genome. Results- There was no association of genetic variants influencing MS with WMH volume using summary statistics in the WMH in stroke cohort (relative risk score =1.014; 95% CI, 0.936-1.110) or in the UK Biobank cohort (relative risk score =1.030; 95% CI, 0.932-1.117). Conversely, assessing the contribution of single nucleotide polymorphisms significantly associated with WMH on the risk of MS there was no significant association (relative risk score =0.930; 95% CI, 0.736-1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to the selection of single nucleotide polymorphisms at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits. Conclusions- Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischemia and MS. We propose that inflammation acts in distinct pathways because of the differing nature of the primary insult.

Collagenous gastritis: An unusual cause of generalized oedema in a child.

Collagenous gastritis is an uncommon gastrointestinal disease in children. Its cause remains uncertain. It may present as severe hypoproteinaemia manifesting as generalized oedema. We report a 15 months old female who presented with pica, generalized body oedema and diarrhoea. Diagnostic workup revealed gastric replacement of the lamina propria by hyalinized collagen on histology. This case seeks to highlight the need for early paediatric gastroenterology referral including oesophagogastroduodenoscopy with multiple tissue biopsies as part of a broad diagnostic workup in children with non-specific gastrointestinal symptoms to improve diagnostic yield and enable accurate histologic diagnosis, so that appropriate therapy can be timeously applied.

Sézary Syndrome Presenting With Renal Involvement.

Sézary syndrome is a rare aggressive leukemic variant of primary cutaneous T-cell lymphoma, typically presenting with erythroderma, lymphadenopathy, and an atypical clonal T-cell population. Though it often involves the spleen and liver, we report a case of Sézary syndrome with renal involvement that was treated successfully. Visceral involvement confers a poor prognosis requiring systemic treatment. The patient we describe was a 66-year-old man who was referred from Dermatology services for deteriorating kidney function. Polymerase chain reaction of genomic DNA from skin and kidney biopsies confirmed a clonal T-cell population matching a population isolated in peripheral blood. The patient was treated initially with alemtuzumab, which led to a significant improvement in kidney function, and he has subsequently received a successful allogeneic stem cell transplant. This case represents a rare cause of decreased kidney function and highlights the role of biopsy in patients with suspected Sézary syndrome.

Arrival of the Fukushima radioactivity plume in North American continental waters.

The large discharge of radioactivity into the northwest Pacific Ocean from the 2011 Fukushima Dai-ichi nuclear reactor accident has generated considerable concern about the spread of this material across the ocean to North America. We report here the first systematic study to our knowledge of the transport of the Fukushima marine radioactivity signal to the eastern North Pacific. Time series measurements of (134)Cs and (137)Cs in seawater revealed the initial arrival of the Fukushima signal by ocean current transport at a location 1,500 km west of British Columbia, Canada, in June 2012, about 1.3 y after the accident. By June 2013, the Fukushima signal had spread onto the Canadian continental shelf, and by February 2014, it had increased to a value of 2 Bq/m(3) throughout the upper 150 m of the water column, resulting in an overall doubling of the fallout background from atmospheric nuclear weapons tests. Ocean circulation model estimates that are in reasonable agreement with our measured values indicate that future total levels of (137)Cs (Fukushima-derived plus fallout (137)Cs) off the North American coast will likely attain maximum values in the 3-5 Bq/m(3) range by 2015-2016 before declining to levels closer to the fallout background of about 1 Bq/m(3) by 2021. The increase in (137)Cs levels in the eastern North Pacific from Fukushima inputs will probably return eastern North Pacific concentrations to the fallout levels that prevailed during the 1980s but does not represent a threat to human health or the environment.

The Relationship Among Change Fatigue, Resilience, and Job Satisfaction of Hospital Staff Nurses.

PURPOSE: The purpose of this study was to examine relationships between change fatigue, resilience, and job satisfaction among novice and seasoned hospital staff nurses. BACKGROUND: Health care is typified by change. Frequent and vast changes in acute care hospitals can take a toll on nurses and cause change fatigue, which has been largely overlooked and under-researched. DESIGN AND METHOD: A descriptive correlational design was employed with 521 hospital staff nurses in one midwestern state. Participants completed three online surveys: (a) Change Fatigue Scale, (b) Connor-Davidson Resilience Scale, and (c) McCloskey/Mueller Satisfaction Scale. FINDINGS: In a multiple regression model, job satisfaction had a statistically significant negative association with change fatigue (p < .001) and significant positive association with resilience (p < .001). A linear trend was found with hospital size (number of beds) and change fatigue (p = .001) and education level and resilience (p = .03). CONCLUSIONS: The results are consistent with job satisfaction among hospital nursing staff being negatively influenced by change fatigue and positively influenced by resilience, although reverse causal connections are also possible. Change fatigue may be increased by larger hospital size (number of beds), and resilience may be increased by higher educational level of hospital staff nurses. CLINICAL RELEVANCE: The study advanced the nursing knowledge on change fatigue, resilience, and job satisfaction of staff nurses working in acute care hospitals. Engaging in strategies aimed at preventing change fatigue in nursing staff can enhance workplace environments, job satisfaction, and retention of nurses.

Probe technologies for clean sampling and measurement of subglacial lakes.

It is 4 years since the subglacial lake community published its plans for accessing, sampling, measuring and studying the pristine, and hitherto enigmatic and very different, Antarctic subglacial lakes, Vostok, Whillans and Ellsworth. This paper summarizes the contrasting probe technologies designed for each of these subglacial environments and briefly updates how these designs changed or were used differently when compared to previously published plans. A detailed update on the final engineering design and technical aspects of the probe for Subglacial Lake Ellsworth is presented. This probe is designed for clean access, is negatively buoyant (350 kg), 5.2 m long, 200 mm in diameter, approximately cylindrical and consists of five major units: (i) an upper power and communications unit attached to an optical and electrical conducting tether, (ii)-(iv) three water and particle samplers, and (v) a sensors, imaging and instrumentation pack tipped with a miniature sediment corer. To date, only in Subglacial Lake Whillans have instruments been successfully deployed. Probe technologies for Subglacial Lake Vostok (2014/15) and Lake Ellsworth (2012/13) were not deployed for technical reasons, in the case of Lake Ellsworth because hot-water drilling was unable to access the lake during the field season window. Lessons learned and opportunities for probe technologies in future subglacial access missions are discussed.

Epicardial wave mapping in human long-lasting persistent atrial fibrillation: transient rotational circuits, complex wavefronts, and disorganized activity.

OBJECTIVES: To characterize the nature of atrial fibrillation (AF) activation in human persistent AF (PerAF) using modern tools including activation, directionality analyses, complex-fractionated electrogram, and spectral information. BACKGROUND: The mechanism of PerAF in humans is uncertain. METHODS AND RESULTS: High-density epicardial mapping (128 electrodes/6.75 cm(2)) of the posterior LA wall (PLAW), LA and RA appendage (LAA, RAA), and RSPV-LA junction was performed in 18 patients with PerAF undergoing open heart surgery. Continuous 10 s recordings were analysed offline. Activation patterns were characterized into four subtypes (i) wavefronts (broad or multiple), (ii) rotational circuits (≥2 rotations of 360°), (iii) focal sources with centrifugal activation of the entire mapping area, or (iv) disorganized activity [isolated chaotic activation(s) that propagate ≤3 bipoles or activation(s) that occur as isolated beats dissociated from the activation of adjacent bipole sites]. Activation at a total of 36 regions were analysed (14 PLAW, 3 RSPV-LA, 12 LAA, and 7 RAA) creating a database of 2904 activation patterns. In the majority of maps, activation patterns were highly heterogeneous with multiple unstable activation patterns transitioning from one to another during each recording. A mean of 3.8 ± 1.6 activation subtypes was seen per map. The most common patterns seen were multiple wavefronts (56.2 ± 32%) and disorganized activity (24.2 ± 30.3%). Only 2 of 36 maps (5.5%) showed a single stable activation pattern throughout the 10-s period. These were stable planar wavefronts. Three transient rotational circuits were observed. Two of the transient circuits were located in the posterior left atrium, while the third was located on the anterior surface of the LAA. Focal activations accounted for 11.3 ± 14.2% of activations and were all short-lived (≤2 beats), with no site demonstrating sustained focal activity. CONCLUSION: Human long-lasting PerAF is characterized by heterogeneous and unstable patterns of activation including wavefronts, transient rotational circuits, and disorganized activity.