The Hepatitis C Virus NS5A Stimulates NS5B During In Vitro RNA Synthesis in a Template Specific Manner

The hepatitis C virus (HCV) NS5B protein contains the RNA dependent RNA polymerase (RdRp) activity that catalyzes the synthesis of the viral genome with other host and viral factors. NS5A is an HCV-encoded protein previously shown to localize to the replisome and be necessary for viral replication. However, its role in replication has not been defined. Using an in vitro biochemical assay, we detected a stimulatory effect of NS5A on the NS5B replication reaction with minimal natural templates. NS5A stimulates replication by NS5B on two templates derived from the 3’ end of the RNA genome (4 fold ± 1.3 fold). A pre-incubation step with the two proteins prior to the replication reaction and substoichiometric levels of NS5A are required for detecting stimulation. With a template derived from the 3’end complementary to the RNA genome (the negative strand) no stimulation was observed. Furthermore, with a synthetic template that allows studying different phases of replication, NS5A stimulates NS5B during elongation. These findings suggest that NS5A stimulates NS5B during synthesis of the complementary (i.e., negative) strand of the RNA genome

Observations from a systematic review of pharmacist- led research in solid organ transplantation: An opinion paper of the American College of Clinical Pharmacy Immunology/Transplantation Practice and Research Network

IntroductionThe contributions of transplant pharmacists to clinical and translational research in the United States are ill- defined and have not been systematically reviewed.ObjectivesThe American College of Clinical Pharmacy Immunology/Transplantation Practice and Research Network conducted a systematic review of available pharmacist- led research publications involving solid organ transplantation with the intent to quantify and describe pharmacist- led research endeavors and their changes over time.MethodsAn electronic search of Scopus was conducted to identify publications in the field of solid organ transplantation by pharmacist authors between January 1, 1975 and May 25, 2017. Articles were excluded if they were written in non- English languages or originated from non- US countries. Review articles, case reports, surveys, basic science research, pre- clinical studies, and non- transplant research were further excluded. Studies were categorized as one of four phases on the clinical and translational research spectrum, adapted from the Harvard Clinical and Translational Science Center description of a T1 to T4 classification system.ResultsA total of 10- 354 publications were identified by the systematic search with 547 full- text English- language publications included in the analysis. Pharmacists served as the first author in 87% of the articles and as the senior author in 67% of the articles. A total of 71% of the articles included more than one pharmacist author. Transplant pharmacists published more studies that employed a retrospective or observational study design (55% and 78%, respectively). A total of 37% of studies were funded. On the spectrum of clinical and translation research, pharmacists were most involved in T3 (translation to practice) research (72%), followed by T2 (translation to patients) research (23%).ConclusionsTransplant pharmacists are increasingly represented in the US literature and frequently published across domains. Further demonstrating the relevance of pharmacist- delivered interventions and outcomes is a critical area of practice focus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163590/2/jac51294.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163590/1/jac51294_am.pd

Feasibility and acceptability of a patient-reported outcome intervention in chronic heart failure

Patients with chronic heart failure (CHF) have symptoms and concerns which are inadequately addressed. Patient-reported outcome measures (PROMs) can potentially improve the identification and management of advanced symptoms and palliative concerns. However, these have not been used in CHF.OBJECTIVES: To examine the feasibility and acceptability of using a PROM-the Integrated Palliative care Outcome Scale (IPOS)-together with heart failure nurse education and training to improve the identification and management of symptoms and concerns among patients with CHF.METHODS: A parallel, mixed methods design with an embedded qualitative component was used to examine the feasibility of recruitment, retention, intervention adherence/compliance and follow-up assessment completion (symptom burden, quality of life, psychological well-being). Patient and nurse qualitative semistructured interviews explored intervention and study design feasibility and its acceptability.RESULTS: Conversion to consent was 46.9% (372 screened, 81 approached, 38 recruited). 66% of patient participants completed the IPOS; 6% of IPOS questionnaire items were missing (non-response). Over two-thirds (65.6%) of these missing items related to three patients. No item was consistently missing; appetite was the most frequent missing item (1.4%). 92% of participants who completed the IPOS completed all follow-up assessments (1-2 days, 1-2 weeks and 4-6 weeks post-IPOS completion) with no missing data. The a priori feasibility objectives were met. Patients and nurses reported the intervention and study design feasible and acceptable.CONCLUSIONS: A palliative-specific PROM-based intervention is feasible and acceptable to both patients with CHF and nurses in nurse-led disease management clinics for the purposes of both clinical care and research.</p

Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus.

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α1-adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.The British Heart Foundatio

Strategies to address the shortcomings of commonly used advanced chronic heart failure descriptors to improve recruitment in palliative care research: A parallel mixed-methods feasibility study

Background:Recruitment challenges contribute to the paucity of palliative care research with advanced chronic heart failure patients.Aim:To describe the challenges and outline strategies of recruiting advanced chronic heart failure patients.Design:A feasibility study using a pre–post uncontrolled design.Setting:Advanced chronic heart failure patients were recruited at two nurse-led chronic heart failure disease management clinics in IrelandResults:Of 372 patients screened, 81 were approached, 38 were recruited (46.9% conversion to consent) and 25 completed the intervention. To identify the desired population, a modified version of the European Society of Cardiology definition was used together with modified New York Heart Association inclusion criteria to address inter-study site New York Heart Association classification subjectivity. These modifications substantially increased median monthly numbers of eligible patients approached (from 8 to 20) and median monthly numbers recruited (from 4 to 9). Analysis using a mortality risk calculator demonstrated that recruited patients had a median 1-year mortality risk of 22.7 and confirmed that the modified eligibility criteria successfully identified the population of interest. A statistically significant difference in New York Heart Association classification was found in recruited patients between study sites, but no statistically significant difference was found in selected clinical parameters between these patients.Conclusion:Clinically relevant modifications to the European Society of Cardiology definition and strategies to address New York Heart Association subjectivity may help to improve advanced chronic heart failure patient recruitment in clinical settings, thereby helping to address the paucity of palliative care research this population

What influences decisions about ongoing stroke rehabilitation for patients with pre-existing dementia or cognitive impairment: a qualitative study?

© The Author(s) 2018. Objective: To identify factors influencing clinicians decision-making about ongoing stroke rehabilitation for people with pre-existing dementia/cognitive impairment and the impact on clinical practice. Design: Qualitative semi-structured interviews with stroke specialist healthcare professionals analysed using thematic analysis. Setting: Acute stroke unit, inpatient stroke rehabilitation units, and community stroke services. Participants: Twenty three professionals from six multidisciplinary stroke teams involved in decision-making about stroke patients’ rehabilitation potential and clinical pathways. Results: Factors influencing decision-making about ongoing rehabilitation were (1) gaining understanding of the individual patient, (2) clinician’s knowledge of dementia/cognitive impairment, (3) predicting rehabilitation potential, (4) organizational constraints, and (5) clinician’s perceptions of their role within the team. Decision-making led to two outcomes, either accommodating the pre-existing dementia/cognitive impairment within delivery of rehabilitation or ending rehabilitation for that patient to allocate limited resources where they were perceived more likely to be effective. Participants felt that patients with pre-existing dementia/cognitive impairment had difficulty demonstrating the required rehabilitation potential within the short timescales available in the current model of service delivery. Participants identified a need for training to improve their knowledge and confidence for decision-making and delivery of rehabilitation for this growing population. Conclusion: Clinicians’ decision-making about ongoing rehabilitation for patients with prestroke dementia/cognitive impairments is influenced by gaps in their knowledge and by service constraints. Increased training and more flexible, patient-centred services would enable clinicians to better accommodate these patients in rehabilitation

Blurred lines: work, eldercare and HRM

peer-reviewedThe full text of this article will not be available in ULIR until the embargo expires on the 27/06/2020Increased levels of female labour market participation have impacted on the ability of families to provide care for elderly relatives in many industrialised societies. While work–family balance has received significant academic attention, less attention has focused specifically on individuals with eldercare responsibility, a cohort which accounts for a growing segment of the labour market internationally. Taking a qualitative research approach this paper uses work/family border theory to the constraints and facilitators to reconciling care and employment for employees working full-time in Ireland. The findings highlight the significant impact that eldercare provision has on employees with regard to day-to-day work commitments. We find that while general work–life balance policies exist within organisations, that the design and functionality of such policies are of limited value to elder caregivers. Furthermore, this paper highlights how the lack of formal HR policies around eldercare within organisations results in a reliance on supervisory discretion. We make some recommendations for organisational level strategies to address the needs of a growing number of caregivers.peer-reviewe

Physical Parameters of the Multiplanet Systems HD 106315 and GJ 9827

HD 106315 and GJ 9827 are two bright, nearby stars that host multiple super-Earths and sub-Neptunes discovered by K2 that are well suited for atmospheric characterization. We refined the planets' ephemerides through Spitzer transits, enabling accurate transit prediction required for future atmospheric characterization through transmission spectroscopy. Through a multiyear high-cadence observing campaign with Keck/High Resolution Echelle Spectrometer and Magellan/Planet Finder Spectrograph, we improved the planets' mass measurements in anticipation of Hubble Space Telescope transmission spectroscopy. For GJ 9827, we modeled activity-induced radial velocity signals with a Gaussian process informed by the Calcium II H&K lines in order to more accurately model the effect of stellar noise on our data. We measured planet masses of M_b = 4.87 ± 0.37 M_⊕, M_c = 1.92 ± 0.49 M_⊕, and M_d = 3.42 ± 0.62 M_⊕. For HD 106315, we found that such activity radial velocity decorrelation was not effective due to the reduced presence of spots and speculate that this may extend to other hot stars as well (T_(eff) > 6200 K). We measured planet masses of M_b = 10.5 ± 3.1 M_⊕ and M_c = 12.0 ± 3.8 M_⊕. We investigated all of the planets' compositions through comparison of their masses and radii to a range of interior models. GJ 9827 b and GJ 9827 c are both consistent with a 50/50 rock-iron composition, GJ 9827 d and HD 106315 b both require additional volatiles and are consistent with moderate amounts of water or hydrogen/helium, and HD 106315 c is consistent with a ~10% hydrogen/helium envelope surrounding an Earth-like rock and iron core

Impact of STROBE Statement Publication on Quality of Observational Study Reporting: Interrupted Time Series versus Before-After Analysis

Background:In uncontrolled before-after studies, CONSORT was shown to improve the reporting of randomised trials. Before-after studies ignore underlying secular trends and may overestimate the impact of interventions. Our aim was to assess the impact of the 2007 STROBE statement publication on the quality of observational study reporting, using both uncontrolled before-after analyses and interrupted time series.Methods:For this quasi-experimental study, original articles reporting cohort, case-control, and cross-sectional studies published between 2004 and 2010 in the four dermatological journals having the highest 5-year impact factors (≥4) were selected. We compared the proportions of STROBE items (STROBE score) adequately reported in each article during three periods, two pre STROBE period (2004-2005 and 2006-2007) and one post STROBE period (2008-2010). Segmented regression analysis of interrupted time series was also performed.Results:Of the 456 included articles, 187 (41%) reported cohort studies, 166 (36.4%) cross-sectional studies, and 103 (22.6%) case-control studies. The median STROBE score was 57% (range, 18%-98%). Before-after analysis evidenced significant STROBE score increases between the two pre-STROBE periods and between the earliest pre-STROBE period and the post-STROBE period (median score2004-0548% versus median score2008-1058%, p<0.001) but not between the immediate pre-STROBE period and the post-STROBE period (median score2006-0758% versus median score2008-1058%, p = 0.42). In the pre STROBE period, the six-monthly mean STROBE score increased significantly, by 1.19% per six-month period (absolute increase 95%CI, 0.26% to 2.11%, p = 0.016). By segmented analysis, no significant changes in STROBE score trends occurred (-0.40%; 95%CI, -2.20 to 1.41; p = 0.64) in the post STROBE statement publication.Interpretation:The quality of reports increased over time but was not affected by STROBE. Our findings raise concerns about the relevance of uncontrolled before-after analysis for estimating the impact of guidelines

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy