At the Service of Community Development: The Professionalization of Volunteer Work in Kenya and Tanzania

This article explores the changing nature of the “volunteer” as an official role within health and development interventions in East Africa. Contemporary development interventions require the engagement of volunteers to act as links between project and community. This role is increasingly professionalized within development architectures with implications for the kinds of people who can engage in volunteering opportunities. Volunteers in development interventions are likely to be drawn from public sector staff and from educated youth seeking access to positions of paid employment. Volunteering as a formal status within the organization of development programs is recognized as a kind of professional work by those seeking to engage with development organizations. Volunteers perform important work in linking development programs with beneficiaries. At the same time, volunteering provides opportunities for personal transformation

Gamma-Ray Studies of Blazars: Synchro-Compton Analysis of Flat Spectrum Radio Quasars

We extend a method for modeling synchrotron and synchrotron self-Compton radiations in blazar jets to include external Compton processes. The basic model assumption is that the blazar radio through soft X-ray flux is nonthermal synchrotron radiation emitted by isotropically-distributed electrons in the randomly directed magnetic field of outflowing relativistic blazar jet plasma. Thus the electron distribution is given by the synchrotron spectrum, depending only on the Doppler factor $\delta_{\rm D}$ and mean magnetic field $B$, given that the comoving emission region size scale R_b^\prime \lesssim c \dD t_v/(1+z), where $t_v$ is variability time and $z$ is source redshift. Generalizing the approach of Georganopoulos, Kirk, and Mastichiadis (2001) to arbitrary anisotropic target radiation fields, we use the electron spectrum implied by the synchrotron component to derive accurate Compton-scattered $\gamma$-ray spectra throughout the Thomson and Klein-Nishina regimes for external Compton scattering processes. We derive and calculate accurate $\gamma$-ray spectra produced by relativistic electrons that Compton-scatter (i) a point source of radiation located radially behind the jet, (ii) photons from a thermal Shakura-Sunyaev accretion disk and (iii) target photons from the central source scattered by a spherically-symmetric shell of broad line region (BLR) gas. Calculations of broadband spectral energy distributions from the radio through $\gamma$-ray regimes are presented, which include self-consistent $\gamma\gamma$ absorption on the same radiation fields that provide target photons for Compton scattering. Application of this baseline flat spectrum radio/$\gamma$-ray quasar model is considered in view of data from $\gamma$-ray telescopes and contemporaneous multi-wavelength campaigns.Comment: Accepted by ApJ. 22 pages, 12 figures, 2 tables. Minor revisions to figures and tex

NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies

To what extent do nurses use research in clinical practice? A systematic review

Background : In the past forty years, many gains have been made in our understanding of the concept of research utilization. While numerous studies exist on professional nurses\u27 use of research in practice, no attempt has been made to systematically evaluate and synthesize this body of literature with respect to the extent to which nurses use research in their clinical practice. The objective of this study was to systematically identify and analyze the available evidence related to the extent to which nurses use research findings in practice. Methods : This study was a systematic review of published and grey literature. The search strategy included 13 online bibliographic databases: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE, HAPI, Web of Science, SCOPUS, OCLC Papers First, OCLC WorldCat, ABI Inform, Sociological Abstracts, and Dissertation Abstracts. The inclusion criteria consisted of primary research reports that assess professional nurses\u27 use of research in practice, written in the English or Scandinavian languages. Extent of research use was determined by assigning research use scores reported in each article to one of four quartiles: low, moderate-low, moderate-high, or high. Results : Following removal of duplicate citations, a total of 12,418 titles were identified through database searches, of which 133 articles were retrieved. Of the articles retrieved, 55 satisfied the inclusion criteria. The 55 final reports included cross-sectional/survey (n = 51) and quasi-experimental (n = 4) designs. A sensitivity analysis, comparing findings from all reports with those rated moderate (moderate-weak and moderate-strong) and strong quality, did not show significant differences. In a majority of the articles identified (n = 38, 69%), nurses reported moderate-high research use. Conclusions : According to this review, nurses\u27 reported use of research is moderate-high and has remained relatively consistent over time until the early 2000\u27s. This finding, however, may paint an overly optimistic picture of the extent to which nurses use research in their practice given the methodological problems inherent in the majority of studies. There is a clear need for the development of standard measures of research use and robust well-designed studies examining nurses\u27 use of research and its impact on patient outcomes. The relatively unchanged self-reports of moderate-high research use by nurses is troubling given that over 40 years have elapsed since the first studies in this review were conducted and the increasing emphasis in the past 15 years on evidence-based practice. More troubling is the absence of studies in which attempts are made to assess the effects of varying levels of research use on patient outcomes.<br /

Regulating E-Cigarettes: Why Policies Diverge

This paper, part of a festschrift in honor of Professor Malcolm Feeley, explores the landscape of e-cigarette policy globally by looking at three jurisdictions that have taken starkly different approaches to regulating e-cigarettes—the US, Japan, and China. Each of those countries has a robust tobacco industry, government agencies entrusted with protecting public health, an active and sophisticated scientific and medical community, and a regulatory structure for managing new pharmaceutical, tobacco, and consumer products. All three are signatories of the World Health Organization’s Framework Convention on Tobacco Control, all are signatories of the Agreement on Trade-Related Aspects of Intellectual Property Rights, and all are members of the World Trade Organization. Which legal, economic, social and political differences between the three countries explain their diverse approaches to regulating e-cigarettes? Why have they embraced such dramatically different postures toward e-cigarettes? In seeking to answer those questions, the paper builds on Feeley\u27s legacy of comparative scholarship, policy analysis, and focus on law in action

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead