Development and presentation of an objective risk stratification tool for healthcare workers when dealing with the COVID-19 pandemic in the UK: risk modelling based on hospitalisation and mortality statistics compared with epidemiological data

This paper presents a tool for objective risk stratification of doctors and healthcare professionals during the COVID-19 pandemic, without requiring disclosure of information that an individual may not wish to share during the risk assessment process. This tool is freely available through the British Medical Association website and is widely used in the National Health Service and other external organisation

Emergency and critical care services in Tanzania: a survey of ten hospitals.

While there is a need for good quality care for patients with serious reversible disease in all countries in the world, Emergency and Critical Care tends to be one of the weakest parts of health systems in low-income countries. We assessed the structure and availability of resources for Emergency and Critical Care in Tanzania in order to identify the priorities for improving care in this neglected specialty. Ten hospitals in four regions of Tanzania were assessed using a structured data collection tool. Quality was evaluated with standards developed from the literature and expert opinion. Important deficits were identified in infrastructure, routines and training. Only 30% of the hospitals had an emergency room for adult and paediatric patients. None of the seven district and regional hospitals had a triage area or intensive care unit for adults. Only 40% of the hospitals had formal systems for adult triage and in less than one third were critically ill patients seen by clinicians more than once daily. In 80% of the hospitals there were no staff trained in adult triage or critical care. In contrast, a majority of equipment and drugs necessary for emergency and critical care were available in the hospitals (median 90% and 100% respectively. The referral/private hospitals tended to have a greater overall availability of resources (median 89.7%) than district/regional hospitals (median 70.6). Many of the structures necessary for Emergency and Critical Care are lacking in hospitals in Tanzania. Particular weaknesses are infrastructure, routines and training, whereas the availability of drugs and equipment is generally good. Policies to improve hospital systems for the care of emergency and critically ill patients should be prioritised

Plugging a hole and lightening the burden: A process evaluation of a practice education team

Aim: To investigate the perceptions of clinical and senior managers about the role of Practice Educators employed in one acute hospital in the UK. Background: Producing nurses who are fit for practice, purpose and academic award is a key issue for nurse education partnership providers in the UK. Various new models for practice learning support structures and new roles within health care institutions have been established. To sustain funding and policy support for these models, there is a need for evaluation research. Design: A process evaluation methodology was employed to determine the current value of a practice education team and to provide information to guide future direction. Methods: Data were collected through semi-structured telephone interviews using a previously designed schedule. All senior nurse managers (N=5) and a purposive sample of clinical managers (n=13) who had personal experience of and perceptions about the role of practice educators provided the data. Interview notes were transcribed, coded and a thematic framework devised to present the results. Results: A number of key themes emerged including: qualities needed for being a successful practice educator; visibility and presence of practice educators; providing a link with the university; ‘plugging a hole’ in supporting learning needs; providing relief to practitioners in dealing with ‘the burden of students’; alleviating the ‘plight of students’; and effects on student attrition. Conclusions: Findings provided evidence for the continued funding of the practice educator role with improvements to be made in dealing with stakeholder expectations and outcomes. Relevance to clinical practice: In the UK, there still remain concerns about the fitness for practice of newly registered nurses, prompting a recent national consultation by the professional regulating body. Despite fiscal pressures, recommendations for further strengthening of all systems that will support the quality of practice learning may continue to sustain practice learning support roles

VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System

The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently ('specialised') or non-covalently ('cargo' effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a 'core' T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with differential effector specificity and efficiency of target cell delivery

Somatic p16INK4a loss accelerates melanomagenesis

Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood

Signaling pathway networks mined from human pituitary adenoma proteomics data

Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins), comparative proteomic data (56 differentially expressed proteins), and nitroproteomic data (17 nitroproteins). There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a pituitary control related to gene expression and cellular development, and no canonical toxicity pathways were identified. Conclusions This pathway network analysis demonstrated that mitochondrial dysfunction, oxidative stress, cell-cycle dysregulation, and the MAPK-signaling abnormality are significantly associated with a pituitary adenoma. These pathway-network data provide new insights into the molecular mechanisms of human pituitary adenoma pathogenesis, and new clues for an in-depth investigation of pituitary adenoma and biomarker discovery.</p

Educational outreach in an integrated clinical management tool for nurse-led non-communicable chronic disease management in primary care in South Africa: pragmatic cluster randomised controlled trial

Background: In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary Care 101 (PC101) is a programme designed to support and expand nurses’ role in NCD care, comprising a clinical management tool with enhanced prescribing provisions for nurses, and educational outreach. We evaluated the effectiveness of the programme on primary care nurses’ capacity to manage NCDs (ISRCTN20283604). Methods and findings: In a cluster randomised controlled trial design, 38 public sector primary care clinics in the Western Cape province, South Africa, were randomised. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV /AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (3227), diabetes (1842), chronic respiratory disease (1157) or screened positive for depression (2466), totalling 4393 patients, were enrolled between March 2011 and October 2011. Primary outcomes were treatment intensification for hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 months, and case detection in the depression cohort. Primary outcome data were analysed for 2110 (97%) intervention and 2170 (97%) control group patients. Treatment intensification rates in intervention clinics were not superior to those in the control group clinics [hypertension: 44% in the intervention group versus 40% in the controls, risk ratio (RR) 1.08 (95% CI: 0.94 to 1.24; p=0.252); diabetes: 57% v 50%, RR 1.10 (0.97 to 1.24;p=0.126); chronic respiratory disease: 14% v 12%, RR 1.08 (0.75 to 1.55; p=0.674); and case detection of depression: 18% v 24%, RR 0.76 (0.53 to 1.10; p=0.142)]. No adverse effects of the nurses’ expanded scope of practice were observed. Limitations of the study include dependence on self-reported diagnoses for inclusion in the patient cohorts, limited data on uptake of PC101 by users, reliance on process outcomes, and insufficient resources to measure important health outcomes, such as HbA1c, at follow-up. Conclusions: Educational outreach to primary care nurses through use of a management tool involving an expanded role in managing NCDs, is feasible and safe but was not associated with treatment intensification or case detection for index diseases. This notwithstanding, the intervention, with adjustments to improve its effectiveness, has been adopted for implementation in primary care clinics throughout South Africa

Acute mucosal pathogenesis of feline immunodeficiency virus is independent of viral dose in vaginally infected cats

<p>Abstract</p> <p>Background</p> <p>The mucosal pathogenesis of HIV has been shown to be an important feature of infection and disease progression. HIV-1 infection causes depletion of intestinal lamina propria CD4+ T cells (LPL), therefore, intestinal CD4+ T cell preservation may be a useful correlate of protection in evaluating vaccine candidates. Vaccine studies employing the cat/FIV and macaque/SIV models frequently use high doses of parenterally administered challenge virus to ensure high plasma viremia in control animals. However, it is unclear if loss of mucosal T cells would occur regardless of initial viral inoculum dose. The objective of this study was to determine the acute effect of viral dose on mucosal leukocytes and associated innate and adaptive immune responses.</p> <p>Results</p> <p>Cats were vaginally inoculated with a high, middle or low dose of cell-associated and cell-free FIV. PBMC, serum and plasma were assessed every two weeks with tissues assessed eight weeks following infection. We found that irrespective of mucosally administered viral dose, FIV infection was induced in all cats. However, viremia was present in only half of the cats, and viral dose was unrelated to the development of viremia. Importantly, regardless of viral dose, all cats experienced significant losses of intestinal CD4+ LPL and CD8+ intraepithelial lymphocytes (IEL). Innate immune responses by CD56+CD3- NK cells correlated with aviremia and apparent occult infection but did not protect mucosal T cells. CD4+ and CD8+ T cells in viremic cats were more likely to produce cytokines in response to Gag stimulation, whereas aviremic cats T cells tended to produce cytokines in response to Env stimulation. However, while cell-mediated immune responses in aviremic cats may have helped reduce viral replication, they could not be correlated to the levels of viremia. Robust production of anti-FIV antibodies was positively correlated with the magnitude of viremia.</p> <p>Conclusions</p> <p>Our results indicate that mucosal immune pathogenesis could be used as a rapid indicator of vaccine success or failure when combined with a physiologically relevant low dose mucosal challenge. We also show that innate immune responses may play an important role in controlling viral replication following acute mucosal infection, which has not been previously identified.</p

Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development

Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development