Acidosis significantly alters immune checkpoint expression profiles of T cells from oesophageal adenocarcinoma patients.

Tumour acidosis contributes to cancer progression by inhibiting anti-tumour immunity. However, the effect of acidosis on anti-tumour T cell phenotypes in oesophageal adenocarcinoma (OAC) is unknown. Therefore, this study investigated the effect of acidosis on anti-tumour T cell profiles and if immune checkpoint blockade (ICB) could enhance anti-tumour T cell immunity under acidosis. Acidic conditions substantially altered immune checkpoint expression profiles of OAC patient-derived T cells, upregulating TIM-3, LAG-3 and CTLA-4. Severe acidosis (pH 5.5) significantly decreased the percentage of central memory CD4+ T cells, an effect that was attenuated by ICB treatment. ICB increased T cell production of IFN-γ under moderate acidosis (pH 6.6) but not severe acidosis (pH 5.5) and decreased IL-10 production by T cells under severe acidic conditions only. A link between lactate and metastasis was also depicted; patients with nodal metastasis had higher serum lactate levels (p = 0.07) which also positively correlated with circulating levels of pro-angiogenic factor Tie-2. Our findings establish that acidosis-induced upregulation of immune checkpoints on T cells may potentially contribute to immune evasion and disease progression in OAC. However, acidic conditions curtailed ICB efficacy, supporting a rationale for utilizing systemic oral buffers to neutralize tumour acidity to improve ICB efficacy. Study schematic-PBMCs were isolated from OAC patients (A) and expanded ex vivo for 7 days using anti-CD3/28 +IL-2 T cell activation protocol (B) and further cultured for 48 h under increasing acidic conditions in the absence or presence of immune checkpoint blockade (nivolumab, ipilimumab or dual nivolumab + ipilimumab) (C). Immunophenotyping was then carried out to assess immune checkpoint expression profiles and anti-tumour T cell phenotypes (D). Serum lactate was assessed in OAC patients (E-F) and levels were correlated with patient demographics (G) and the levels of circulating immune/pro-angiogenic cytokines that were determined by multiplex ELISA (H). Key Findings-severe acidic conditions upregulated multiple immune checkpoints on T cells (I). Efficacy of ICB was curtailed under severe acidic conditions (J). Circulating lactate levels positively correlated with circulating levels of pro-angiogenic factor tie-2 and higher serum lactate levels were found in patients who had nodal metastasis (K).

Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance.

The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione-S-transferase (AmGSTF1) as a functional biomarker of MHR in black-grass (Alopecurus myosuroides). This study provides further insights into the role of AmGSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type AmGSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the AmGSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of AmGSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to AmGSTF1 was investigated showing a high affinity for derivatives bearing a O-5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds.

Confronting the opioid crisis with consumer health information: a look at East Tennessee.

BACKGROUND: Starting in the 1990s, health care providers began prescribing opioids to patients as pain relievers, believing they were safe. However, many patients became addicted to these pills. In 2017, the US Department of Health and Human Services declared a public health emergency to fight the opioid epidemic. This crisis was prevalent in East Tennessee, where many residents were prescribed opioids. CASE PRESENTATION: Librarians at an academic medical center library in East Tennessee analyzed the health information requests related to pain, mental health, and addiction over the last fifteen years. We reviewed the pattern of requests related to these topics, the counties requesting this information, and the impact that these hospital policies had on these requests. CONCLUSIONS: From 2005 to 2014, there were few requests about mental health, pain, and substance abuse. However, once the library moved into the hospital and there was an increase in awareness of opioid addiction, requests on those topics increased. Most of the requests were about pain, with the height occurring in 2017, during which year the public health emergency to fight the epidemic was declared. Additionally, 2017 was the year the hospital implemented visitor limitations for patients with infections associated with intravenous drug use, which might explain the drastic drop in substance abuse information requests in 2018. Future outreach will target counties that have a high opioid prescription rate.

Making sense of concept analysis.

BACKGROUND: Concept analysis is frequently the first step novice nurse researchers take when beginning their work. However, the value of concept analysis in generating theory is debated, and although there are many models researchers can use, few provide guidance for applying them or overviews of their philosophical underpinnings. AIM: To share learning about challenges encountered when undertaking concept analysis and to present an adaptation of Rodgers ( 1989 ) model created to overcome these. DISCUSSION: The authors explore the philosophical underpinning of several models of concept analysis and present an adapted model based on the work of Rogers ( 1989 ) and Tofthagen and Fagerstrøm ( 2010 ). CONCLUSION: Concept analysis is a valuable tool when used with an understanding of a model's philosophical underpinnings and sufficient measures are taken to assure analytical depth, rigour and transparency. IMPLICATIONS FOR PRACTICE: The experiences of a novice nurse researcher described in this paper will be helpful in informing others who are starting a study.

Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.

OBJECTIVE: To study malabsorption and malnutrition after curative resection of esophageal and gastric cancer. DESIGN: Prospective cohort study. BACKGROUND: Improved cure rates for esophageal and gastric cancer have increased focus on health-related quality of life (HR-QL) in survivorship. Although malnutrition is well described in long-term follow-up, and gastrointestinal symptoms are common, data on gut and pancreatic-related malabsorption are scant. METHODS: Disease-free patients at least 18 months after esophageal or gastric oncologic resections represented the study cohort. A modified Gastrointestinal Symptom Rating Scale questionnaire was completed, and weight, fecal elastase (FE), albumin, vitamins, and micronutrients measured preoperatively and at 1, 6, and 18 to 24 months postoperatively. Small intestinal bacterial overgrowth (SIBO) and changes in body composition were also evaluated postoperatively. RESULTS: At a median follow-up of 23 months, 45 of 66 patients in a consecutive series were disease-free. Mean weight (78 ±â€Š19 vs 67 ±â€Š16 kg), body mass index (27 ±â€Š5 vs 24 ±â€Š5 kg/m), Vitamin A (1.7 ±â€Š0.6 vs 1.2 ±â€Š0.4 umol/L), and Vitamin E (28 ±â€Š7 vs 20 ±â€Š7 umol/L) were significantly decreased (P < 0.01) at last follow-up compared with preoperatively. Malabsorption was evident in 73% of patients, of whom 44% had FE < 200 µg/g and 38% had evidence of SIBO. Total body fat-free mass (175 ±â€Š96 vs 84 ±â€Š71, P < 0.001) and skeletal muscle index (44 ±â€Š8 vs 39 ±â€Š8, P = 0.007) were significantly decreased at 18 to 24 months. CONCLUSIONS: Malabsorption and malnutrition are prevalent in survivorship of esophageal and stomach cancer. This may be underappreciated, and both gut and pancreatic insufficiency represent modifiable targets in the interdisciplinary approach to recovery of HR-QL.

Living with hepatitis C: a phenomenological study.

AIMS AND OBJECTIVES: To explore the experience of adults living with hepatitis C over time. BACKGROUND: Hepatitis C virus is a growing problem affecting thousands of people worldwide. The majority of individuals infected develop chronic liver disease, but treatment is not always successful, leaving many to live with the virus indefinitely. Experiences of living with hepatitis C are poorly understood yet essential to meet the needs of an increasing number of affected people. DESIGN: A qualitative study using a descriptive phenomenological methodology. METHODS: Unstructured interviews were conducted with 23 hepatitis C-positive individuals in the East of England; participants were interviewed twice within a year. RESULTS: Data analysis revealed six themes of the experience of living with hepatitis C: hepatitis C and self; hepatitis C, self and others; self and handling hepatitis C; self and handling hepatitis C treatment issues; living with the consequences of hepatitis C; self, hepatitis C and thoughts of the future. CONCLUSIONS: Diagnosis of hepatitis C can disrupt people's sense of identity and trigger a life transition. A complex range of factors create uncertainty for people living with hepatitis C. Many struggle to make a healthy transition to life with the condition, instead living in a state of sustained uncertainty. RELEVANCE TO CLINICAL PRACTICE: Nurses working within a chronic care framework of ongoing advice and support can improve experiences for those living with hepatitis C. Practice aimed at reducing both the disruptive effect of the diagnosis and the uncertainties it creates can help facilitate a transition to life with the disease.

Patient- and family-centred care on an acute adult cardiac ward.

This paper outlines a service improvement project undertaken in one acute cardiac ward within a regional NHS trust in the east of England that explored the impact of advancing patient- and family-centred care within an acute adult setting. The project was implemented and evaluated over a 9-month period between March and December 2012 and data collected via a pre and post-intervention survey. The results demonstrated that the majority of family carers wanted to be involved in patient care. The provision of flexible family visiting,facilitated and supported family carer involvement in care provision and improved partnership working between family carers and the multidisciplinary team, had a positive impact on the patient and family carer experience. This project has demonstrated the value of involving family carers in acute adult inpatient care provision and the importance of flexible family visiting to enable this to be successful.

Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy.

AIM: Use of immune checkpoint blockade to enhance T cell-mediated immunity within the hostile tumour microenvironment (TME) is an attractive approach in oesophageal adenocarcinoma (OAC). This study explored the effects of the hostile TME, including nutrient deprivation and hypoxia, on immune checkpoint (IC) expression and T cell phenotypes, and the potential use of nivolumab to enhance T cell function under such conditions. METHODS AND RESULTS: ICs were upregulated on stromal immune cells within the tumour including PD-L2, CTLA-4 and TIGIT. OAC patient-derived PBMCs co-cultured with OE33 OAC cells upregulated LAG-3 and downregulated the co-stimulatory marker CD27 on T cells, highlighting the direct immunosuppressive effects of tumour cells on T cells. Hypoxia and nutrient deprivation altered the secretome of OAC patient-derived PBMCs, which induced upregulation of PD-L1 and PD-L2 on OE33 OAC cells thus enhancing an immune-resistant phenotype. Importantly, culturing OAC patient-derived PBMCs under dual hypoxia and glucose deprivation, reflective of the conditions within the hostile TME, upregulated an array of ICs on the surface of T cells including PD-1, CTLA-4, A2aR, PD-L1 and PD-L2 and decreased expression of IFN-γ by T cells. Addition of nivolumab under these hostile conditions decreased the production of pro-tumorigenic cytokine IL-10. CONCLUSION: Collectively, these findings highlight the immunosuppressive crosstalk between tumour cells and T cells within the OAC TME. The ability of nivolumab to suppress pro-tumorigenic T cell phenotypes within the hostile TME supports a rationale for the use of immune checkpoint blockade to promote anti-tumour immunity in OAC. Study schematic: (A) IC expression profiles were assessed on CD45+ cells in peripheral whole blood and infiltrating tumour tissue from OAC patients in the treatment-naïve setting. (B) PBMCs were isolated from OAC patients and expanded ex vivo for 5 days using anti-CD3/28 + IL-2 T cell activation protocol and then co-cultured for 48 h with OE33 cells. T cell phenotypes were then assessed by flow cytometry. (C) PBMCs were isolated from OAC patients and expanded ex vivo for 5 days using anti-CD3/28 + IL-2 T cell activation protocol and then further cultured under conditions of nutrient deprivation or hypoxia for 48 h and T cell phenotypes were then assessed by flow cytometry. KEY FINDINGS: (A) TIGIT, CTLA-4 and PD-L2 were upregulated on CD45+ immune cells and CTLA-4 expression on CD45+ cells correlated with a subsequent decreased response to neoadjuvant regimen. (B) Following a 48 h co-culture with OE33 cells, T cells upregulated LAG-3 and decreased CD27 co-stimulatory marker. (C) Nutrient deprivation and hypoxia upregulated a range of ICs on T cells and decreased IFN-γ production by T cells. Nivolumab decreased IL-10 production by T cells under nutrient deprivation-hypoxic conditions.

Innovations and action research to develop research skills for nursing and midwifery practice: the Innovations in Nursing and Midwifery Practice Project study.

AIMS AND OBJECTIVES: To develop sustainable resources and activity in one hospital to encourage, support and build research activity and innovation among nurses and midwives. BACKGROUND: Much resource is spent internationally to enable nurses and midwives to critique and quote research papers. The evidence suggests that little resource is focussed on enabling staff to conduct structured interventions that implement research as a service improvement activity, or enable nurses and midwives to undertake research in their clinical areas. DESIGN: Two cycles of action research took place in the hospital led by a steering group of insiders and outsiders. Each cycle was evaluated through interviews with participants and analysis of steering group meeting records. METHOD: Action research methodology was used to develop partnership working between the hospital and university. A steering group of participants in the project led the development and made decisions based on findings from the evaluation stages of each cycle. RESULTS: The data demonstrate that the process is one of the slow snowball effects that gathered momentum. Key skills such as leadership, resourcing and time management are required alongside research skills. CONCLUSIONS: Nursing research capacity can be developed in institutions where there are individuals with an enthusiasm to drive the agenda. Structures and processes need to be clear and transparent as well as supportive at the individual level. Change of this nature takes time and sustained effort. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates that a combination of strong leadership, partnership working and development of clear infrastructure enabled nurses and midwives who provide direct patient care to develop, implement and evaluate their own service improvement/research initiatives. Enabling nurses and midwives to use research methods in their practice increases the amount of nurse/midwife-led evidence-based innovation.

A personal insight into researcher positionality.

AIM: To highlight observations on the dilemmas of insider research. BACKGROUND: Researchers in qualitative research have traditionally been thought of as positioned inside or outside the social group being studied. However, there is recognition of the blurring of the apparent Separation between these two positions. This paper discusses the ethical and methodological dilemmas involved as an 'insider' when negotiating access to the field and recruiting participants. REVIEW METHODS: This is a reflective paper. CONCLUSION: The personal insight into researcher positionality provided in this paper shows that qualitative researchers need to consider carefully the potential risks to participants when conducting insider research.

Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma.

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.

Modern oncological and operative outcomes in oesophageal cancer: the St. James's hospital experience.

BACKGROUND: Oesophageal cancer has a reputation for poor survival, and a relatively high risk of major postoperative morbidity and mortality. Encouragingly, a recent international cancer registry study reports a doubling of survival outcomes in Ireland over the last 20 years. This study focused on both oncologic and operative outcomes in patients treated with curative intent requiring surgery at a high-volume center. METHODS: All patients undergoing surgery or multimodal therapy with curative intent from 2009 to 2018 were studied. All data was recorded prospectively and maintained internally. The period 2009-2013 was compared with 2014-2018 to monitor any change in trends. RESULTS: Four hundred and seventy-five patients (adenocarcinoma 77%, mean age 65; 76% male; 64% neoadjuvant therapy) underwent open surgical resection, 54% via en bloc 2-stage, 19.8% en bloc 3-stage, and 26.5% by a transhiatal approach. New onset atrial fibrillation was the commonest index complication, in 108 (22.7%), 80 (18%) developed suspected pneumonia/respiratory tract infection, 20 (4.2%) an anastomotic leak, and 25 (5.2%) a chyle leak. The 90-day mortality rate was 1.2% and 0.8% at 30 days. The median survival was 77.17 months, with a 5-year survival of 56%. CONCLUSION: Consistent with registry data on population survival for oesophageal cancer, this study highlights markedly improved survival outcomes in patients treated curatively, reflecting international trends, as well as low mortality rates; however, cardiorespiratory complications remain significant.

An exploration of lecturer as facilitator within the context of problem-based learning.

Although the concept and practice of problem-based learning (PBL) has been explored extensively in different arenas, the perspective of the lecturer as facilitator has not featured prominently in these discussions. There has been relatively little attention focused on lecturers' personal pedagogical values and beliefs and how these interact with the discourse and rhetoric of problem-based learning. The aim of this study therefore was to explore the role of lecturer as facilitator within a PBL context. Using a grounded theory methodology, 12 problem-based seminars in a pre-registration nursing programme were observed and the lecturers then interviewed, using the method of semi-structured interviews. This work demonstrated that there were differences in interpretation and application of the role of facilitator by lecturers, and this was mainly dependent upon their personal pedagogical beliefs and values. This study has highlighted that there is a need for further debate about the gap between rhetoric and reality in PBL and the need for a more consistent approach to facilitation by lecturers undertaking this role.

Binary nanoparticle superlattices in the semiconductor-semiconductor system: CdTe and CdSe.

We report binary nanoparticle superlattices obtained by self-assembly of two different semiconductor quantum dots. Such a system is a means to include two discretized, quantum-confined, and complimentary semiconductor units in close proximity, for purposes of band gap matching and/or energy transfer. From a range of possible structures predicted, we observe an exclusive preference for the formation of Cuboctahedral AB13 and AB5 (isostructural with CaCu5) obtained in the system of 8.1 nm CdTe and 4.4 nm CdSe nanoparticles. For this system, a possible ionic origin for the formation of structures with lower packing densities was ruled out on the basis of electrophoretic mobility measurements. To understand further the principles of superlattice formation, we constructed space-filling curves for binary component hard spheres over the full range of radius ratio. In addition, the pair interaction energies due to core-core and ligand-ligand van der Waals (VDW) forces are estimated. The real structures are believed to form under a combined influence of entropic driving forces (following hard-sphere space filling principles) and the surface (due to ligand-ligand VDW).

Standards for midwife practitioners of external cephalic version: A Delphi study.

INTRODUCTION: expansion of advanced and specialist midwifery practitioner roles across professional boundaries requires an evidence-based framework to evaluate achievement and maintenance of competency. In order to develop the role of Breech Specialist Midwife to include the autonomous performance of external cephalic version within one hospital, guidance was required on standards of training and skill development, particularly in the use of ultrasound. METHODS: a three-round Delphi survey was used to determine consensus among an expert panel, including highly experienced obstetric and midwife practitioners, as well as sonographers. The first round used mostly open-ended questions to gather data, from which statements were formed and returned to the panel for evaluation in subsequent rounds. FINDINGS: standards for achieving and maintaining competence to perform ECV, and in the use of basic third trimester ultrasound as part of this practice, should be the same for midwives and doctors. The maintenance of proficiency requires regular practice. CONCLUSIONS: midwives can appropriately expand their sphere of practice to include ECV and basic third trimester ultrasound, according to internal guidelines, following the completion of a competency-based training programme roughly equivalent to those used to guide obstetric training. Ideally, ECV services should be offered in organised clinics where individual practitioners in either profession are able to perform approximately 30 or more ECVs per year in order to maintain an appropriate level of skill.

An action research approach for developing research and innovation in nursing and midwifery practice: building research capacity in one NHS foundation trust.

The National Health Service in the United Kingdom is committed to a process of reform centred on quality care and innovative practice. Central to this process is the need for research capacity building within the workforce. The aim of this study was to develop an infrastructure for research capacity building within one National Health Service Foundation Trust. Using an Action Research methodology, sixteen individuals were purposefully selected from a population of nurses and midwives to participate in the study. This nonprobability sampling method enabled the researchers to select participants on the basis of who would be most informative about existing research capacity building structures and processes within the Trust. Data were collected in the form of semi-structured individual interviews with each participant. The main findings were that research activity was not embedded in the culture of the organisation, and initiating and undertaking change was a complex process. As a result, a range of structures and processes which were considered necessary to enable the Trust move forward in developing capacity and capability for research were developed and implemented. This paper reports the first two stages of this process, namely: the findings from the pre-step and an outline of how these findings were used to create an infrastructure to support research capacity building within one NHS Foundation Trust Hospital in the United Kingdom.

Social networks: a profile of the elderly who self-neglect.

BACKGROUND: Self-neglect is an independent risk factor for early mortality in older people and has been linked to depression and the occurrence of mental and physical decline. Sound social networks have been shown to slow the process of decline in the elderly, and currently little is known about the social networks associated with elder self-neglect. The aim of this study was to explore the social networks associated with elder self-neglect compared with a matched-control group. METHODS: Ninety-one Adult Protective Services-validated cases of elder self-neglect were compared on formal and informal social network factors with 91controls matched for age, race, gender, and socio-economic status. RESULTS: Elders in the self-neglect group were significantly less likely to (1) Live with a spouse, (2) Live with others, (3) Have weekly contact with children or siblings, (4) Visit with neighbors and friends and (5) Participate in religious activities. CONCLUSIONS: Less adequate social resources related to family, friends, and religious affiliations are significantly associated with elder self-neglect.