Melanoma in humans and dogs is considered highly immunogenic; however, the function of tumor-infiltrating lymphocytes (TILs) is often suppressed in the tumor microenvironment. In humans, current ...immunotherapies target checkpoint molecules (such as PD-L1, expressed by tumor cells), inhibiting their suppressive effect over TILs. The role of PD-L2, an alternative PD-1 ligand also overexpressed in malignant tumors and in patients with anti-PD-L1 resistance, remains poorly understood. In the current study, we evaluated the expression of checkpoint molecule mRNAs in canine melanoma and TILs. Analysis of checkpoint molecule gene expression was performed by RT-qPCR (real-time quantitative polymerase chain reaction) using total RNA isolated from formalin-fixed and paraffin-embedded melanomas (n = 22) and melanocytomas (n = 9) from the Virginia Tech Animal Laboratory Services archives. Analysis of checkpoint molecule expression revealed significantly higher levels of PDCD1 (PD-1) and CD274 (PD-L1) mRNAs and an upward trend in PDCD1LG2 (PD-L2) mRNA in melanomas relative to melanocytomas. Immunohistochemistry revealed markedly increased numbers of CD3+ T cells in the highest PD-1-expressing subgroup of melanomas compared to the lowest PD-1 expressors, whereas densities of IBA1+ cells (macrophages) were similar in both groups. CD79a+ cell numbers were low for both groups. As in human melanoma, overexpression of the PD-1/PD-L1/PD-L2 axis is a common feature of canine melanoma. High expression of PD-1 and PD-L1 correlates with increased numbers of CD3+ cells. Additionally, the high level of IBA1+ cells in melanomas with low PD-1 expression and low CD3+ cells levels suggest that the expression of checkpoint molecules is modulated by interactions between T cells and cancer cells rather than histiocytes.
Across species, including humans, elevated levels of brain estrogen receptor (ER) α are associated with enhanced cognitive aging, even in the absence of circulating estrogens. In rodents, short-term ...estrogen treatment, such as that commonly used in the menopausal transition, results in long-term increases in ERα levels in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ERα enhances cognitive aging remain unclear. Here we demonstrate in aging female rats that insulin-like growth factor-1 (IGF-1), which can activate ER via ligand-independent mechanisms, requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ERα via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by short-term estradiol treatment. Forty days of estradiol exposure following ovariectomy results in maintenance of neuroestrogen levels that persist beyond the period of hormone treatment, allowing for continued interactions between IGF-1 and neuroestrogen signaling, elevated levels of hippocampal ERα, and ultimately enhanced memory. Collectively, results demonstrate that short-term estradiol use following loss of ovarian function has long-lasting effects on hippocampal function and memory by dynamically regulating cellular mechanisms that promote activity of ERα in the absence of circulating estrogens. Translational impacts of these findings suggest lasting cognitive benefits of short-term estrogen use near menopause and highlight the importance of hippocampal ERα, independent from the role of circulating estrogens, in regulating memory in aging females.
Declines in ovarian hormones following menopause coincide with increased risk of cognitive decline. Because of potential health risks, current recommendations are that menopausal estrogen therapy be limited to a few years. Long-term consequences for the brain and memory of this short-term midlife estrogen therapy are unclear. Here, in a rodent model of menopause, we determined mechanisms by which short-term midlife estrogen exposure can enhance hippocampal function and memory with cognitive benefits and molecular changes enduring long after termination of estrogen exposure. Our model indicates long-lasting benefits of maintaining hippocampal estrogen receptor function in the absence of ongoing estrogen exposure and suggests potential strategies for combating age-related cognitive decline.
Community health workers, known as Village Health Teams (VHTs) in Uganda, play a central role in increasing access to community-based health services. The objective of this research is to explore ...tensions that may emerge as VHTs navigate multiple roles as community members and care providers particularly when providing sensitive reproductive health and HIV care.
Twenty-five VHTs from a rural clinic in Uganda completed semi-structured interviews focused on experiences providing services. Interview questions focused on challenges VHTs face providing services and strategies for improving quality care. After translation from Luganda and transcription, interviews were analyzed using content analysis to identify emergent themes.
Most VHTs were female (n = 16). The average age was 46, and average length of VHT work, 11 years. Analyses revealed that all VHTs capitalized upon the duality of their position, shifting roles depending upon context. Three themes emerged around VHTs' perceptions of their roles: community insiders, professional outsiders, and intermediaries. A caregiver "insider" role facilitated rapport and discussion of sensitive issues. As community members, VHTs leveraged existing community structures to educate clients in familiar settings such as "drinking places". However, this role posed challenges as some VHTs felt compelled to share their own resources including food and transport money. Occupying a professional outsider role offered VHTs respect. Their specialized knowledge gave them authority to counsel others on effective forms of family planning. However, some VHTs faced opposition, suspicions about their motives, and violence in this role. In balancing these two roles, the VHTs adopted a third as intermediaries, connecting the community to services in the formalized health care system. Participants suggested that additional training, ongoing supervision, and the opportunity to collaborate with other VHTs would help them better navigate their different roles and, ultimately, improve the quality of service.
As countries scale up family planning and HIV services using VHTs, supportive supervision and ethical dilemma training are recommended so VHTs are prepared for the challenges of assuming multiple roles within communities.
Copines make up a family of calcium-dependent, phospholipid-binding proteins found in numerous eukaryotic organisms. Copine proteins consist of two C2 domains at the N-terminus followed by an A ...domain similar to the von Willebrand A domain found in integrins. We are studying copine protein function in the model organism,
, which has six copine genes,
. Previous research showed that cells lacking the
gene exhibited a cytokinesis defect, a contractile vacuole defect, and developmental defects. To provide insight into the role of CpnA in these cellular processes, we used column chromatography and immunoprecipitation to isolate proteins that bind to CpnA. These proteins were identified by mass spectrometry. One of the proteins identified was actin. Purified CpnA was shown to bind to actin filaments in a calcium-dependent manner in vitro.
cells exhibited defects in three actin-based processes: chemotaxis, cell polarity, and adhesion. These results suggest that CpnA plays a role in chemotaxis and adhesion and may do so by interacting with actin filaments.
Aims
To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006–10 (before) and 2011–13 (after NNP started in January 2011) and to assess ...cost‐effectiveness.
Design
This was a pre–post evaluation of a national policy. Cost‐effectiveness was assessed by prescription costs against life‐years gained per opioid‐related death (ORD) averted.
Setting
Scotland, in community settings and all prisons.
Intervention
Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose.
Measurements
ORDs as identified by National Records of Scotland. Look‐back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011–13 versus 2006–10. Prescription costs were assessed against 1 or 10 life‐years gained per averted ORD.
Findings
In 2006–10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011–13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% 95% confidence interval (CI) = 1.6–5.4%). This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19–65) during 2011–13, when 12 000 naloxone kits were issued at current prescription cost of £225 000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4–6.7%).
Conclusions
Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid‐related deaths that occurred in the 4 weeks following release from prison.
Background
Scotland was the first country to implement minimum unit pricing for alcohol nationally. Minimum unit pricing aims to reduce alcohol-related harms and to narrow health inequalities. ...Minimum unit pricing sets a minimum retail price based on alcohol content, targeting products preferentially consumed by high-risk drinkers. This study comprised three components.
Objectives
This study comprised three components assessing alcohol consumption and alcohol-related attendances in emergency departments, investigating potential unintended effects of minimum unit pricing on alcohol source and drug use, and exploring changes in public attitudes, experiences and norms towards minimum unit pricing and alcohol use.
Design
We conducted a natural experiment study using repeated cross-sectional surveys comparing Scotland (intervention) and North England (control) areas. This involved comparing changes in Scotland following the introduction of minimum unit pricing with changes seen in the north of England over the same period. Difference-in-difference analyses compared intervention and control areas. Focus groups with young people and heavy drinkers, and interviews with professional stakeholders before and after minimum unit pricing implementation in Scotland allowed exploration of attitudes, experiences and behaviours, stakeholder perceptions and potential mechanisms of effect.
Setting
Four emergency departments in Scotland and North England (component 1), six sexual health clinics in Scotland and North England (component 2), and focus groups and interviews in Scotland (component 3).
Participants
Research nurses interviewed 23,455 adults in emergency departments, and 15,218 participants self-completed questionnaires in sexual health clinics. We interviewed 30 stakeholders and 105 individuals participated in focus groups.
Intervention
Minimum unit pricing sets a minimum retail price based on alcohol content, targeting products preferentially consumed by high-risk drinkers.
Results
The odds ratio for an alcohol-related emergency department attendance following minimum unit pricing was 1.14 (95% confidence interval 0.90 to 1.44;
p
= 0.272). In absolute terms, we estimated that minimum unit pricing was associated with 258 more alcohol-related emergency department visits (95% confidence interval –191 to 707) across Scotland than would have been the case had minimum unit pricing not been implemented. The odds ratio for illicit drug consumption following minimum unit pricing was 1.04 (95% confidence interval 0.88 to 1.24;
p
= 0.612). Concerns about harms, including crime and the use of other sources of alcohol, were generally not realised. Stakeholders and the public generally did not perceive price increases or changed consumption. A lack of understanding of the policy may have caused concerns about harms to dependent drinkers among participants from more deprived areas.
Limitations
The short interval between policy announcement and implementation left limited time for pre-intervention data collection.
Conclusions
Within the emergency departments, there was no evidence of a beneficial impact of minimum unit pricing. Implementation appeared to have been successful and there was no evidence of substitution from alcohol consumption to other drugs. Drinkers and stakeholders largely reported not noticing any change in price or consumption. The lack of effect observed in these settings in the short term, and the problem-free implementation, suggests that the price per unit set (£0.50) was acceptable, but may be too low. Our evaluation, which itself contains multiple components, is part of a wider programme co-ordinated by Public Health Scotland and the results should be understood in this wider context.
Future work
Repeated evaluation of similar policies in different contexts with varying prices would enable a fuller picture of the relationship between price and impacts.
Trial registration
Current Controlled Trials ISRCTN16039407.
Funding
This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in
Public Health Research
; Vol. 9, No. 11. See the NIHR Journals Library website for further project information.
People who are insecurely housed and use drugs are disproportionately affected by drug poisonings. Nurses are uniquely positioned to utilize harm reduction strategies to address the needs of the ...whole person. Needle debris encompasses drug paraphernalia discarded in public spaces. Studying needle debris provides a strategic opportunity to identify where drugs are being used and target public health strategies accordingly.
Our aim in this article is to illustrate how spatial video geonarratives (SVG) combined GPS technology interviews, and videos of locations with needle debris, can elicit valuable data for nursing research.
Using SVG required knowledge of how to collect data wearing cameras and practice sessions were necessary. A Miufly camera worn at waist height on a belt provided the stability to walk while interviewing stakeholders. We wore the cameras and conducted go-along interviews with outreach workers, while filming the built environment. Upon completion of data collection, both the interview and GPS information were analysed using Wordmapper software.
This methodology resulted in data presented uniquely in both a visual map and narrative. These data were richer than if a single modality had been used. These data highlighted specific contextual factors that were related to the location of needle debris, which created opportunities for nursing interventions to support people experiencing vulnerability.
Understanding the changing spatial structure of ethnic grocery retailing in Canadian urban regions provides insights into ethnic business development and the well-being of residents, particularly ...relating to the accessibility to healthy food options. This study explores this through a case study of Chinese and South Asian grocery retailing in the Toronto Census Metropolitan Area, focusing on the changing spatial relationship between ethnic grocery business distribution, ethnic residential patterns in 2001 and 2016. The paper highlights the varying levels of accessibility to co-ethnic and mainstream retailers for Chinese and South Asian residents in Toronto. An integrated marginalization-accessibility index is developed to reveal the spatial mismatch between the level of material deprivation and grocery store access for Chinese and South Asian residents. The results of the study show that Chinese and South Asian grocery retailers and residents have suburbanized over the study period. Index results indicate that some census tracts experienced limited access to both mainstream and ethnic grocery stores, particularly among the South Asian community. There is a growing proportion of areas that are relatively well-serviced by Chinese and South Asian grocery but exhibit a limited presence of mainstream retailers, with ethnic grocers filling market gaps not served by mainstream retailers.
Abstract
Aims
To assess the effectiveness for
Scotland
's National Naloxone Programme (NNP) by comparison between 2006–10 (before) and 2011–13 (after NNP started in
January
2011) and to assess ...cost‐effectiveness.
Design
This was a pre–post evaluation of a national policy. Cost‐effectiveness was assessed by prescription costs against life‐years gained per opioid‐related death (ORD) averted.
Setting
Scotland
, in community settings and all prisons.
Intervention
Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose.
Measurements
ORDs as identified by National Records of
Scotland
. Look‐back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011–13 versus 2006–10. Prescription costs were assessed against 1 or 10 life‐years gained per averted ORD.
Findings
In 2006–10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011–13 followed prison release (76 of 1212,
P
< 0.001; this represented a difference of 3.5% 95% confidence interval (CI) = 1.6–5.4%). This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19–65) during 2011–13, when 12 000 naloxone kits were issued at current prescription cost of £225 000.
Scotland
's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4–6.7%).
Conclusions
Scotland
's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid‐related deaths that occurred in the 4 weeks following release from prison.
PDF
