'Don't cross the line, you're a researcher and not an educator': Incorporating indigenous researchers' moral perspectives to improve ethical protocols in health research.

Given that researchers from North America and Europe author most global scientific publications, indigenous frontline researcher perspectives are rarely incorporated in the general research enterprise and ethics. Addressing this shortcoming, we analyzed a subset of data from a larger study. We present results from semi-structured in-depth ethnographic interviews with nine indigenous research assistants (RAs) conducted in Southern Africa four years after implementing a national HIV/AIDS study collaboratively implemented by national, U.S., and European-based stakeholders. The aim is to elucidate how these frontline researchers understand and interpret the task of maintaining their role as researchers and when they felt it more appropriate to cross to prevention educator or interventionist. The obtained results demonstrate how practices intended to protect participants and produce minimally biased ethical data create a conflict for frontline researchers by pitting operational ethics against their humanity. RAs understood and accepted the standard study procedures and the need to maintain their role as researchers. Nevertheless, a majority chose to provide unsolicited information or advice to participants despite the risk of potentially losing their job or causing harm to participants. RAs justified their decision to intervene by the lack and questionable quality of local resources/referrals and the long turnaround from data collection to prevention programming. This article demonstrates how practical exigencies in fulfilling IRB/ethics oversight and designing studies that produce the expected standard of evidence to influence policy and programmatic decisions inadvertently stifle opportunities to translate research into action. We offer specific points of reflection for researchers trained in High Income Country (HIC) perspectives towards decolonizing and improving practices in designing ethical research and establishing reflexive work environments with indigenous researchers.

Identifying breast cancer patients who gain the most dosimetric benefit from deep inspiration breath hold radiotherapy.

INTRODUCTION: Deep inspiration breath hold (DIBH) has been proven to reduce cardiac dose for women receiving left breast and chest wall radiation therapy. However, it utilises extra departmental resources and patient exertion. The aim of this exploratory study was to investigate if any factors existed that could identify breast cancer patients who may benefit most from DIBH, to facilitate appropriate utilisation of departmental resources. METHODS: Left-sided breast cancer patients aged 18-70 years, and right-sided breast cancer patients with internal mammary nodes included, were recruited. DIBH and free breathing (FB) plans were created for all patients. Patient demographic and clinical history were recorded. Variables including lung threshold value, lung volume, patient separation, maximum heart in field, volume of planning target volume (PTV), heart dose, ipsilateral lung dose were compared between plans. RESULTS: Plans for 31 patients were analysed. No correlations were found between lung threshold value or patient separation and cardiac dose. Moderate to strong correlations were found with BMI, PTV volume and lung volume change however no definitive thresholds were determined. A significant difference was found in the maximum heart in field between DIBH and FB (P < 0.001) with those patients with greater than 0.7 cm heart in the field on the FB scan demonstrating greater reductions in mean heart dose. CONCLUSION: Maximum heart in the field of greater than 0.7 cm in FB could be a potential factor to identify patients who may benefit most from DIBH. This factor warrants investigation in a larger patient cohort to test its validity.

Deep inspiration breath hold in breast cancer: Development and analysis of a patient experience questionnaire.

INTRODUCTION: Evidence that Deep Inspiration Breath Hold (DIBH) can reduce cardiac dose during left-sided breast radiation therapy (RT) has led to widespread uptake of this technology. There is a paucity of published information documenting the impact of this technique on the patient's treatment experience. The aim of this study was to develop a tool to assess the patient's experience with the introduction of DIBH using the Elekta® Active Breathing Coordinator (ABC) in a single institution. METHODS: A patient experience questionnaire was developed and was completed at three different stages of the patient's treatment; at planning, during the second week of treatment (day 6-10) and during the final week of treatment. RESULTS: Questionnaire data were collected from 30 patients, who underwent DIBH breast treatment during the period March 2016 to May 2017. Patients were very happy with their use of the ABC equipment and most felt they were well supported and informed during their treatment. Levels of general fatigue and personal anxiety were identified to significantly increase from planning to the conclusion of treatment (P = 0.002 and P < 0.001 respectively). CONCLUSIONS: This study produced a useful tool to measure patient experience during DIBH treatment. It demonstrated that the use of the technique was acceptable to patients and did not increase their distress. It provided a compelling case for the provision of tailored, well-communicated information, consistent routine and emotional support for patients throughout their entire treatment. The tool could be employed to assess the patient experience as new technologies are introduced into RT.

Matriptase Induction of Metalloproteinase-Dependent Aggrecanolysis In Vitro and In Vivo: Promotion of Osteoarthritic Cartilage Damage by Multiple Mechanisms.

OBJECTIVE: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA. METHODS: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies. RESULTS: The addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage. CONCLUSION: Matriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA.

Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA(-/-) mice.

Fragility fractures caused by osteoporosis affect millions of people worldwide every year with significant levels of associated morbidity, mortality and costs to the healthcare economy. The pathogenesis of declining bone mineral density is poorly understood but it is inherently related to increasing age. Growing evidence in recent years, especially that provided by mouse models, suggest that accumulating somatic mitochondrial DNA mutations may cause the phenotypic changes associated with the ageing process including osteoporosis. Methods to study mitochondrial abnormalities in individual osteoblasts, osteoclasts and osteocytes are limited and impair our ability to assess the changes seen with age and in animal models of ageing. To enable the assessment of mitochondrial protein levels, we have developed a quadruple immunofluorescence method to accurately quantify the presence of mitochondrial respiratory chain components within individual bone cells. We have applied this technique to a well-established mouse model of ageing and osteoporosis and show respiratory chain deficiency.

Social Context of Adherence in an Open-Label 1 % Tenofovir Gel Trial: Gender Dynamics and Disclosure in KwaZulu-Natal, South Africa.

CAPRISA 008, an open-label extension study of tenofovir gel with coitally-related dosing, provided an opportunity to explore the relationship between product adherence and gender dynamics in a context where women knew they were receiving an active product with evidence of HIV prevention effectiveness. Interviews with 63 CAPRISA 008 participants and 13 male partners in KwaZulu-Natal, South Africa, highlighted that the process of negotiating gel use was determined in part by relationship dynamics including the duration of the relationship, the living situation, an evaluation of the relationship (e.g., partner intimacy and relationship expectations) and culturally-defined steps for formalizing the relationship. While disclosure facilitated adherence for many, others reported using the gel effectively with no disclosure, and in some situations disclosure was a barrier to adherence. Women should be supported in their choice about what to disclose and have opportunity to use this and similar products without their partners' knowledge or acquiescence.

A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo.

We report a chimeric monoclonal antibody (mAb) directed to a neo-epitope that is exposed in the IgG lower hinge following proteolytic cleavage. The mAb, designated 2095-2, displays specificity for IdeS-generated F(ab')2 fragments, but not for full-length IgG or for closely-related F(ab')2 fragments generated with other proteases. A critical component of the specificity is provided by the C-terminal amino acid of the epitope corresponding to gly-236 in the IgG1 (also IgG4) hinge. By its ability to bind to IdeS-cleaved anti-CD20 mAb, mAb 2095-2 fully restored antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against WIL2-S cells to the otherwise inactive anti-CD20 IgG1 F(ab')2 fragment. Similarly, 2095-2 reinstated ADCC against MDA-MB-231 cells to an anti-CD142 IgG1 F(ab')2 fragment. mAb 2095-2 was also capable of eliciting both CDC and ADCC to IgG4 F(ab')2 fragments, an IgG subclass that has weaker ADCC and CDC when intact relative to intact IgG1. The in vitro cell-based efficacy of 2095-2 was extended to the in vivo setting using platelets as a cell clearance surrogate. In a canine model, the co-administration of 2095-2 together with IdeS-generated, platelet-targeting anti-CD41/61 F(ab')2 fragment not only restored platelet clearance, but did so at a rate and extent of clearance that exceeded that of intact anti-CD41/61 IgG at comparable concentrations. To further explore this unexpected amplification effect, we conducted a rat study in which 2095-2 was administered at a series of doses in combination with a fixed dose of anti-CD41/61 F(ab')2 fragments. Again, the combination, at ratios as low as 1:10 (w/w) 2095-2 to F(ab')2, proved more effective than the anti-CD41/61 IgG1 alone. These findings suggest a novel mechanism for enhancing antibody-mediated cell-killing effector functions with potential applications in pathologic settings such as tumors and acute infections where protease activity is abundant.

Glycogen synthase kinase 3 inhibition stimulates human cartilage destruction and exacerbates murine osteoarthritis.

OBJECTIVE: To assess the role of glycogen synthase kinase 3 (GSK-3) as a regulator of cartilage destruction in human tissue and a murine model of osteoarthritis (OA). METHODS: Surgical destabilization of the medial meniscus (DMM) was performed to induce experimental murine OA, and joint damage was assessed histologically. Bovine nasal and human OA cartilage samples were incubated with interleukin-1 (IL-1) plus oncostatin M (OSM) and GSK-3 inhibitor. Collagen and proteoglycan release was assessed by hydroxyproline measurement and dye binding assay, collagenase activity was assessed by bioassay, and gene expression was analyzed by real-time polymerase chain reaction. Human articular chondrocytes were isolated by enzymatic digestion and cultured prior to gene silencing and immunoblotting of cell lysates and nuclear fractions. RESULTS: Mice treated with GSK-3 inhibitor exhibited significantly greater cartilage damage compared with sham-operated control mice. GSK-3 inhibition in bovine cartilage dramatically accelerated IL-1 plus OSM-stimulated degradation, concomitant with a profound increase in collagenase activity. GSK-3 inhibitor induced collagen release from human OA cartilage in the presence of IL-1 plus OSM and increased proteoglycan loss. Gene expression profiling of resorbing OA cartilage revealed a marked procatabolic switch in gene expression upon GSK-3 inhibition. This was mirrored in human articular chondrocytes following GSK3 silencing, particularly with the GSK-3ß isoform. GSK-3 inhibition or silencing led to enhanced IL-1 plus OSM-stimulated abundance and activity of Jun, and silencing of c-jun ameliorated GSK-3 inhibitor-mediated procatabolic gene expression. CONCLUSION: GSK-3 is an important regulator of matrix metalloproteinase (MMP)-mediated joint destruction, the inhibition of which by proinflammatory stimuli de-represses catabolic gene expression. Therapeutic strategies that maintain cartilage GSK-3 activity may therefore help curtail aberrant MMP activity during pathologic joint destruction.

CrowdOutAIDS: crowdsourcing youth perspectives for action.

To develop a strategy for how to better engage young people in decision-making processes on AIDS, UNAIDS launched the participatory online policy project CrowdOutAIDS in 2011. A total of 3,497 young people aged 15-29 from 79 countries signed up to nine online forums, and volunteers recruited through the online platform hosted 39 community-based offline forums with an additional 1,605 participants. This article describes the participatory approach of using social media and crowdsourcing solutions to integrate youth perspectives into strategy and policy processes. In these forums, youth consistently identified the need to change the way sex and relationships are dealt with through changing how sex is talked about, putting comprehensive sexuality education in place, and overcoming social and cultural taboos. The outcome document recommended three major priorities: dispel taboos surrounding sex and sexuality, eliminate stigma and discrimination against young people living with HIV, and remove social and legal barriers. Six strategic actions were also recommended: strengthen young people's skills for effective leadership, ensure full youth participation in the AIDS response, increase access to HIV-related information, strengthen strategic networks, increase UNAIDS's outreach to young people, and increase young people's access to financial support. Through leveraging social media and crowdsourcing, it is possible to integrate grassroots perspectives from across the globe into a new model of engagement and participation, which should be further explored for community empowerment and mobilization.

Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center.

OBJECTIVE: To better understand the feasibility of using imatinib, a tyrosine kinase inhibitor, to treat active diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We performed a 6-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study of imatinib in patients with active dcSSc. Data on safety, modified Rodnan skin thickness scores (MRSS), Health Assessment Questionnaire (HAQ) scores, patient's and physician's global assessments (100-mm visual analog scale), and biomarkers in serum and skin biopsy samples were collected. We used a 4:1 randomization strategy (imatinib 200 mg administered twice a day versus placebo), stratifying according to current use of methotrexate. The plan was to enroll 20 dcSSc patients. RESULTS: After enrolling 10 patients (9 receiving active drug and 1 receiving placebo), we found poor tolerability and high rates of adverse events with imatinib, and study enrollment was discontinued. There was no significant difference in the mean MRSS in all patients who took imatinib (31.1 at baseline versus 29.4 at 6 months) or in only those who completed 6 months of imatinib (31.0 at baseline versus 30.3 at 6 months), and there was no difference in the C-reactive protein level, erythrocyte sedimentation rate, physician's global assessment, patient's global assessment, response to the Health Transition query, or the HAQ scores between those who did and those who did not complete 6 months of therapy. Side effects were edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea, alopecia, and anemia. Most side effects occurred within the first week of treatment, and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was poorly tolerated. Two patients were hospitalized because of side effects of the medication. In general, biomarker levels in plasma and skin did not change. CONCLUSION: Imatinib was poorly tolerated, and this could limit its application in SSc. The study was too small to form conclusions about the efficacy of imatinib in SSc.

Results of a Pilot Randomized Placebo-Controlled Trial in Primary and Secondary Raynaud's Phenomenon with St. John's Wort: Detecting Changes in Angiogenic Cytokines When RP Improves.

Objectives.To perform a 6-week double-blind RCT in Raynaud's phenomenon (RP) comparing the plant extract St. John's Wort (SJW) to placebo. Methods. RP patients having at least 7 attacks per week were stratified by primary and secondary RP and within secondary by systemic sclerosis or other connective tissue disease. Subjects completed a daily standardized diary recording all RP attacks (frequency, duration and severity). Serum levels of 18 inflammatory and angiogenic cytokines were measured pre- and post-treatment. Results. Eighteen patients completed the study; 8 received SJW and 10 placebo. The decrease in mean number of attacks per day was 0.75 with SJW and 1.01 with placebo, P = 0.06. Attack duration and severity were not different between groups. Cytokine analyses demonstrated no between-groups differences. Combining treatment groups, those with >50% improvement in frequency of attacks yielded a significant increase in E-selectin (P = 0.049), MMP-9 (P = 0.011), G-CSF (P = 0.02), and VEGF (P = 0.012) pre- versus post-treatment. A ≥50% improvement in severity of attacks corresponded to a significant increase in levels of sVCAM-1 (P = 0.003), sICAM-1 (P = 0.007), and MCP-1 (P = 0.004). Conclusions. There were no clinical or biomarker benefit of SJW versus placebo in RP. However, combining all patients, there were changes in some cytokines that may be further investigated.

Development of a murine model of lymph node metastases suitable for immunotoxicity studies.

INTRODUCTION: Immunosuppressive drugs are associated with an increased risk of infections and in some cases neoplasia, particularly non-melanoma skin cancers. This paper describes the development of a model to test the effects of immunosuppressive drugs on local invasion and metastases of a squamous cell carcinoma in syngeneic, immunocompetent mice. METHODS: SCC VII cells were labeled with 655 quantum dots (QDs), injected intramuscularly into C3H HEN mice and traffic and progressive growth in the draining popliteal lymph node were evaluated. RESULTS: SCC VII cells express RAE-1, an NKG2D ligand, and were sensitive to natural killer (NK) cells in vitro. QDs were stable in SCC VII cells and showed no evidence of toxicity to the cells. In vivo, confocal microscopy showed that QD-labeled SCC VII cells could migrate to the draining node and microfluorimetry showed progressive traffic of QDs to the node. There was no evidence of systemic toxicity of QDs. Primary immunosuppression in SCID and SCID-beige mice and treatment of normal mice with immunosuppressive agents (anti-asialoGM1 and cyclophosphamide) can enhance traffic of QDs and/or metastases to the draining lymph node. In contrast, cyclosporine had no effect on traffic or metastases. CONCLUSION: This model of local invasion and metastases may be useful in immunotoxicology for identifying and characterizing the hazard posed by selective immunosuppressive drugs.

Addressing the HIV/AIDS-food insecurity syndemic in sub-Saharan Africa.

Recently a few vocal health experts have suggested that some of the billions of dollars currently used to prevent and treat HIV and AIDS be reallocated to address more basic problems such as malnutrition, tuberculosis, malaria, and enteric and diarrheal disease caused by lack of access to clean water. While not universally agreed upon, this reassessment of policy priorities acknowledges that there are multiple other health problems that deserve renewed attention from the international community. It also highlights the fact that the impacts of the HIV pandemic are exacerbated by widespread poverty, food insecurity and malnutrition, and gender inequality. Nowhere is this more evident than in sub-Saharan Africa, where multiple epidemics conflate and seriously compromise the survival of individuals and communities. Given the widespread occurrence of famine in sub-Saharan Africa, issues of food and economic security become of paramount importance in efforts to address the region's HIV epidemics. This paper examines the historical, political-economic, and cultural dimensions of the HIV epidemic in the context of the growing problem of food and economic insecurity. Furthermore, using theoretical frameworks that emphasize the dynamic interrelation between HIV/AIDS and food insecurity, we present suggestions for combining traditional HIV-prevention strategies with food production and nutritioneducation programming. In light of the complex interactions between HIV/AIDS and food insecurity and the lack of accessible treatment modalities, such programming could potentially reduce the risk for transmission of HIV through behavioural changes and improved nutritional and immune status, and increase the life expectancy of people living with HIV or AIDS.

Health seeking behavior by families of children suspected to have malaria in Kabale: Uganda.

BACKGROUND: Malaria is common among communities of Kabale district, and many young children die of the illness. Despite a good distribution of health facilities, able to handle malaria patients, families and individuals tend to depend on self-treatment, or private clinics where drugs used may be of doubtful quality. This study reports on health seeking behaviour by families with children suspected to have malaria. METHODOLOGY: A community-based, cross-sectional survey among 209 rural peasant families living in 12 villages, chosen from the 5 most malaria-affected sub-counties was done. Using a questionnaire, respondents' reactions to the disease and what decisions they took were recorded. Reasons for choices such as drugs used, location of treatment and malaria control methods were recorded. RESULTS: Ninety seven percent lived within easy reach of a public health facility. Over 2/3 knew how malaria was transmitted and how it presented. They believed it was best treated at public heath facilities using western type of medicine. Fifty percent of the children, who attended public health units, were treated within 24 of illness. Thirty eight percent of the caretakers knew how to correctly use chloroquine. The caretakers relied on fever, vomiting and refusal to feed as the main symptoms for their diagnosis of malaria. Only 31% of the families sought treatment from government health facilities. Fifty three percent of the families sought treatment from drug shops/vendors. Unfortunately only 38% of the families knew the correct regimen of chloroquine, 4.3% for sulpha-doxine pyrimethamine and 0.5% for quinine. One quarter could afford malaria treatment, and one out of five missed treatment because of poverty. Concerning prevention, 90% stated at least one method but only 21.2% used them. CONCLUSIONS: Despite reasonable knowledge for diagnosis of malaria, awareness of correct treatment is limited. Paradoxically government health units appear to play a minor role in the treatment of malaria.

Collect RTAs names and addresses only, says NHS.

NURSES are to be spared the embarrassment of collecting charges from road traffic accident victims.

Nurses rush to help in omagh bomb atrocity.

N urses flocked from both sides of the border to help treat casualties from Saturday's bombing in Omagh, Co Tyrone.

Trusts block right to see medical notes.

MIDWIFE Amanda Shaw is among thousands of angry patients and relatives who claim they have been given the runaround by GPs and hospitals over access to medical records.

Work-related asthma rockets.

NURSES ARE ideally placed to help the government in its battle against the alarming rise in occupational asthma, according to an asthma charity. Ministers now consider the problem a health priority.

Nurse with criminal past loses job offer.

A SOMERSET nurse has turned to his MP for justice after he lost a job opportunity clue to a spent conviction.