Targeting DNA mismatches with rhodium metalloinsertors

DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch repair (MMR)-deficient cancers. These rhodium metalloinsertors bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique among small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers

Use of country of birth as an indicator of refugee background in health datasets

BACKGROUND: Routine public health databases contain a wealth of data useful for research among vulnerable or isolated groups, who may be under-represented in traditional medical research. Identifying specific vulnerable populations, such as resettled refugees, can be particularly challenging; often country of birth is the sole indicator of whether an individual has a refugee background. The objective of this article was to review strengths and weaknesses of different methodological approaches to identifying resettled refugees and comparison groups from routine health datasets and to propose the application of additional methodological rigour in future research. DISCUSSION: Methodological approaches to selecting refugee and comparison groups from existing routine health datasets vary widely and are often explained in insufficient detail. Linked data systems or datasets from specialized refugee health services can accurately select resettled refugee and asylum seeker groups but have limited availability and can be selective. In contrast, country of birth is commonly collected in routine health datasets but a robust method for selecting humanitarian source countries based solely on this information is required. The authors recommend use of national immigration data to objectively identify countries of birth with high proportions of humanitarian entrants, matched by time period to the study dataset. When available, additional migration indicators may help to better understand migration as a health determinant. Methodologically, if multiple countries of birth are combined, the proportion of the sample represented by each country of birth should be included, with sub-analysis of individual countries of birth potentially providing further insights, if population size allows. United Nations-defined world regions provide an objective framework for combining countries of birth when necessary. A comparison group of economic migrants from the same world region may be appropriate if the resettlement country is particularly diverse ethnically or the refugee group differs in many ways to those born in the resettlement country. SUMMARY: Routine health datasets are valuable resources for public health research; however rigorous methods for using country of birth to identify resettled refugees would optimize usefulness of these resources

Intimate Partner Violence Documentation and Awareness in an Urban Emergency Department.

Background Domestic violence rates in smaller cities have been reported to be some of the highest in Canada. It is highly likely that the staff at emergency departments (ED) will come in contact with victims of intimate partner violence in their daily practice. The purpose of this study is to better understand current practices for detecting intimate partner violence, staff awareness and knowledge regarding intimate partner violence, and barriers to questioning about intimate partner violence in the ED. Methods A standardized retrospective chart review captured domestic violence documentation rates in patients presenting to the ED, and a cross-sectional online survey was distributed to the ED staff. Results We found documentation about intimate partner violence in 4.64% of all included patient charts. No documentation was noted in the domestic violence field. Significantly, 16.4% of the ED staff reported never questioning female patients about intimate partner violence; 83.6% enquired when they thought it appropriate, and none asked routinely. None of the staff used a structured screening tool, and 81.8% of the ED staff had not received any formal training. Partner presence was the most common barrier to asking about intimate partner violence, followed by a lack of access to domestic violence management information, and a lack of knowledge regarding intimate partner violence. Conclusions Our findings suggest that the current documentation tools are not being properly utilized. Low rates of intimate partner violence documentation in high-risk patients and lack of education indicate that there is a need to improve current practices. In order to improve identification of this important problem, appropriate training and education about intimate partner/domestic violence are required to increase staff comfort as well as knowledge about available community resources for the victims

Endocrine and metabolic interactions in healthy pregnancies and hyperinsulinemic pregnancies affected by polycystic ovary syndrome, diabetes and obesity

During pregnancy, the fetoplacental unit is key in the pronounced physiological endocrine changes which support pregnancy, fetal development and survival, birth and lactation. In healthy women, pregnancy is characterized by changes in insulin sensitivity and increased maternal androgen levels. These are accompanied by a suite of mechanisms that support fetal growth, maintain glucose homeostasis and protect both mother and fetus from adverse effects of pregnancy induced insulin and androgen excess. In pregnancies affected by endocrine, metabolic disorders such as polycystic ovary syndrome (PCOS), diabetes and obesity, there is an imbalance of beneficial and adverse impacts of pregnancy induced endocrine changes. These inter-related conditions are characterized by an interplay of hyperinsulinemia and hyperandrogenism which influence fetoplacental function and are associated with adverse pregnancy outcomes including hypertensive disorders of pregnancy, macrosomia, preterm delivery and caesarean section. However, the exact underlying mechanisms and relationships of the endocrine and metabolic milieu in these disorders and the impact they have on the prenatal endocrine environment and developing fetus remain poorly understood. Here we aim to review the complex endocrine and metabolic interactions in healthy women during normal pregnancies and those in pregnancies complicated by hyperinsulinemic disorders (PCOS, diabetes and obesity). We also explore the relationships between these endocrine and metabolic differences and the fetoplacental unit, pregnancy outcomes and the developing fetus

A Family of Rhodium Complexes with Selective Toxicity towards Mismatch Repair-Deficient Cancers

Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium–oxygen ligand coordination, termed “Rh–O” metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh–O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]^(2+), all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh–O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and pK_a values of 8.1–9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh–O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment

Special Issue “International Conference of Spirituality in Healthcare. Creating Space for Spirituality in Healthcare,”—Trinity College Dublin 2017

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).This is an editorial of a Special Issue pertaining to the “International Conference of Spirituality in Healthcare. Creating a Space for Spirituality in Healthcare” Trinity College Dublin 2017. This was the third International Spirituality in Healthcare Conference hosted by Trinity College Dublin, with future annual conferences planned. This conference has provided a space to facilitate clinicians, healthcare practitioners and academics to present and debate current issues with this domain. This editorial summarises some of the papers that have been published arising from that conference.publishedVersio

Introducing and integrating perinatal mental health screening:Development of an equity-informed evidence-based approach

Background: Pregnancy is a time of increased risk for developing or re-experiencing mental illness. Perinatal mental health screening for all women is recommended in many national guidelines, but a number of systems-level and individual barriers often hinder policy implementation. These barriers result in missed opportunities for detection and early intervention and are likely to be experienced disproportionately by women from culturally and linguistically diverse backgrounds, including women of refugee backgrounds. The objectives of this study were to develop a theory-informed, evidence-based guide for introducing and integrating perinatal mental health screening across health settings and to synthesize the learnings from an implementation initiative and multisectoral partnership between the Centre of Perinatal Excellence (COPE), and a university-based research centre. COPE is a nongovernmental organization (NGO) commissioned to update the Australian perinatal mental health guidelines, train health professionals and implement digital screening. Methods: In this case study, barriers to implementation were prospectively identified and strategies to overcome them were developed. A pilot perinatal screening programme for depression and anxiety with a strong health equity focus was implemented and evaluated at a large public maternity service delivering care to a culturally diverse population of women in metropolitan Melbourne, Australia, including women of refugee background. Strategies that were identified preimplementation and postevaluation were mapped to theoretical frameworks. An implementation guide was developed to support future policy, planning and decision-making by healthcare organizations. Results: Using a behavioural change framework (Capability, Opportunity, Motivation–Behaviour Model), the key barriers, processes and outcomes are described for a real-world example designed to maximize accessibility, feasibility and acceptability. A Programme Logic Model was developed to demonstrate the relationships of the inputs, which included stakeholder consultation, resource development and a digital screening platform, with the outcomes of the programme. A seven-stage implementation guide is presented for use in a range of healthcare settings. Conclusions: These findings describe an equity-informed, evidence-based approach that can be used by healthcare organizations to address common systems and individual-level barriers to implement perinatal depression and anxiety screening guidelines. Patient or Public Contribution: These results present strategies that were informed by prior research involving patients and staff from a large public antenatal clinic in Melbourne, Australia. This involved interviews with health professionals from the clinic such as midwives, obstetricians, perinatal mental health and refugee health experts and interpreters. Interviews were also conducted with women of refugee background who were attending the clinic for antenatal care. A steering committee was formed to facilitate the implementation of the perinatal mental health screening programme comprising staff from key hospital departments, GP liaison, refugee health and well-being, the NGO COPE and academic experts in psychology, midwifery, obstetrics and public health. This committee met fortnightly for 2 years to devise strategies to address the barriers, implement and evaluate the programme. A community advisory group was also formed that involved women from eight different countries, some of refugee background, who had recently given birth at the health service. This committee met bimonthly and was instrumental in planning the implementation and evaluation such as recruitment strategies, resources and facilitating an understanding of the cultural complexity of the women participating in the study.</p

Introducing and integrating perinatal mental health screening:Development of an equity-informed evidence-based approach

Background: Pregnancy is a time of increased risk for developing or re-experiencing mental illness. Perinatal mental health screening for all women is recommended in many national guidelines, but a number of systems-level and individual barriers often hinder policy implementation. These barriers result in missed opportunities for detection and early intervention and are likely to be experienced disproportionately by women from culturally and linguistically diverse backgrounds, including women of refugee backgrounds. The objectives of this study were to develop a theory-informed, evidence-based guide for introducing and integrating perinatal mental health screening across health settings and to synthesize the learnings from an implementation initiative and multisectoral partnership between the Centre of Perinatal Excellence (COPE), and a university-based research centre. COPE is a nongovernmental organization (NGO) commissioned to update the Australian perinatal mental health guidelines, train health professionals and implement digital screening. Methods: In this case study, barriers to implementation were prospectively identified and strategies to overcome them were developed. A pilot perinatal screening programme for depression and anxiety with a strong health equity focus was implemented and evaluated at a large public maternity service delivering care to a culturally diverse population of women in metropolitan Melbourne, Australia, including women of refugee background. Strategies that were identified preimplementation and postevaluation were mapped to theoretical frameworks. An implementation guide was developed to support future policy, planning and decision-making by healthcare organizations. Results: Using a behavioural change framework (Capability, Opportunity, Motivation–Behaviour Model), the key barriers, processes and outcomes are described for a real-world example designed to maximize accessibility, feasibility and acceptability. A Programme Logic Model was developed to demonstrate the relationships of the inputs, which included stakeholder consultation, resource development and a digital screening platform, with the outcomes of the programme. A seven-stage implementation guide is presented for use in a range of healthcare settings. Conclusions: These findings describe an equity-informed, evidence-based approach that can be used by healthcare organizations to address common systems and individual-level barriers to implement perinatal depression and anxiety screening guidelines. Patient or Public Contribution: These results present strategies that were informed by prior research involving patients and staff from a large public antenatal clinic in Melbourne, Australia. This involved interviews with health professionals from the clinic such as midwives, obstetricians, perinatal mental health and refugee health experts and interpreters. Interviews were also conducted with women of refugee background who were attending the clinic for antenatal care. A steering committee was formed to facilitate the implementation of the perinatal mental health screening programme comprising staff from key hospital departments, GP liaison, refugee health and well-being, the NGO COPE and academic experts in psychology, midwifery, obstetrics and public health. This committee met fortnightly for 2 years to devise strategies to address the barriers, implement and evaluate the programme. A community advisory group was also formed that involved women from eight different countries, some of refugee background, who had recently given birth at the health service. This committee met bimonthly and was instrumental in planning the implementation and evaluation such as recruitment strategies, resources and facilitating an understanding of the cultural complexity of the women participating in the study.</p

Research Personnel Exposure to Carbon Dioxide During Euthanasia Procedures

Carbon dioxide (CO2) is a commonly used euthanasia agent in animal facilities. This procedure is carried out by replacing oxygen with carbon dioxide in animal cages, thus providing a quick and painless method of euthanasia. Unfortunately, there has been limited research on the potential effects of human exposure to CO2 during euthanasia procedures. Following a previous carbon dioxide exposure study in the vivarium at Rowan SOM in 2016, the CO2 cylinders and euthanasia chambers have been relocated to room 153 Science Center and the vivarium has adopted a localized exhaust that helps remove the contaminant at the source. While the results from the 2016 study were within the Occupational Health and Safety (OSHA) and American Conference of Governmental Industrial Hygienist (ACGIH) carbon dioxide exposure limits, the research team replicated the study to ensure compliance at the new euthanasia chamber location