IRB Decision-Making about Minimal Risk Research with Pregnant Participants.

Pregnant individuals are often excluded from research without clear justification, even when the research poses minimal risk of harm to the fetus. Little is known about institutional review board (IRB) decision-making practices when reviewing such research. We conducted a survey of current and former IRB personnel in the United States to elicit their interpretations of "minimal risk"-a formal regulatory category-and to identify factors that may influence IRB decisions to approve or disapprove research involving pregnant participants. Study results revealed some consensus among IRB members about the risk level of individual research procedures and hypothetical study vignettes. However, we uncovered important variations not only in the assessment of risk but also in the willingness of IRB members to approve minimal risk research that includes pregnant women. Based on our findings, guidance is needed to assist IRB members in characterizing risk, applying federal regulations, and appropriately ensuring the inclusion or justified exclusion of pregnant people in research.

Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response.

Zika virus, influenza, and Ebola have called attention to the ways in which infectious disease outbreaks can severely - and at times uniquely - affect the health interests of pregnant women and their offspring. These examples also highlight the critical need to proactively consider pregnant women and their offspring in vaccine research and response efforts to combat emerging and re-emerging infectious diseases. Historically, pregnant women and their offspring have been largely excluded from research agendas and investment strategies for vaccines against epidemic threats, which in turn can lead to exclusion from future vaccine campaigns amidst outbreaks. This state of affairs is profoundly unjust to pregnant women and their offspring, and deeply problematic from the standpoint of public health. To ensure that the needs of pregnant women and their offspring are fairly addressed, new approaches to public health preparedness, vaccine research and development, and vaccine delivery are required. This Guidance offers 22 concrete recommendations that provide a roadmap for the ethically responsible, socially just, and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens. The Guidance was developed by the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group - a multidisciplinary, international team of 17 experts specializing in bioethics, maternal immunization, maternal-fetal medicine, obstetrics, pediatrics, philosophy, public health, and vaccine research and policy - in consultation with a variety of external experts and stakeholders.

Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis.

The Anaphase Promoting Complex (APC) coactivator Cdh1 drives proper cell cycle progression and is implicated in the suppression of tumorigenesis. However, it remains elusive how Cdh1 restrains cancer progression and how tumor cells escape the inhibition of Cdh1. Here we report that Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner. Depleting Cdh1 accelerates breast cancer cell proliferation and cooperates with PTEN loss to promote breast tumor progression in mice. Hyperactive c-Src, on the other hand, reciprocally inhibits the ubiquitin E3 ligase activity of APCCdh1 through direct phosphorylation of Cdh1 at its N-terminus, which disrupts the interaction between Cdh1 and the APC core complex. Furthermore, pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function to repress a panel of APCCdh1 oncogenic substrates. Our findings reveal a reciprocal feedback circuit of Cdh1 and c-Src in the crosstalk between the cell cycle machinery and the c-Src signaling pathway.

Women's views about contraception requirements for biomedical research participation.

The scientific and ethical importance of including women of reproductive age in biomedical research is widely acknowledged. Concerns about preventing fetal exposure to research interventions have motivated requirements for contraception among reproductive aged women in biomedical studies-often irrespective of risks and benefits or a woman's actual potential for pregnancy, raising important questions about when such requirements are appropriate. The perspectives of women themselves on these issues are largely unexplored. We conducted 140 interviews, 70 in the U.S. and 70 in Malawi, with women either living with or at-risk for HIV, exploring their views about the practice of requiring contraception in clinical trials. A majority of women interviewed from both countries indicated overall support for the practice, with seven themes characterizing advantages and disadvantages raised: reproductive control, health effects, prevention of fetal harm, burden on women, deferral to authority, autonomy regarding enrollment and birth control method, and relationship concerns. While women in the US frequently raised prevention of fetal harm as a key advantage, many other positives noted by women in both countries were related to contraception use in general, not specific to a trial context. With regard to disadvantages, U.S. women tended to focus on biomedical risks such as side effects and impact on fertility, whereas Malawian women focused on the social risks of contraception requirements, including violations of trust in marital relations and suspicions of potential infidelity. Given the potential benefits and burdens highlighted, contraception in research should be sensitive to actual fetal risk assessments; directed where justified at optimizing effective pregnancy prevention; responsive to women's reproductive preferences; and made available as an ancillary benefit even where risk thresholds do not justify requirement-in order to facilitate trials that are both ethical and robustly oriented around the interests and lives of women who will participate in them.

Beyond "Vessels and Vectors": A Global Review of Registered HIV-Related Clinical Trials with Pregnant Women.

BACKGROUND: Since the early 1990s, the HIV research agenda has prioritized to some degree the inclusion of pregnant women. However, concerns remain regarding the extent to which pregnant women's own health needs are addressed, representation in trials of HIV preventives or treatments for comorbidities, and equitable study of newer medications during pregnancy. METHODS: We employed a keyword search of the International Clinical Trials Registry Platform to identify interventional HIV-related trials conducted with pregnant women between January 2001 and December 2015. Retained trials were coded according to several key variables (e.g., study endpoints, trial phase, study compound) and analyzed using information provided in the database. RESULTS: In total, 63 trials studying use of a pharmacological compound during pregnancy were conducted across 35 countries and sponsored by 74 unique organizations, including pharmaceutical companies. Of trials analyzed, 86% (n = 54) listed maternal outcomes as a primary endpoint. More than 35% (n = 23) of trials assessed pharmacokinetic parameters of a study compound during pregnancy. Of 45 trials specifically studying HIV-related medication(s), just 4% (n = 2) focused on HIV preventives. One trial studied tuberculosis in HIV-infected pregnant women; 11 studied malaria. On average, medications were studied during pregnancy 4.4 years after licensure. CONCLUSIONS: Our findings demonstrate that trials with pregnant women are conducted across a range of countries and sponsors, and much progress has been made to better address pregnant women's own health needs in HIV research. However, our findings confirm other concerns, for example, lack of HIV preventives studied and the lag between medication licensure and study during pregnancy.

Acerca de la transferencia delirante (transferencia psicótica) / On delusional transference (transference psychosis) / A propos du transfert délirant (transfert psychotique)

En la primera parte del artículo, Margaret Little parte de las dificultades técnicas que plantean las interpretaciones tranferenciales en determinados pacientes, que no responden a un grupo definido, y que la llevan a interrogarse sobre el tipo de transferencia que desarrollan. La ausencia de la cualidad «como sí» en este tipo de transferencia lleva a la autora a una reevaluación de la comprensión y de la técnica de dichos tratamientos. En la segunda parte del artículo, M. Little se esfuerza por insertar sus reflexiones clínicas en el marco del pensamiento psicoanalítico de entonces. Propone pensar ciertos fenómenos a partir de su concepto de «unidad básica del ser» como un estado primordial de indiferenciación

In the first part of the paper, Little outlines the technical difficulties raised by transference interpretations in certain patients, who do not fit within a clearly defined group, which prompts her to question the type of transference developed by these patients. The absence of the "as if" quality in this type of transference leads the author to re-evaluate both our understanding of, and technical approach to, these treatments. In the second part of the article, Little endeavours to insert her clinical reflections within the context of psychoanalytic thought of the time. She postulates that certain phenomena be considered in reference to her concept of "basic unit of being" as a primal state of undifferentiation

Dans la première partie de l'article M. Little part des difficultés techniques posées par les interprétations transférentielles chez certains patients qui ne correspondent pas a un groupe défini et qui la mènent à s'interroger sur le type de transfert qu'ils développent. La carence d'une qualité «Comme si» dans ce type de transfert amene l'auteure a une réévaluation de la compréhension et de la technique de ces traitements. Dans la seconde partie de l'article M. Little essaye s'insérer ses réflexions cliniques dans le cadre de la pensée psychanalytique de son temps. Ell propose de réfléchir à certains phénomènes a partit de son concept «d'unité basique de l'être» comme un etat primordial d'indifférentiation

Research with Pregnant Women: New Insights on Legal Decision-Making.

U.S. researchers and scholars often point to two legal factors as significant obstacles to the inclusion of pregnant women in clinical research: the Department of Health and Human Services' regulatory limitations specific to pregnant women's research participation and the fear of liability for potential harm to children born following a pregnant woman's research participation. This article offers a more nuanced view of the potential legal complexities that can impede research with pregnant women than has previously been reflected in the literature. It reveals new insights into the role of legal professionals throughout the research pathway, from product conception to market, and it highlights a variety of legal factors influencing decision-making that may slow or halt research involving pregnant women. Our conclusion is that closing the evidence gap created by the underrepresentation and exclusion of pregnant women in research will require targeted attention to the role of legal professionals and the legal factors that influence their decisions.

Research with pregnant women: a call to action.

Despite a global need for the use of medication during pregnancy, the medical research community lacks robust evidence for safety and efficacy of treatments and preventives often taken by pregnant women. Given the biological differences between pregnant women and the rest of the population, the need to gather data on the ways in which medications behave in the pregnant body is critical to the health of pregnant women and their offspring. Three ethical reasons are central to this need: 1. Pregnant women deserve access to effective treatment, 2. Pregnant women deserve access to safe treatment, and 3. Pregnant women deserve equitable access to trials carrying the prospect of direct benefit. In this paper, we introduce and frame this Supplement Issue, which presents important conference proceedings of the 2016 Global Forum on Bioethics in Research meeting held in Buenos Aires, Argentina, on the 3rd and 4th of November.

Advancing HIV research with pregnant women: navigating challenges and opportunities.

OBJECTIVE: Concerns about including pregnant women in research have led to a dearth of evidence to guide safe and effective treatment and prevention of HIV in pregnancy. To better understand why these evidence gaps persist and inform guidance for responsible inclusion of pregnant women in the HIV research agenda, we aimed to learn what HIV experts perceive as barriers and constraints to conducting this research. METHODS: We conducted a series of group and one-on-one consultations with 62 HIV investigators and clinicians to elicit their views and experiences conducting HIV research involving pregnant women. Thematic analysis was used to identify priorities and perceived barriers to HIV research with pregnant women. RESULTS: Experts discussed a breadth of needed research, including safety, efficacy, and appropriate dosing of: newer antiretrovirals for pregnant women, emerging preventive strategies, and treatment for coinfections. Challenges to conducting research on pregnancy and HIV included ethical concerns, such as how to weigh risks and benefits in pregnancy; legal concerns, such as restrictive interpretations of current regulations and liability issues; financial and professional disincentives, including misaligned funder priorities and fear of reputational damage; and analytical and logistical complexities, such as challenges recruiting and retaining pregnant women to sufficiently power analyses. CONCLUSION: Investigators face numerous challenges to conducting needed HIV research with pregnant women. Advancing such research will require clearer guidance regarding ethical and legal uncertainties; incentives that encourage rather than discourage investigators to undertake such research; and a commitment to earlier development of safety and efficacy data through creative trial designs.

Implicating municipalities in addressing household food insecurity in Canada: A pan-Canadian analysis of news print media coverage.

OBJECTIVES: Household food insecurity (HFI) affects approximately 13% of Canadian households and is especially prevalent among low-income households. Actions to address HFI have been occurring primarily at the local level, despite calls for greater income supports from senior governments to reduce poverty. News media may be reinforcing this trend, by emphasizing food-based solutions to HFI and the municipal level as the site where action needs to take place. The objective of this study was to examine the level and framing of print news media coverage of HFI action in Canada. METHODS: Using a quantitative newspaper content analysis approach, we analyzed 547 articles gathered from 2 national and 16 local/regional English-language newspapers published between January 2007 and December 2012. RESULTS: News coverage increased over time, and over half was produced from Ontario (33%) and British Columbia (22%) combined. Of the 374 articles that profiled a specific action, community gardens/urban agriculture was most commonly profiled (17%), followed by food banks/meal programs (13%); 70% of articles implicated governments to take action on HFI, and of these, 43% implicated municipal governments. Article tone was notably more negative when senior governments were profiled and more neutral and positive when municipal governments were profiled. CONCLUSION: News media reporting of this issue in Canada may be placing pressure on municipalities to engage in food-based actions to address HFI. A more systematic approach to HFI action in Canada will require more balanced media reporting that acknowledges the limitations of food-based solutions to the income-based problem of HFI.

Should Canadian health promoters support a food stamp-style program to address food insecurity?

Food insecurity is an urgent public health problem in Canada, affecting 4 million Canadians in 2012, including 1.15 million children, and associated with significant health concerns. With little political will to address this significant policy issue, it has been suggested that perhaps it is time for Canada to try a food stamp-style program. Such a program could reduce rates of food insecurity and improve the nutritional health of low-income Canadians. In this article, we explore the history of the US food stamp program; the key impetus of which was to support farmers and agricultural interests, not to look after the needs of people living in poverty. Though the US program has moved away from its roots, its history has had a lasting legacy, cementing an understanding of the problem as one of lack of food, not lack of income. While the contemporary food stamp program, now called Supplemental Nutrition Assistance Program (SNAP), reduces rates of poverty and food insecurity, food insecurity rates in the USA are significantly higher than those in Canada, suggesting a food stamp-style program per se will not eliminate the problem of food insecurity. Moreover, a food stamp-style program is inherently paternalistic and would create harm by reducing the autonomy of participants and generating stigma, which in itself has adverse health effects. Consequently, it is ethically problematic for health promoters to advocate for such a program, even if it could improve diet quality.

Nursing student placements in clinical research.

Research is part of the remit of the NHS and consequently many patients participate in research studies. Clinical nurses have a vital role in research, since they care for patients who participate in studies and act as patient advocates during research. However, nursing students are rarely provided with an opportunity to undertake a research placement. They therefore have a limited understanding of what being a research participant involves for patients. This article describes the type of research carried out in an NHS trust in northwest England, how research placements were set up in that trust and the beneficial effects on learning of such placements. The aim of the article is to encourage other research nurses to set up student placements and encourage nursing students to request research placements.

Serum mannose-binding lectin concentration, but not genotype, is associated with Clostridium difficile infection recurrence: a prospective cohort study.

BACKGROUND: Mannose-binding lectin (MBL) plays a key role in the activation of the lectin-complement pathway of innate immunity, and its deficiency has been linked with several acute infections. However, its role in predisposing to, or modulating disease severity in, Clostridium difficile infection (CDI) has not been investigated. METHODS: We prospectively recruited 308 CDI case patients and 145 control patients with antibiotic-associated diarrhea (AAD). CDI outcome measures were disease severity, duration of symptoms, 30-day mortality, and 90-day recurrence. Serum concentrations of MBL were determined using a commercial enzyme-linked immunosorbent assay transferred to an electrochemiluminescence-based platform. MBL2 polymorphisms were typed using a combination of pyrosequencing and TaqMan genotyping assays. RESULTS: The frequency of the MBL2 genetic variants was similar to that reported in other white populations. MBL serum concentrations in CDI and AAD subjects were determined by MBL2 exonic variants B, C, and D and the haplotypes (LYPB, LYQC, and HYPD). There was no difference in either MBL concentrations or genotypes between cases and controls. MBL concentration, but not genotype, was a determinant of CDI recurrence (odds ratios, 3.18 [95% confidence interval {CI}, 1.40-7.24] and 2.61 [95% CI, 1.35-5.04] at the <50 ng/mL and <100 ng/mL cutoff points, respectively; P < .001). However, neither MBL concentration nor MBL2 genotype was linked with the other CDI outcomes. CONCLUSIONS: Serum MBL concentration did not differentiate between CDI cases and AAD controls, but among CDI cases, MBL concentration, but not genotype, was associated with CDI recurrence, indicating that MBL acts as a modulator of disease, rather than a predisposing factor.

Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study.

Measurement of both calprotectin and lactoferrin in faeces has successfully been used to discriminate between functional and inflammatory bowel conditions, but evidence is limited for Clostridium difficile infection (CDI). We prospectively recruited a cohort of 164 CDI cases and 52 controls with antibiotic-associated diarrhoea (AAD). Information on disease severity, duration of symptoms, 30-day mortality and 90-day recurrence as markers of complicated CDI were recorded. Specimens were subject to microbiological culture and PCR-ribotyping. Levels of faecal calprotectin (FC) and lactoferrin (FL) were measured by ELISA. Statistical analysis was conducted using percentile categorisation. ROC curve analysis was employed to determine optimal cut-off values. Both markers were highly correlated with each other (r2 = 0.74) and elevated in cases compared to controls (p<0.0001; ROC>0.85), although we observed a large amount of variability across both groups. The optimal case-control cut-off point was 148 mg/kg for FC and 8.1 ng/µl for FL. Median values for FL in CDI cases were significantly greater in patients suffering from severe disease compared to non-severe disease (104.6 vs. 40.1 ng/µl, p = 0.02), but were not significant for FC (969.3 vs. 512.7 mg/kg, p = 0.09). Neither marker was associated with 90-day recurrence, prolonged CDI symptoms, positive culture results and colonisation by ribotype 027. Both FC and FL distinguished between CDI cases and AAD controls. Although FL was associated with disease severity in CDI patients, this showed high inter-individual variability and was an isolated finding. Thus, FC and FL are unlikely to be useful as biomarkers of complicated CDI disease.

Midwifery support in labour: how important is it to stay in the room?

This paper draws on the findings of an observational study of intrapartum care in Scotland, UK. Observations lasting up to three hours were undertaken of 49 labour episodes. Quantitative data gathered through the study identified associations between women's feelings about the support they received and the proportion of time that their midwife was present in the labour room and between the midwife's presence and the type of birth. Reflections on the care observed during the 104 hours of observations identified several key consequences of the midwife's absence from the room: heightened anxiety of the woman and her birth partner; a reduction in opportunities to build rapport and offer support; and a reduction in the midwife's ability to monitor the progress of the labour accurately. The study also found that those midwives who were out of the room more, were less supportive of the women in their care when they were in the room.

Municipal-level responses to household food insecurity in Canada: a call for critical, evaluative research.

Household food insecurity (HFI) is a persistent public health problem affecting 3.8 million Canadians. While the causes of HFI are rooted in income insecurity, solutions to HFI have been primarily food-based, with the bulk of activity occurring at the municipal level across Canada. We conceptualize these municipal-level actions as falling within three models: "charitable", "household improvements and supports" and "community food systems". Many initiatives, especially non-charitable ones, generate widespread support, as they aim to increase participants' food security using an empowering and dignified approach. While these initiatives may offer some benefits to their participants, preliminary research suggests that any food-based solution to an income-based problem will have limited reach to food-insecure households and limited impact on participants' experience of HFI. We suspect that widespread support for the local-level food-based approach to HFI has impeded critical judgement of the true potential of these activities to reduce HFI. As these initiatives grow in number across Canada, we are in urgent need of comprehensive and comparative research to evaluate their impact on HFI and to ensure that municipal-level action on HFI is evidence-based.

Is the interleukin 8 promoter polymorphism rs4073/-251T >A associated with Clostridium difficile infection?

The interleukin 8 gene single-nucleotide polymorphism rs4073/-251T >A predisposes to Clostridium difficile infection (CDI), but this association has not been independently validated. In this study, we were unable to replicate this association in either a white cohort or by meta-analysis, suggesting that rs4073/-251T >A is unlikely to constitute a major risk factor for CDI.