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'Partnership Working in Public Health' presents the findings from a detailed study of public health partnerships in England. The lessons from the research are used to explore the governent's changes in public health, their likely impact and the implications for the future of public health partnerships.

Key Points The nuclear factor-κB (NF-κB)–inhibitor of NF-κB kinase (IKK) pathway can promote the growth and survival of many solid and haematological maligancies and therefore has the potential to provide numerous targets for novel anticancer therapies. Most attention has focused on the development of IKKβ inhibitors, but it is now clear that IKKβ has many NF-κB-independent functions and its inhibition could result in undesired effects. Although it is apparent that NF-κB subunits have important roles in tumorigenesis and the response to cancer therapy, their individual contributions have not been clearly defined. The NF-κB response is highly pleiotropic and the consequences of its activation can be context dependent. NF-κB is not always tumour promoting and it can exhibit tumour suppressor-like activities. Crosstalk with tumour-suppressor proteins, such as p53, provides an important mechanism for regulating NF-κB activity and function in cancer. Tumour suppressors can inhibit the tumour-promoting activities of NF-κB subunits while facilitating their ability to suppress cancer progression. Understanding the regulation and function of the NF-κB subunits in cancer provides opportunities for the development of new therapies and allows the better use of existing drugs that affect NF-κB–IKK activity. Nuclear factor-κB (NF-κB) has many functions in cancer, hence the need for drugs that can modulate its activity. In order to achieve this, Neil D. Perkins argues that the complex roles of the individual NF-κB subunits must be considered. It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.

Key Points The nuclear factor (NF)-κB, inhibitor of NF-κB (IκB) and IκB kinase (IKK) pathway is activated in response to various stimuli in many cell types. NF-κB is activated by many mechanisms, including the canonical pathway, which activates the IKK complex and results in the degradation of IκB in response to inflammatory stimuli. Several NF-κB- and IκB-independent substrates for the IKK proteins are now being identified. These indicate that in addition to induction of NF-κB, these kinases might function to programme the overall cellular response to specific activating stimuli. The consequences of NF-κB activation can vary depending on the context in which activation occurs. This modulation is at least in part due to the regulation of NF-κB subunits in the nucleus, where they translocate after release from cytoplasmic IκB proteins. One mechanism of regulating NF-κB subunit function is through post-translational modifications such as phosphorylation and acetylation. This allows other cell-signalling proteins to influence NF-κB function and therefore serves as a mechanism to integrate their activities with the NF-κB and IKK pathway. NF-κB subunits can also bind DNA cooperatively and activate transcription synergistically with heterologous transcription factors. As independent cell-signalling pathways regulate many of these factors, this provides another mechanism through which NF-κB and IKK activity can be integrated with the overall cellular response to multiple stimuli. Feedback loops exist in which the activation of NF-κB target genes can influence the later time points of the NF-κB response to specific cell stimuli. Crosstalk with the Jun N-terminal kinase (JNK), p53 and nuclear-receptor pathways provide specific examples of the diversity of mechanisms that exist to link NF-κB function to other important networks that regulate cell fate, the immune response and inflammation. The complexity of the mechanisms regulating NF-κB function presents both a challenge and an opportunity when seeking to exploit NF-κB function in a clinical setting. Results indicate that care must be taken when using NF-κB or IKK inhibitors in the clinic, but they also indicate that understanding these pathways will improve diagnostic capabilities and maximize the effectiveness of such inhibitors. Rather than functioning in isolation, the activities of nuclear factor (NF)-κB and inhibitor of NF-κB kinase (IKK) proteins are integrated with diverse cell-signalling pathways, including the JNK, p53 and nuclear-receptor pathways. This crosstalk determines the consequences of NF-κB and IKK activation and, ultimately, cell fate. Nuclear factor (NF)-κB and inhibitor of NF-κB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-κB or IKK function contributes to many human diseases, including cancer. However, the NF-κB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-κB and IKK activation and, ultimately, cell fate.

Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses. In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18–40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria—the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1:1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00467363. Overall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0·0984; absolute difference in livebirth rate 5·09% [95% CI −0·84 to 11·02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0·7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0·0446; absolute difference in livebirth rate 9·20% [0·51 to 17·89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0·7406; absolute difference in livebirth rate 1·71% [−6·37 to 9·79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss. Preconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss. Eunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).

When the genes encoding NF- κ B subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in cancer. Because of its homology to v-Rel, which transforms chicken B cells together with the important role c-Rel can have as a regulator of B- and T-cell proliferation, most attention has focussed on its role in B-cell lymphomas, where the REL gene is frequently amplified. However, a growing number of reports now indicate that c-Rel has important functions in many solid tumours, although studies in mice suggest it may not always function as an oncogene. Moreover, c-Rel is a critical regulator of fibrosis, which provides an environment for tumour development in many settings. Overall, c-Rel is emerging as a complex regulator of tumorigenesis, and there is still much to learn about its functions in human malignancies and the response to cancer therapies.

Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive. We aimed to determine the relationship of preconception phthalate metabolite exposure with ) fecundability and pregnancy loss and ) markers of potential biological mechanisms, including reproductive hormones, inflammation, and oxidative stress. Data were collected from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a preconception study following 1,228 women who were attempting pregnancy, for up to six menstrual cycles and throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a consecutive 3-d pooled urine sample at enrollment. Pregnancy was determined through urinary human chorionic gonadotropin (hCG) at the expected date of menses during each cycle and pregnancy loss as an observed loss following positive hCG. Highly sensitive C-reactive protein (hsCRP) and isoprostanes were measured at enrollment, and reproductive hormones were measured during the follicular phase, ovulation, and luteal phase. Discrete-time Cox proportional hazards models evaluated the relationship of phthalate metabolites with fecundability and weighted Poisson models with robust variance evaluated the risk of pregnancy loss. An interquartile range (IQR) higher mono-(2-ethylhexyl) phthalate [ ; 95% confidence interval (CI): 0.78, 1.00], mono-butyl phthalate ( ; 95% CI: 0.70, 0.96), and mono-benzyl phthalate ( ; 95% CI: 0.74, 0.98) was associated with lower fecundability. No consistent associations were observed with pregnancy loss. Preconception phthalates were consistently associated with higher hsCRP and isoprostanes, as well as lower estradiol and higher follicle-stimulating hormone across the menstrual cycle. Women's preconception exposure to phthalates was associated with lower fecundability, changes in reproductive hormones, and increased inflammation and oxidative stress. The pre- and periconception periods may represent sensitive windows for intervening to limit the reproductive toxicity of phthalate exposure. https://doi.org/10.1289/EHP12287.

Costs can hamper the evaluation of the effectiveness of new biomarkers. Analysis of smaller numbers of pooled specimens has been shown to be a useful cost-cutting technique. The Youden index (J), a function of sensitivity (q) and specificity (p), is a commonly used measure of overall diagnostic effectiveness. More importantly, J is the maximum vertical distance or difference between the ROC curve and the diagonal or chance line; it occurs at the cut-point that optimizes the biomarker's differentiating ability when equal weight is given to sensitivity and specificity. Using the additive property of the gamma and normal distributions, we present a method to estimate the Youden index and the optimal cut-point, and extend its applications to pooled samples. We study the effect of pooling when only a fixed number of individuals are available for testing, and pooling is carried out to save on the number of assays. We measure loss of information by the change in root mean squared error of the estimates of the optimal cut-point and the Youden index, and we study the extent of this loss via a simulation study. In conclusion, pooling can result in a substantial cost reduction while preserving the effectiveness of estimators, especially when the pool size is not very large.

The implementation science literature acknowledges a need for engagement of key stakeholders when designing, delivering and evaluating implementation work. To date, the literature reports minimal or focused stakeholder engagement, where stakeholders are engaged in either barrier identification and/or barrier prioritisation. This paper begins to answer calls from the literature for the development of tools and guidance to support comprehensive stakeholder engagement in implementation research and practice. The paper describes the systematic development of the Implementation-STakeholder Engagement Model (I-STEM) in the context of an international, large-scale empirical implementation study (ImpleMentAll) aimed at evaluating the effectiveness of a tailored implementation toolkit. The I-STEM is a sensitising tool that defines key considerations and activities for undertaking stakeholder engagement activities across an implementation process. In-depth, semistructured interviews and observations were conducted with implementers who were tailoring implementation strategies to integrate and embed internet-based cognitive behavioural therapy (iCBT) services in 12 routine mental health care organisations in nine countries in Europe and Australia. The analytical process was informed by principles of first- and third-generation Grounded Theory, including constant comparative method. We conducted 55 interviews and observed 19 implementation-related activities (e.g., team meetings and technical support calls). The final outcome of our analysis is expressed in an initial version of the I-STEM, consisting of five interrelated concepts: engagement objectives, stakeholder mapping, engagement approaches, engagement qualities and engagement outcomes. Engagement objectives are goals that implementers plan to achieve by working with stakeholders in the implementation process. Stakeholder mapping involves identifying a range of organisations, groups or people who may be instrumental in achieving the engagement objectives. Engagement approaches define the type of work that is undertaken with stakeholders to achieve the engagement objectives. Engagement qualities define the logistics of the engagement approach. Lastly, every engagement activity may result in a range of engagement outcomes. The I-STEM represents potential avenues for substantial stakeholder engagement activity across key phases of an implementation process. It provides a conceptual model for the planning, delivery, evaluation and reporting of stakeholder engagement activities. The I-STEM is nonprescriptive and highlights the importance of a flexible, iterative approach to stakeholder engagement. It is developmental and will require application and validation across a range of implementation activities. Patient contribution to ImpleMentAll trial was facilitated by GAMIAN-Europe at all stages-from grant development to dissemination. GAMIAN-Europe brings together a wide variety of patient representation organisations (local, regional and national) from almost all European countries. GAMIAN-Europe was involved in pilot testing the ItFits-toolkit and provided their views on the various aspects, including stakeholder engagement. Patients were also represented in the external advisory board providing support and advice on the design, conduct and interpretation of the wider project, including the development of the ItFits-toolkit. ClinicalTrials.gov NCT03652883. Retrospectively registered on 29 August 2018.

Purpose It is thought that total energy intake in women is increased during the luteal versus follicular phase of the menstrual cycle; however, less is understood regarding changes in diet composition (i.e., macro- and micronutrient intakes) across the cycle. The aim of this study was to investigate changes in macronutrient, micronutrient, and food group intakes across phases of the menstrual cycle among healthy women, and to assess whether these patterns differ by ovulatory status. Methods The BioCycle study (2005–2007) was a prospective cohort study of 259 healthy regularly menstruating women age 18–44 who were followed for up to two menstrual cycles. Dietary intake was measured using 24-h dietary recalls, and food cravings were assessed via questionnaire, up to four times per cycle, corresponding to menses, mid-follicular, expected ovulation, and luteal phases. Linear mixed models adjusting for total energy intake were used to evaluate changes across the cycle. Results Total protein ( P  = 0.03), animal protein ( P  = 0.05), and percent of caloric intake from protein ( P  = 0.02) were highest during the mid-luteal phase compared to the peri-ovulatory phase. There were also significant increases in appetite, craving for chocolate, craving for sweets in general, craving for salty flavor, and total craving score during the late luteal phase compared to the menstrual, follicular, and ovulatory phases ( P  < 0.001). Conclusions Our findings suggest an increased intake of protein, and specifically animal protein, as well as an increase in reported food cravings, during the luteal phase of the menstrual cycle independent of ovulatory status. These results highlight a plausible link between macronutrient intake and menstrual cycle phase.

Background Preconception pregnancy risk profiles—characterizing the likelihood that a pregnancy attempt results in a full-term birth, preterm birth, clinical pregnancy loss, or failure to conceive—can provide critical information during the early stages of a pregnancy attempt, when obstetricians are best positioned to intervene to improve the chances of successful conception and full-term live birth. Yet the task of constructing and validating risk assessment tools for this earlier intervention window is complicated by several statistical features: the final outcome of the pregnancy attempt is multinomial in nature, and it summarizes the results of two intermediate stages, conception and gestation, whose outcomes are subject to competing risks, measured on different time scales, and governed by different biological processes. In light of this complexity, existing pregnancy risk assessment tools largely focus on predicting a single adverse pregnancy outcome, and make these predictions at some later, post-conception time point. Methods We reframe the individual pregnancy attempt as a multistate model comprised of two nested multinomial prediction tasks: one corresponding to conception and the other to the subsequent outcome of that pregnancy. We discuss the estimation of this model in the presence of multiple stages of outcome missingness and then introduce an inverse-probability-weighted Hypervolume Under the Manifold statistic to validate the resulting multivariate risk scores. Finally, we use data from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial to illustrate how this multistate competing risks framework might be utilized in practice to construct and validate a preconception pregnancy risk assessment tool. Results In the EAGeR study population, the resulting risk profiles are able to meaningfully discriminate between the four pregnancy attempt outcomes of interest and represent a significant improvement over classification by random chance. Conclusions As illustrated in our analysis of the EAGeR data, our proposed prediction framework expands the pregnancy risk assessment task in two key ways—by considering a broader array of pregnancy outcomes and by providing the predictions at an earlier, preconception intervention window—providing obstetricians and their patients with more information and opportunities to successfully guide pregnancy attempts.