The Prospective Association between Early Life Growth and Breast Density in Young Adult Women.

Breast density is a strong intermediate endpoint to investigate the association between early-life exposures and breast cancer risk. This study investigates the association between early-life growth and breast density in young adult women measured using Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA). OBS measurements were obtained for 536 female Raine Cohort Study participants at ages 27-28, with 268 completing DXA measurements. Participants with three or more height and weight measurements from ages 8 to 22 were used to generate linear growth curves for height, weight and body mass index (BMI) using SITAR modelling. Three growth parameters (size, velocity and timing) were examined for association with breast density measures, adjusting for potential confounders. Women who reached their peak height rapidly (velocity) and later in adolescence (timing) had lower OBS-breast density. Overall, women who were taller (size) had higher OBS-breast density. For weight, women who grew quickly (velocity) and later in adolescence (timing) had higher absolute DXA-breast density. Overall, weight (size) was also inversely associated with absolute DXA-breast density, as was BMI. These findings provide new evidence that adolescent growth is associated with breast density measures in young adult women, suggesting potential mediation pathways for breast cancer risk in later life.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Advocating for Policy Change: Examples Emerging From a Medical-Legal Partnership in Primary Care.

Medical-legal partnerships bring legal services directly into clinical settings. Policy advocacy is often opportunistic and varies across partnerships. Our objective was to study policy advocacy that emerged from a medical-legal partnership in Toronto over a four-year period. This study consisted of a document review and thematic analysis, triangulated with data from interviews with legal team members and health providers. We defined policy advocacy as actions associated with attempts to change policy or legislation. The medical-legal partnership engaged in seven distinct cases of policy advocacy: disability support form requirements, changing workplace review, challenging barriers to citizenship, housing, publicly funded medication program (pharma care), safe injection sites, and the need for increased social assistance. Actions taken included presentations at conferences and submissions of briefs to government. We found that a medical-legal partnership resulted in policy advocacy with issues arising from both the health and the legal team with impacts likely greater than if each group had acted alone.

Sensorineural correlates of failed functional recovery after natural regeneration of vestibular hair cells in adult mice.

Vestibular hair cells (HCs) are mechanoreceptors that sense head motions by modulating the firing rate of vestibular ganglion neurons (VGNs), whose central processes project to vestibular nucleus neurons (VNNs) and cerebellar neurons. We explored vestibular function after HC destruction in adult Pou4f3+/DTR (DTR) mice, in which injections of high-dose (50 ng/g) diphtheria toxin (DT) destroyed most vestibular HCs within 2 weeks. At that time, DTR mice had lost the horizontal vestibulo-ocular reflex (aVORH), and their VNNs failed to upregulate nuclear cFos expression in response to a vestibular stimulus (centrifugation). Five months later, 21 and 14% of HCs were regenerated in utricles and horizontal ampullae, respectively. The vast majority of HCs present were type II. This degree of HC regeneration did not restore the aVORH or centrifugation-evoked cFos expression in VNNs. The failure to regain vestibular pathway function was not due to degeneration of VGNs or VNNs because normal neuron numbers were maintained after HC destruction. Furthermore, sinusoidal galvanic stimulation at the mastoid process evoked cFos protein expression in VNNs, indicating that VGNs were able to regulate VNN activity after HC loss. aVORH and cFos responses in VNNs were robust after low-dose (25 ng/g) DT, which compared to high-dose DT resulted in a similar degree of type II HC death and regeneration but spared more type I HCs in both organs. These findings demonstrate that having more type I HCs is correlated with stronger responses to vestibular stimulation and suggest that regenerating type I HCs may improve vestibular function after HC loss.

Experiences of informal caregivers of people with dementia in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: This review aims to synthesize the experiences of informal caregivers of people with dementia in low- and middle-income countries (LMICs). INTRODUCTION: Globally, the burden of dementia is increasing disproportionately in LMICs. Informal caregivers play a vital role and face multiple challenges in LMICs, even though they also often lack the awareness and skills to provide adequate care for people living with dementia. Many LMICs have limited resources and caregivers lack support services. Understanding their experiences and perceptions may improve interventions, helping caregivers to better support those living with dementia. INCLUSION CRITERIA: Studies from all settings in LMICs will be considered. Qualitative data from qualitative or mixed methods studies that explore caregivers' experiences and perceptions will be included in this review. Participants are informal caregivers of people diagnosed with dementia at any stage, regardless of age, gender, or their relationship with people living with dementia. METHODS: This review will follow the JBI methodology for a qualitative systematic reviews, with meta-aggregation as the synthesis method. The review will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A 3-step search strategy will be used to locate published and unpublished studies in MEDLINE, CINAHL, Embase, PsycINFO, AgeLine, LILACS, African Index Medicus, ProQuest Dissertations and Theses, Open Dissertations, Web of Science Core Collection, and Google Scholar. There will be no date or language limitations. All studies will be screened against the inclusion criteria and data will be extracted and critically appraised for methodological quality by 2 independent reviewers using JBI tools. Confidence in the final synthesized findings will be assessed using the ConQual approach. REVIEW REGISTRATION: PROSPERO CRD42023453814.

The distribution of breast density in women aged 18 years and older.

PURPOSE: Age and body mass index (BMI) are critical considerations when assessing individual breast cancer risk, particularly for women with dense breasts. However, age- and BMI-standardized estimates of breast density are not available for screen-aged women, and little is known about the distribution of breast density in women aged < 40. This cross-sectional study uses three different modalities: optical breast spectroscopy (OBS), dual-energy X-ray absorptiometry (DXA), and mammography, to describe the distributions of breast density across categories of age and BMI. METHODS: Breast density measures were estimated for 1,961 Australian women aged 18-97 years using OBS (%water and %water + %collagen). Of these, 935 women had DXA measures (percent and absolute fibroglandular dense volume, %FGV and FGV, respectively) and 354 had conventional mammographic measures (percent and absolute dense area). The distributions for each breast density measure were described across categories of age and BMI. RESULTS: The mean age was 38 years (standard deviation = 15). Median breast density measures decreased with age and BMI for all three modalities, except for DXA-FGV, which increased with BMI and decreased after age 30. The variation in breast density measures was largest for younger women and decreased with increasing age and BMI. CONCLUSION: This unique study describes the distribution of breast density measures for women aged 18-97 using alternative and conventional modalities of measurement. While this study is the largest of its kind, larger sample sizes are needed to provide clinically useful age-standardized measures to identify women with high breast density for their age or BMI.

Implementing GRADE in systematic reviews that adhere to JBI methodological conduct.

GRADE is a methodological approach used to establish certainty in a body of evidence and is now widely adopted among the evidence synthesis and guideline development community. JBI is an international evidence-based health care organization that provides guidance for a range of evidence synthesis approaches. The GRADE approach is currently endorsed for use in a subset of JBI systematic reviews; however, there is some uncertainty regarding when (and how) GRADE may be implemented in reviews that follow JBI methodology.

Common tool structures and approaches to risk of bias assessment: implications for systematic reviewers.

There are numerous tools available to assess the risk of bias in individual studies in a systematic review. These tools have different structures, including scales and checklists, which may or may not separate their items by domains. There are also various approaches and guides for the process, scoring, and interpretation of risk of bias assessments, such as value judgments, quality scores, and relative ranks. The objective of this commentary, which is part of the JBI Series on Risk of Bias, is to discuss some of the distinctions among different tool structures and approaches to risk of bias assessment and the implications of these approaches for systematic reviewers.

Comparison of bias adjustment in meta-analysis using data-based and opinion-based methods.

INTRODUCTION: Several methods exist for bias adjustment of meta-analysis results, but there has been no comprehensive comparison with unadjusted methods. We compare 6 bias-adjustment methods with 2 unadjusted methods to examine how these different methods perform. METHODS: We re-analyzed a meta-analysis that included 10 randomized controlled trials. Two data-based methods (Welton's data-based approach and Doi's quality effects model) and 4 opinion-informed methods (opinion-based approach, opinion-based distributions combined statistically with data-based distributions, numerical opinions informed by data-based distributions, and opinions obtained by selecting areas from data-based distributions) were used to incorporate methodological quality information into the meta-analytical estimates. The results of these 6 methods were compared with 2 unadjusted models: the DerSimonian-Laird random effects model and Doi's inverse variance heterogeneity model. RESULTS: The 4 opinion-based methods returned the random effects model estimates with wider uncertainty. The data-based and quality effects methods returned different results and aligned with the inverse variance heterogeneity method with some minor downward bias adjustment. CONCLUSION: Opinion-based methods seem to only add uncertainty rather than bias adjust.

The revised JBI critical appraisal tool for the assessment of risk of bias for quasi-experimental studies.

Systematic reviews of effectiveness offer a rigorous synthesis of the best evidence available regarding the effects of interventions or treatments. Randomized controlled trials are considered the optimal study design for evaluating the effectiveness of interventions and are the ideal study design for inclusion in a systematic review of effectiveness. In the absence of randomized controlled trials, quasi-experimental studies may be relied on to provide information on treatment or intervention effectiveness. However, such studies are subject to unique considerations regarding their internal validity and, consequently, the assessment of the risk of bias of these studies needs to consider these features of design and conduct. The JBI Effectiveness Methodology Group has recently commenced updating the suite of JBI critical appraisal tools for quantitative study designs to align with the latest advancements in risk of bias assessment. This paper presents the revised critical appraisal tool for risk of bias assessment of quasi-experimental studies; offers practical guidance for its use; provides examples for interpreting the results of risk of bias assessment; and discusses major changes from the previous version, along with the justifications for those changes.

The impact of height and weight on rescreening rates within a population-based breast screening program.

INTRODUCTION: Women with obesity are at increased risk of post-menopausal breast cancer and less likely to participate in breast screening. This study investigates the impact of asking women their height and weight within a population-based screening program, and the association of BMI with rescreening status. METHODS: Data regarding 666,130 screening events from 318,198 women aged 50-74 attending BreastScreen Western Australia between 2016 and 2021 were used to compare crude and age-standardised rescreening rates over time. Mixed effects logistic regression was used to investigate associations of BMI with rescreening status. RESULTS: Rescreening rates for women screened since 2016 were within 1.8% points from the previous reporting period, stratified by screening round. Increasing BMI was associated with decreased likelihood of returning to breast screening (OR = 0.993, 95% CI: 0.988-0.998; OR = 0.989, 95% CI: 0.984-0.994; OR = 0.985, 95% CI: 0.982-0.987 for women screening for the first, second and third+ time, respectively). CONCLUSIONS: This large, prospective study supports implementation of routine height and weight collection within breast screening programs. It shows that asking women their height and weight does not deter them from returning to screening and that women with increased BMI are less likely to rescreen, highlighting a need for targeted interventions to improve screening barriers for women living with obesity.

Feasibility and Usability of EnergyPoints: A Mobile Health App to Guide Acupressure Use for Cancer Symptom Management.

OBJECTIVE: To examine the feasibility and usability of EnergyPoints™, an innovative mobile health app that teaches and guides people with cancer to implement daily acupressure to self-manage their fatigue and sleep disturbances. METHODS AND INTERVENTION: The study used an integrated agile, human-centered approach. Adults (age 18 years and over) with cancer experiencing at least moderate fatigue, and living in the Greater New York City community, were recruited from social media, patient advocacy groups, and referrals. Twenty participants (in 3 sprints of 3, 5, and 12) were video-recorded thinking aloud while using the app for the first time. They then used the app at home to self-administer acupressure (twice daily for 1 week) while continuously wearing a fitness tracker. Each participant completed an exit interview and modified Computer System Usability Questionnaire post-participation. RESULTS: Participants were ages 40 to 76 years and 65% female; 65% were non-Hispanic white. Mean pass rates per ritual exceeded 80%. Users completed (totally or partially) greater than 90% of stimulating acupressure and 70% of relaxing acupressure rituals. Sprint 3 SPs totally completed at least 1 ritual 87% of the time. The majority agreed or strongly agreed the app was easy to use (90%), easy to learn (85%), easy to understand (75%), and effective in helping perform self-acupressure (85%). In an analysis of ease of completing 5 key tasks, all successfully completed the tasks; 3 users required some assistance. Of 654 usability statements, those coded as personal experience/context (197), content related to acupressure learning (105), and content related to the onboarding/profile (71) were most frequent. The design team integrated recommendations into the app before the next sprint. CONCLUSIONS: Findings supported feasibility and usability, as well as acceptability, and led to significant alterations and improvements. EnergyPoints™ offers an opportunity to mainstream acupressure and help cancer survivors self-manage their symptoms.

Characteristics and Challenges of Providing Acupuncture and Chinese Herbal Medicine in Oncology Treatment: Report of Survey Data and Experience of Five Unique Clinical Settings.

Acupuncture is an integrative therapy with strong evidence to support its use in the oncology setting, yet barriers exist for implementation into conventional medical clinics. Though acupuncture is recommended in clinical practice guidelines for oncology, there is little data in the literature showing how acupuncture and other related therapies, including herbal medicine are successfully implemented in some oncology clinics, while others experience barriers to care. To characterize the current use of acupuncture (ACU) and herbal medicine (HM) in oncology clinics, we collected general demographic and usage data from 5 example clinics. In addition, to better understand the barriers faced by ACU and HM clinics in implementing acupuncture as a treatment modality, a survey was deployed to 2320 members of the Society for Integrative Oncology. This article examines the characteristics of oncology settings around the world, and shares data from the survey on the use of these therapies in the field of oncology. The primary barrier to acupuncture care, as reported by providers, was cost. With just under 70% of the oncologists reporting it as the most important obstacle. Additional barriers to implementation included concerns about competency and training, accessibility and safety of herbal medicine during treatment. Though acupuncture is being incorporated into more conventional oncology settings, organized strategies for implementation involving payers and policymakers is needed.

Predatory journals and their practices present a conundrum for systematic reviewers and evidence synthesisers of health research: A qualitative descriptive study.

Predatory journals are a blemish on scholarly publishing and academia and the studies published within them are more likely to contain data that is false. The inclusion of studies from predatory journals in evidence syntheses is potentially problematic due to this propensity for false data to be included. To date, there has been little exploration of the opinions and experiences of evidence synthesisers when dealing with predatory journals in the conduct of their evidence synthesis. In this paper, the thoughts, opinions, and attitudes of evidence synthesisers towards predatory journals and the inclusion of studies published within these journals in evidence syntheses were sought. Focus groups were held with participants who were experienced evidence synthesisers from JBI (previously the Joanna Briggs Institute) collaboration. Utilising qualitative content analysis, two generic categories were identified: predatory journals within evidence synthesis, and predatory journals within academia. Our findings suggest that evidence synthesisers believe predatory journals are hard to identify and that there is no current consensus on the management of these studies if they have been included in an evidence synthesis. There is a critical need for further research, education, guidance, and development of clear processes to assist evidence synthesisers in the management of studies from predatory journals.

Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures.

BACKGROUND: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. RESULTS: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). CONCLUSION: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. IMPACT: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.

Use of conditional estimates of effect in cancer epidemiology: An application to lung cancer treatment.

BACKGROUND: In oncology clinical trials, there is the assumption that randomization sufficiently balances confounding covariates and therefore average treatment effects are usually reported. This paper explores the wider benefits provided by conditioning on covariates for reasons other than mitigation of confounding. METHODS: We reanalyzed the data from primary randomized controlled trials listed in two meta-analyses to explore the significance of conditioning on smoking status in terms of the effect magnitude of treatment on progression free survival in non-small cell lung cancer. RESULTS: The reanalysis revealed that conditioning on smoking status using sub-group analyses provided the closest empiric estimate of individual treatment effect based on smoking status and significantly reduced the heterogeneity of treatment effect observed across studies. In addition, smoking status was determined to be a modifier of the effect of treatment. CONCLUSION: Conditioning on prognostic covariates in randomized trials in oncology helps generate the closest empiric estimates of individual treatment benefit, addresses heterogeneity due to varying covariate distributions across trials and facilitates future decision making as well as evidence synthesis. Conditioning using sub-group analyses also allows examination for effect modification in meta-analysis.

Reporting of 3Rs Approaches in Preclinical Animal Experimental Studies-A Nationwide Study.

The 3Rs aim to refine animal welfare, reduce animal numbers, and replace animal experiments. Investigations disclose that researchers are positive towards 3Rs recommendations from peers. Communication of 3Rs approaches via primary preclinical animal experimental literature may become a fast-forward extension to learn relevant 3Rs approaches if such are reported. This study investigates 3Rs-reporting in peer-reviewed preclinical animal research with at least one author affiliated to a Danish university. Using a systematic search and random sampling, we included 500 studies from 2009 and 2018. Reporting was low and improvement over time limited. A word search for 3R retrieved zero results in 2009 and 3.2% in 2018. Reporting on 3Rs-related sentences increased from 6.4% in 2009 to 18.4% in 2018, "reduction" increased from 2.4% to 8.0%, and "refinement" from 5.2% to 14.4%. Replacement was not reported. Reporting of the methodology was missing. For "reduction", methodology was mentioned in one study in 2009 and 11 studies in 2018, and for "refinement" in 9 and 21, respectively. Twenty-one studies stated compliance with ARRIVE-guidelines or similar without disclosure of details. Reporting of 3Rs approaches in preclinical publications is currently insufficient to guide researchers. Other strategies, e.g., education, interdisciplinary collaboration, and 3Rs funding initiatives, are needed.

Effectiveness of dual active ingredient insecticide-treated nets in preventing malaria: A systematic review and meta-analysis.

Malaria vectors have demonstrated resistance to pyrethroid-based insecticides used in insecticide-treated nets, diminishing their effectiveness. This systematic review and meta-analysis investigated two forms of dual active-ingredient (DAI) insecticide-treated nets (ITN(s)) for malaria prevention. A comprehensive search was conducted on July 6th 2022. The databases searched included PubMed, Embase, CINAHL, amongst others. Trials were eligible if they were conducted in a region with ongoing malaria transmission. The first DAI ITN investigated were those that combined a pyrethroid with a non-pyrethroid insecticides. The second DAI ITN investigated were that combined a pyrethroid with an insect growth regulator. These interventions were compared against either a pyrethroid-only ITN, or ITNs treated with pyrethroid and piperonyl-butoxide. Assessment of risk of bias was conducted in duplicate using the Cochrane risk of bias 2 tool for cluster-randomised trials. Summary data was extracted using a custom data-extraction instrument. This was conducted by authors THB, JCS and SH. Malaria case incidence was the primary outcome and has been meta-analysed, adverse events were narratively synthesised. The review protocol is registered on PROSPERO (CRD42022333044). From 9494 records, 48 reports were screened and 13 reports for three studies were included. These studies contained data from 186 clusters and all reported a low risk of bias. Compared to pyrethroid-only ITNs, clusters that received pyrethroid-non-pyrethroid DAI ITNs were associated with 305 fewer cases per 1000-person years (from 380 fewer cases to 216 fewer cases) (IRR = 0.55, 95%CI: 0.44-0.68). However, this trend was not observed in clusters that received pyrethroid-insect growth regulator ITNs compared to pyrethroid-only ITNs (from 280 fewer cases to 135 more) (IRR = 0.90, 95%CI: 0.73-1.13). Pyrethroid-non-pyrethroid DAI ITNs demonstrated consistent reductions in malaria case incidence and other outcomes across multiple comparisons. Pyrethroid-non-pyrethroid DAI ITNs may present a novel intervention for the control of malaria.