Dehydrodieugenol isolated from Ocotea cymbarum induces cell death in human breast cancer cell lines by dysregulation of intracellular copper concentration.

In this work, two neolignans - dehydrodieugenol (1) and dehydrodieugenol B (2) - were isolated from leaves of Ocotea cymbarum (H. B. K.) Ness. (Lauraceae). When tested against two human breast cancer cell lines (MCF7 and MDA-MB-231), compound 1 was inactive (IC50 > 500 µM) whereas compound 2 displayed IC50 values of 169 and 174 µM, respectively. To evaluate, for the first time in the literature, the synergic cytotoxic effects of compounds 1 and 2 with ion Cu2+, both cell lines were incubated with equimolar solutions of these neolignans and Cu(ClO4)2·6H2O. Obtained results revealed no differences in cytotoxicity upon the co-administration of compound 2 and Cu2+. However, the combination of compound 1 and Cu2+ increases the cytotoxicity against MCF7 and MDA-MB-231 cells, with IC50 values of 165 and 204 µM, respectively. The activity of compound 1 and Cu2+ in MCF7 spheroids regarding the causes/effects considering the tumoral microenvironment were accessed using fluorescence staining and imaging by fluorescence microscopy. This analysis enabled the observation of a higher red filter fluorescence intensity in the quiescence zone and the necrotic core, indicating a greater presence of dead cells, suggesting that the combination permeates the spheroid. Finally, using ICP-MS analysis, the intracellular copper disbalance caused by mixing compound 1 and Cu2+ was determined quantitatively. The findings showcased a 50-fold surge in the concentration of Cu2+ compared with untreated cells (p > 0.0001) - 18.7 ng of Cu2+/mg of proteins and 0.37 ng of Cu2+/mg of protein, respectively. Conversely, the concentration of Cu2+ in cells treated with compound 1 was similar to values of the negative control group (0.29 ng of Cu2+/mg of protein). This alteration allowed us to infer that compound 1 combined with Cu2+ induces cell death through copper homeostasis dysregulation.

Transhumeral prosthesis use affects upper body kinematics and kinetics.

BACKGROUND: Transhumeral (TH) limb loss leads to loss of body mass and reduced shoulder range of motion. Despite most owning a prosthesis, prosthesis abandonment is common. The consequence of TH limb loss and prosthesis use and disuse during gait may be compensation in the upper body, contributing to back pain or injury. Understanding the impact of not wearing a TH prosthesis on upper body asymmetries and spatial-temporal aspects of gait will inform how TH prosthesis use and disuse affects the body. RESEARCH QUESTION: Does TH limb loss alter upper body asymmetries and spatial-temporal parameters during gait when wearing and not wearing a prosthesis compared to able-bodied controls? METHODS: Eight male TH limb loss participants and eight male control participants completed three gait trials at self-selected speeds. The TH limb loss group performed trials with and without their prosthesis. Arm swing, trunk angular displacement, trunk-pelvis moment, and spatial-temporal aspects were compared using non-parametric statistical analyses. RESULTS: Both TH walking conditions showed greater arm swing in the intact limb compared to the residual (p≤0.001), resulting in increased asymmetry compared to the control group (p≤0.001). Without the prosthesis, there was less trunk flexion and lateral flexion compared to the control group (p≤0.001). Maximum moments between the trunk and pelvis were higher in the TH group than the control group (p≤0.05). Spatial-temporal parameters of gait did not differ between the control group and either TH limb loss condition. SIGNIFICANCE: Prosthesis use affects upper body kinematics and kinetics, but does not significantly impact spatial-temporal aspects of gait, suggesting these are compensatory actions. Wearing a prosthesis helps achieve more normative upper body kinematics and kinetics than not wearing a prosthesis, which may help limit back pain. These findings emphasize the importance of encouraging at least passive use of prostheses for individuals with TH limb loss.

On the utility of ultrafast MS1-only proteomics in drug target discovery studies based on thermal proteome profiling method.

Advances in high-throughput high-resolution mass spectrometry and the development of thermal proteome profiling approach (TPP) have made it possible to accelerate a drug target search. Since its introduction in 2014, TPP quickly became a method of choice in chemical proteomics for identifying drug-to-protein interactions on a proteome-wide scale and mapping the pathways of these interactions, thus further elucidating the unknown mechanisms of action of a drug under study. However, the current TPP implementations based on tandem mass spectrometry (MS/MS), associated with employing lengthy peptide separation protocols and expensive labeling techniques for sample multiplexing, limit the scaling of this approach for the ever growing variety of drug-to-proteomes. A variety of ultrafast proteomics methods have been developed in the last couple of years. Among them, DirectMS1 provides MS/MS-free quantitative proteome-wide analysis in 5-min time scale, thus opening the way for sample-hungry applications, such as TPP. In this work, we demonstrate the first implementation of the TPP approach using the ultrafast proteome-wide analysis based on DirectMS1. Using a drug topotecan, which is a known topoisomerase I (TOP1) inhibitor, the feasibility of the method for identifying drug targets at the whole proteome level was demonstrated for an ovarian cancer cell line.

Beta-catenin Alterations in Post-Chemotherapy Yolk Sac Tumor, Postpubertal-Type with Enteroblastic Features.

Post-chemotherapy postpubertal-type yolk sac tumors (YST) with glandular and solid phenotypes are aggressive and commonly resistant to systemic chemotherapy. These neoplasms show morphologic features that significantly overlap with those of somatic carcinomas with "enteroblastic" or "fetal" phenotype (the preferred terminology depends on the site of origin). They often present as very late recurrences, and their diagnosis is challenging because they frequently affect patients in an age group at risk for carcinomas of somatic origin. Recently, we incidentally identified examples of post-chemotherapy glandular and solid YST with "enteroblastic" phenotypes and nuclear expression of beta-catenin, prompting us to further evaluate the prevalence of this phenomenon. We found nuclear expression of beta-catenin in 10/34 such tumors (29%). A subset of cases (n=6) with nuclear beta-catenin expression was further analyzed with a DNA sequencing panel and fluorescence in situ hybridization (FISH) for isochromosome 12p [i(12p); 5 tumors]. Sequencing identified exon 3 CTNNB1 variants in 3/6 (50%) analyzed cases and FISH was positive for i(12p) in 5/5 cases. In conclusion, a significant subset of post-chemotherapy YST with glandular/solid architecture and "enteroblastic" phenotype demonstrates beta-catenin alterations, suggesting that activation of Wnt signaling may play a role in the progression of these neoplasms. Moreover, nuclear beta-catenin expression in these tumors represents a potential diagnostic pitfall given that carcinomas of true somatic origin with overlapping morphology may also be positive for this marker.

Deciduous teeth from the New Hampshire Birth Cohort Study: Early life environmental and dietary predictors of dentin elements.

BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

Using Artificial Intelligence to Improve the Accuracy of a Wrist-Worn, Noninvasive Glucose Monitor: A Pilot Study.

BACKGROUND: Self-monitoring of glucose is important to the successful management of diabetes; however, existing monitoring methods require a degree of invasive measurement which can be unpleasant for users. This study investigates the accuracy of a noninvasive glucose monitoring system that analyses spectral variations in microwave signals. METHODS: An open-label, pilot design study was conducted with four cohorts (N = 5/cohort). In each session, a dial-resonating sensor (DRS) attached to the wrist automatically collected data every 60 seconds, with a novel artificial intelligence (AI) model converting signal resonance output to a glucose prediction. Plasma glucose was measured in venous blood samples every 5 minutes for Cohorts 1 to 3 and every 10 minutes for Cohort 4. Accuracy was evaluated by calculating the mean absolute relative difference (MARD) between the DRS and plasma glucose values. RESULTS: Accurate plasma glucose predictions were obtained across all four cohorts using a random sampling procedure applied to the full four-cohort data set, with an average MARD of 10.3%. A statistical analysis demonstrates the quality of these predictions, with a surveillance error grid (SEG) plot indicating no data pairs falling into the high-risk zones. CONCLUSIONS: These findings show that MARD values approaching accuracies comparable to current commercial alternatives can be obtained from a multiparticipant pilot study with the application of AI. Microwave biosensors and AI models show promise for improving the accuracy and convenience of glucose monitoring systems for people with diabetes.

Clinical Practice Guidelines to Support Capacity Building in Orthopaedic Surgical Outreach: An International Consensus Building Approach.

BACKGROUND: Surgical outreach to low- and middle-income countries (LMICs) by organizations from high- income countries is on the rise to help address the growing burden of conditions warranting surgery. However, concerns remain about the impact and sustainability of such outreach. Leading organizations (e.g., the World Health Organization) advocate for a capacity-building approach to ensure the safety, quality, and sustainability of the local health-care system. Despite this, to our knowledge, no guidelines exist to inform such efforts. We aimed to develop clinical practice guidelines (CPGs) to support capacity-building in orthopaedic surgical outreach utilizing a multistakeholder and international voting panel. METHODS: We followed a modified American Academy of Orthopaedic Surgeons (AAOS) CPG development process. We systematically reviewed the existing literature across 7 predefined capacity-building domains (partnership, professional development, governance, community impact, finance, coordination, and culture). A writing panel composed of 6 orthopaedic surgeons with extensive experience in surgical outreach reviewed the existing literature and developed a consensus-based CPG for each domain. We created an international voting panel of orthopaedic surgeons and administrators who have leadership roles in outreach organizations or hospitals with which outreach organizations partner. Members individually reviewed the CPGs and voted to approve or disapprove each guideline. A CPG was considered approved if >80% of panel members voted to approve it. RESULTS: An international voting panel of 14 surgeons and administrators from 6 countries approved all 7 of the CPGs. Each CPG provides recommendations for capacity-building in a specific domain. For example, in the domain of partnership, the CPG recommends the development of a documented plan for ongoing, bidirectional partnership between the outreach organization and the local team. In the domain of professional development, the CPG recommends the development of a needs-based curriculum focused on both surgical and nonsurgical patient care utilizing didactic and hands-on techniques. CONCLUSIONS: As orthopaedic surgical outreach grows, best-practice CPGs to inform capacity-building initiatives can help to ensure that resources and efforts are optimized to support the sustainability of care delivery at local sites. These guidelines can be reviewed and updated in the future as evidence that supports capacity-building in LMICs evolves.The global burden of disease warranting surgery is substantial, and morbidity and mortality from otherwise treatable conditions remain disproportionately high in low- and middle-income countries (LMICs)1,2. It is estimated that up to 2 million (about 40%) of injury-related deaths in LMICs could be avoided annually if mortality rates were reduced to the level of those in high-income countries (HICs)3. Despite this, progress toward improved access to safe, timely surgery in resource-poor areas has been slow. Historically, nongovernmental organizations (NGOs) have tried to address unmet surgical needs through short-term outreach trips; however, growing criticism has highlighted the limitations of short-term trips, including limited follow-up, an increased burden on the local workforce, and further depletion of local resources4-6. In light of ongoing concerns, public health priorities have shifted toward models that emphasize long-term capacity-building rather than short-term care delivery. Capacity-building is an approach to health-care development that builds independence through infrastructure development, sustainability, and enhanced problem-solving while taking context into account7,8.

Associations of Perinatal Metal and Metalloid Exposures with Early Child Behavioral Development Over Time in the New Hampshire Birth Cohort Study.

Research on the neurodevelopmental effects of metal(loid)s has focused mainly on outcomes assessed at one time point, even though brain development progresses over time. We investigated biomarkers of perinatal exposure to metals and changes in child behavior over time. We followed 268 participants from the prospective New Hampshire Birth Cohort Study between birth and age 5 years. We measured arsenic (As), copper (Cu), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) in toenails from 6-week-old infants. The Behavioral Symptoms Index (BSI), externalizing, and internalizing symptoms were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2) at ages 3 and 5 years. Multivariable linear regression was used to estimate associations of metals with behavior change, calculated as the difference in symptom raw scores between 3 and 5 years, in addition to the associations for symptom scores at 3 and 5 years separately. Sex-specific associations were also explored using stratified models and a sex-metal interaction term. Adjusted associations of metals and change in behavior varied by exposure and outcome. Each 1 µg/g increase in ln toenail Cu was associated with improved behavior between 3 and 5 years [BSI: ß = - 3.88 (95%CI: - 7.12, - 0.64); Externalizing problems: ß = - 2.20 (95%CI: - 4.07, - 0.33)]. Increasing Zn was associated with increased externalizing behavior over time (ß = 3.42 (95%CI: 0.60, 6.25). Sex-stratified analyses suggested more pronounced associations among boys compared to girls. Perinatal exposure to metals may alter behavioral development between ages 3 and 5 years. Findings support the need for more research on associations between metals and neurodevelopment over longer time periods.

Correction: Computer-Facilitated Screening and Brief Intervention for Alcohol Use Risk in Adolescent Patients of Pediatric Primary Care Offices: Protocol for a Cluster Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/55039.].

Bidirectional epigenetic editing reveals hierarchies in gene regulation.

CRISPR perturbation methods are limited in their ability to study non-coding elements and genetic interactions. In this study, we developed a system for bidirectional epigenetic editing, called CRISPRai, in which we apply activating (CRISPRa) and repressive (CRISPRi) perturbations to two loci simultaneously in the same cell. We developed CRISPRai Perturb-seq by coupling dual perturbation gRNA detection with single-cell RNA sequencing, enabling study of pooled perturbations in a mixed single-cell population. We applied this platform to study the genetic interaction between two hematopoietic lineage transcription factors, SPI1 and GATA1, and discovered novel characteristics of their co-regulation on downstream target genes, including differences in SPI1 and GATA1 occupancy at genes that are regulated through different modes. We also studied the regulatory landscape of IL2 (interleukin-2) in Jurkat T cells, primary T cells and chimeric antigen receptor (CAR) T cells and elucidated mechanisms of enhancer-mediated IL2 gene regulation. CRISPRai facilitates investigation of context-specific genetic interactions, provides new insights into gene regulation and will enable exploration of non-coding disease-associated variants.

A Near-Infrared Luminescent Cr(III) N-Heterocyclic Carbene Complex.

Photoluminescent coordination complexes of Cr(III) are of interest as near-infrared spin-flip emitters. Here, we explore the preparation, electrochemistry, and photophysical properties of the first two examples of homoleptic N-heterocyclic carbene complexes of Cr(III), featuring 2,6-bis(imidazolyl)pyridine (ImPyIm) and 2-imidazolylpyridine (ImPy) ligands. The complex [Cr(ImPy)3]3+ displays luminescence at 803 nm on the microsecond time scale (13.7 µs) from a spin-flip doublet excited state, which transient absorption spectroscopy reveals to be populated within several picoseconds following photoexcitation. Conversely, [Cr(ImPyIm)2]3+ is nonemissive and has a ca. 500 ps excited-state lifetime.

Risk factors predicting need for the pediatric intensive care unit (PICU) post-hematopoietic cell transplant, PICU utilization, and outcomes following HCT: a single center retrospective analysis.

Hematopoietic cell transplant (HCT) is a curative treatment for multiple malignant and non-malignant disorders. While morbidity and mortality have decreased significantly over the years, some patients still require management in the pediatric intensive care unit (PICU) during their HCT course for additional respiratory, cardiovascular, and/or renal support. We retrospectively reviewed pediatric patients (0-18 years) who underwent HCT from January 2015-December 2020 at our institution to determine risk factors for PICU care and evaluate PICU utilization and outcomes. We also assessed pulmonary function testing (PFT) data to determine if differences were noted between PICU and non-PICU patients as well as potential evolution of pulmonary dysfunction over time. Risk factors of needing PICU care were lower age, lower weight, having an underlying inborn error of metabolism, and receiving busulfan-based conditioning. Nearly half of PICU encounters involved use of each of respiratory support types including high-flow nasal cannula, non-invasive positive pressure ventilation, and mechanical ventilation. Approximately one-fifth of PICU encounters involved renal replacement therapy. Pulmonary function test results largely did not differ between PICU and non-PICU patients at any timepoint aside from individuals who required PICU care having lower DLCO scores at one-year post-HCT. Future directions include consideration of combining our data with other centers for a multi-center retrospective analysis with the goal of gathering and reporting additional multi-center data to work toward continuing to decrease morbidity and mortality for patients undergoing HCT.

Internal Catalysis in Dynamic Hydrogels with Associative Thioester Cross-Links.

Thioesters are an essential functional group in biosynthetic pathways, which has motivated their development as reactive handles in probes and peptide assembly. Thioester exchange is typically accelerated by catalysts or elevated pH. Here, we report the use of bifunctional aromatic thioesters as dynamic covalent cross-links in hydrogels, demonstrating that at physiologic pH in aqueous conditions, transthioesterification facilitates stress relaxation on the time scale of hundreds of seconds. We show that intramolecular hydrogen bonding is responsible for accelerated exchange, evident in both molecular kinetics and macromolecular stress relaxation. Drawing from concepts in the vitrimer literature, this system exemplifies how dynamic cross-links that exchange through an associative mechanism enable tunable stress relaxation without altering stiffness.

Chemical composition of extracts and fractions from Miconia ibaguensis (MELASTOMATACEAE) leaves and evaluation of biological activities.

The study aimed to assess the chemical composition of Miconia ibaguensis leaves extracts and fractions obtained from the ethanolic extract (EE), along with evaluating their antifungal, antibacterial, antidiabetic, and antioxidant activities. The ethyl acetate fraction (EAF) exhibited potent antifungal activity against Candida spp (1.95 - 3.90 µg mL-1) and potent antioxidant activity in the DPPH (1.74 ± 0.07 µg mL-1), FRAP (654.01 ± 42.09 µmol ETrolox/gsample), and ORAC (3698.88 ± 37.28 µmol ETrolox/gsample) methods. The EE displayed inhibition against the α-amylase enzyme (8.42 ± 0.05 µg mL-1). Flavonoids, hydrolysable tannins, triterpenoids, and phenolic acids, identified in the EE and fractions via (-)-HPLC-ESI-MS/MS analysis, were found to contribute to the species' biological activity potentially. These findings suggest promising avenues for further research and potential applications in pharmacology and natural products, offering new possibilities in the fight against global health issues.

Speciation of toxic metals in metal finishing filter cake by X-ray absorption spectroscopy.

The speciation of Cr, Zn, Cu and Pb in two metal finishing filter cakes (TX and ST) was investigated by X-ray absorption spectroscopy (XAS) complemented by X-ray fluorescence (XRF) and X-ray diffraction (XRD). XRF showed that concentrations of Cr, Zn, Cu and Pb were 1.4%, 0.19%, 0.20% and 0.01%, respectively, in TX, and 12.6%, 3.3%, 1.3% and 0.21% in ST. No crystalline phases were detected in TX by XRD whereas ST was dominated by calcite. Cr and Fe K edge XAS showed Cr to be trivalent and octahedrally coordinated, co-precipitated with Fe as CrxFe1-x-(oxy)hydroxides in both filter cakes. Zn, P and Ca K edge XAS showed that 2ZnCO3∙3Zn(OH)2 and Zn3(PO4)2 were the dominant zinc-containing phases, with combined tetrahedral and octahedral coordination; Zn phases were slightly more crystalline in TX than ST. Pb L3 edge X-ray absorption near edge spectroscopy (XANES) found that Pb was likely adsorbed on amorphous SiO2. Cu, Si and S K edge XAS showed that all Cu was divalent, and the dominant copper phases were found to be Cu2Cl(OH)3, Cu(OH)2 and CuSO4·5H2O for ST, whereas Cu appeared to adsorb to amorphous SiO2 for TX, which contained much less Pb. Cr is thus immobilized in the filter cakes in a phase with low solubility at environmentally feasible pH values, whereas Zn, Cu and Pb could be released when the pH decreases below 8 or above 11. These findings are significant for the development of waste management regulations and/or metal recovery methods (e.g., hydro/pyrometallurgy).

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: design and methods for three linked randomised controlled trials.

INTRODUCTION: Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients. METHODS AND ANALYSIS: Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention. ETHICS AND DISSEMINATION: The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website. TRIAL REGISTRATION NUMBERS: NCT05575128, NCT05685511, NCT05697835, pre-results.

Fertility Knowledge and Educational Experiences of Graduating Medical Students: A Multi-Institution Survey.

Objective: Our goal was to assess the fertility knowledge and educational experiences of graduating U.S. medical students to evaluate areas of improvement for future educational interventions. Design: Web-based cross-sectional survey. Subjects: Medical students graduating in 2023 from the University of Miami Miller School of Medicine (SOM), New York University (NYU) Grossman SOM, Wayne State University SOM, Perelman SOM at the University of Pennsylvania, and Mayo Clinic Alix SOM. Main Outcome Measures: Fertility-related knowledge and educational experiences of U.S. medical students in their final year of school. Results: In total, 117 students (14.4%) completed the survey. The average knowledge score was 78%. Twenty-three (22%) overestimated the age of most precipitous fertility decline, and 50 (52%) overestimated the chance of getting pregnant for a 40-year-old person with ovaries. One-third of students (30, 32%) incorrectly believe that physicians have equivalent infertility rates to the general population. Students were less cognizant of male fertility issues, incorrectly believing there was no negative impact on male fertility by age (43, 42%) among other factors. Seventy-five (81%) reported less than 5 hours of fertility-related education in medical school. Only one-third (32%) were satisfied or very satisfied with the fertility education they received. In an open-response question, students expressed interest in additional education on transgender and cancer patient care, fertility preservation, assisted reproductive technologies, and reproductive life planning in medicine. Conclusions: There is a need and an opportunity for medical education programs to enhance fertility education. Giving students and trainees the knowledge required to make informed decisions for their family-building purposes and improving their ability to counsel patients adequately should be a goal of future educational endeavors. The data collected in this study will serve as a guide for the development of fertility-related learning modules for medical students and trainees.

What time-varying network models based on functional analysis tell us about the course of a patient's problem.

Background: Relations among psychological variables are assumed to be complex and to vary over time. Personalized networks can model multivariate complex interactions. The development of time-varying networks allows to model the variation of parameters over time. Objectives: We aimed to determine the value of time-varying networks for clinical practice. Methods: We applied time-varying mixed graphical models (TV-MGM) and time-varying vector autoregressive models (TV-VAR) to intensive longitudinal data of nine participants with depressive symptoms (n = 6) or anxiety (n = 3). Results: Most of the participants showed temporal changes in network topology within the assessment period of 30 days. Time-varying networks of participants with small, medium, and large time variability in edge parameters clearly show the different temporal evolvements of dynamic interactions between variables. The case example indicates clinical utility but also limitations to the application of time-varying networks in clinical practice. Conclusion: Time-varying network models provide a data-driven and exploratory approach that could complement current diagnostic standards by reflecting interacting, often mutually reinforcing processes of mental health problems and by accounting for variation over time. They can be used to generate hypotheses for further confirmatory and clinical testing.

An online qualitative study exploring wants and needs for a cooking programme during pregnancy in the UK and Ireland.

BACKGROUND: Optimal maternal nutrition is associated with better pregnancy and infant outcomes. Culinary nutrition programmes have potential to improve diet quality during pregnancy. Therefore, this research aimed to understand the experiences of cooking and the wants and needs of pregnant women regarding a cooking and food skills programme in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Online focus group discussions with pregnant women and those who had experienced a pregnancy in the UK or ROI were conducted between February and April 2022. Two researchers conducted a thematic analysis. Seven focus groups with ROI participants (n = 24) and six with UK participants (n = 28) were completed. RESULTS: Five themes were generated. These were (1) cooking during pregnancy: barriers, motivators and solutions; (2) food safety, stress and guilt; (3) need for cooking and food skills programmes and desired content; (4) programme structure; (5) barriers and facilitators to programme participation. Overall, there was support for a programme focusing on broad food skills, including planning, food storage, using leftovers and to manage pregnancy-specific physiological symptoms such as food aversions. Participants emphasised the importance of inclusivity for a diverse range of people and lifestyles for programme design and content. CONCLUSIONS: Current findings support the use of digital technologies for culinary nutrition interventions, potentially combined with in-person sessions using a hybrid structure to enable the development of a support network.

The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.