Effect of intraovarian platelet-rich plasma injection on IVF outcomes in women with poor ovarian response: the PROVA randomized controlled trial.

STUDY QUESTION: Does intraovarian platelet-rich plasma (PRP) injection increase the number of mature oocytes obtained after controlled ovarian stimulation (COS) in young women with poor ovarian response (POR) undergoing IVF? SUMMARY ANSWER: Intraovarian PRP injection procedure does not improve mature oocyte yield after COS in women less than 38 years old with an established IVF history of POR. WHAT IS KNOWN ALREADY: POR is frequently encountered among the infertile population and the number of women seeking infertility treatment related to POR is increasing. Effective treatment options for this patient population to conceive with autologous oocytes are lacking. Case series and cohort studies suggest that intraovarian PRP injection may improve follicular recruitment in women with premature ovarian insufficiency (POI) and POR, yet robust randomized studies have not been performed to date to determine the clinical utility of this intervention. STUDY DESIGN, SIZE, DURATION: This was a multi-center randomized controlled trial (RCT) conducted at university-affiliated reproductive centers in the USA and Turkey, between January 2020 and November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients who met inclusion criteria (<38 years old, two or more prior cycles with <3 oocytes retrieved; and without single gene disorders, prior ovarian surgery, endometriomas, BMI >35 kg/m2, or severe male factor infertility) were randomized to either the PRP or control group. Patients in both groups subsequently underwent COS, oocyte retrieval, ICSI, preimplantation genetic testing for aneuploidy (PGT-A), and single euploid embryo transfer. Number of metaphase II (MII) oocytes obtained was the primary outcome. Secondary outcomes included ovarian reserve tests (antral follicle count [AFC] and anti-Müllerian hormone [AMH]), blastocyst and euploid blastocyst yields, and sustained implantation. The study was powered to detect a difference of one mature oocyte obtained at oocyte retrieval. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 83 patients met inclusion criteria and were randomized to receive autologous intraovarian PRP injection (n = 41) or to no intervention (n = 42). No significant differences were observed in number of MII oocytes retrieved per cycle (2.8 ± 2.4 vs 3.1 ± 3.3 in PRP vs control, respectively; P = 0.9), blastocysts (1.0 ± 1.3 vs 1.3 ± 2.1, P = 0.8), or euploid blastocysts (0.8 ± 1.1 vs 0.9 ± 1.6; P = 0.5). Similarly, no differences were observed in the likelihood of obtaining at least one euploid blastocyst (45% vs 37%, P = 0.4; relative risk [RR], 95% CI = 0.9, 0.6-1.2) or the rate of sustained implantation (31% vs 29%, P = 0.9; RR 1.0, 0.7-1.3). Posttreatment AFC (7.9 ± 4.5 vs 6.8 ± 4.8, P = 0.3) and AMH (0.99 ± 0.98 vs 0.7 ± 0.6, P = 0.2) were also not different between the groups. LIMITATIONS, REASONS FOR CAUTION: Results from this RCT may not be generalizable to other PRP preparations owing to heterogeneity and lack of standardization. The control groups did not undergo a sham ovarian injection, which would have been relevant had the results shown benefit of PRP injection. Only patients with POR were included in this study, and these results may not be generalizable to more severe diminution of ovarian reserve, as seen with POI. WIDER IMPLICATIONS OF THE FINDINGS: The intraovarian PRP injection procedure does not improve mature oocyte yield or other parameters of IVF outcome in women less than 38 years old with an established IVF history of POR. The results from this study do not support the use of intraovarian PRP injection in this population. STUDY FUNDING/COMPETING INTEREST(S): Departmental funds were used and no external funding was requested for this study. ES is a consultant for and receives grant funding from the Foundation for Embryonic Competence. All other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registry Identifier: NCT04163640. TRIAL REGISTRATION DATE: 15 November 2019. DATE OF FIRST PATIENT'S ENROLMENT: 24 February 2020.

When should ART workups be done: Following a tiered approach, or all on day one?

Complete ART workups should be performed before any embryo transfer.

Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide.

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.

Metacognitive Management of Attention in Online Learning.

Performance during training is a poor predictor of long-term retention. Worse yet, conditions of training that produce rapidly improving performance typically do not produce long-lasting, generalizable learning. As a result, learners and instructors alike can be misled into adopting training or educational experiences that are suboptimal for producing actual learning. Computer-based educational training platforms can counter this unfortunate tendency by providing only productive conditions of instruction-even if they are unintuitive (e.g., spacing instead of massing). The use of such platforms, however, introduces a different liability: being easy to interrupt. An assessment of this possible liability is needed given the enormous disruption to modern education brought about by COVID-19 and the subsequent widespread emergency adoption of computer-based remote instruction. The present study was therefore designed to (a) explore approaches for detecting interruptions that can be reasonably implemented by an instructor, (b) determine the frequency at which students are interrupted during a cognitive-science-based digital learning experience, and (c) establish the extent to which the pandemic and ensuing lockdowns affected students' metacognitive ability to maintain engagement with their digital learning experiences. Outliers in time data were analyzed with increasing complexity and decreasing subjectivity to identify when learners were interrupted. Results indicated that only between 1.565% and 3.206% of online interactions show evidence of learner interruption. And although classroom learning was inarguably disrupted by the pandemic, learning in the present, evidence-based platform appeared to be immune.

Long-term recreational exercise patterns in adolescents and young adults: Trajectory predictors and associations with health, mental-health, and educational outcomes.

Individual and societal factors influencing the formation of long-term recreational exercise habits during the transition from adolescence to young adulthood are not well explored. Using data from the Longitudinal Survey of Australian Youth (LSAY), a population-representative cohort study of Young People followed from age 15 to 25, we aimed to (1) model longitudinal recreational exercise trajectories from age 16 to 24, (2) examine predictors at age 15 of entering these trajectories, and (3) explore the association between the trajectories and health, mental health and educational achievement outcomes measured at the final study wave (age 25). Self-reported recreational exercise frequency data from 9353 LSAY participants were analysed using group-based trajectory modelling. We modelled the evolution of two patterns of recreational exercise behaviour: daily exercise, as per public health guidelines (Model 1); and at least once weekly exercise (Model 2). Model 1 trajectories were guideline-adherent exercisers (17.9% of the sample), never guideline exercisers (27.5%), guideline drop-outs (15.2%) and towards guideline (39.4%); Model 2 trajectories were weekly exercise (69.5% of the sample), decreasing (17.4%), increasing (4.8%), and infrequent (8.3%). For both models, at age 15, trajectory membership was predicted by gender, self-efficacy, time spent participating in sport, time spent watching TV, parental socioeconomic status, and academic literacy. At age 25, people in the guideline-adherent exerciser trajectory (model 1) reported better general health relative to other trajectories, Those in the weekly exerciser trajectory (model 2) had better general health and reduced rates of psychological distress, were happier with life and were more optimistic for the future relative to participants in less than weekly trajectory groups. Exercise-promoting interventions for Young People should specifically address the needs of females, people with low self-efficacy, reluctant exercisers, higher academic achievers, and those experiencing socioeconomic disadvantage.

PM2.5 Is Insufficient to Explain Personal PAH Exposure.

To understand how chemical exposure can impact health, researchers need tools that capture the complexities of personal chemical exposure. In practice, fine particulate matter (PM2.5) air quality index (AQI) data from outdoor stationary monitors and Hazard Mapping System (HMS) smoke density data from satellites are often used as proxies for personal chemical exposure, but do not capture total chemical exposure. Silicone wristbands can quantify more individualized exposure data than stationary air monitors or smoke satellites. However, it is not understood how these proxy measurements compare to chemical data measured from wristbands. In this study, participants wore daily wristbands, carried a phone that recorded locations, and answered daily questionnaires for a 7-day period in multiple seasons. We gathered publicly available daily PM2.5 AQI data and HMS data. We analyzed wristbands for 94 organic chemicals, including 53 polycyclic aromatic hydrocarbons. Wristband chemical detections and concentrations, behavioral variables (e.g., time spent indoors), and environmental conditions (e.g., PM2.5 AQI) significantly differed between seasons. Machine learning models were fit to predict personal chemical exposure using PM2.5 AQI only, HMS only, and a multivariate feature set including PM2.5 AQI, HMS, and other environmental and behavioral information. On average, the multivariate models increased predictive accuracy by approximately 70% compared to either the AQI model or the HMS model for all chemicals modeled. This study provides evidence that PM2.5 AQI data alone or HMS data alone is insufficient to explain personal chemical exposures. Our results identify additional key predictors of personal chemical exposure.

Predicting personal PAH exposure using high dimensional questionnaire and wristband data.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a class of pervasive environmental pollutants with a variety of known health effects. While significant work has been completed to estimate personal exposure to PAHs, less has been done to identify sources of these exposures. Comprehensive characterization of reported sources of personal PAH exposure is a critical step to more easily identify individuals at risk of high levels of exposure and for developing targeted interventions based on source of exposure. OBJECTIVE: In this study, we leverage data from a New York (NY)-based birth cohort to identify personal characteristics or behaviors associated with personal PAH exposure and develop models for the prediction of PAH exposure. METHODS: We quantified 61 PAHs measured using silicone wristband samplers in association with 75 questionnaire variables from 177 pregnant individuals. We evaluated univariate associations between each compound and questionnaire variable, conducted regression tree analysis for each PAH compound and completed a principal component analysis of for each participant's entire PAH exposure profile to determine the predictors of PAH levels. RESULTS: Regression tree analyses of individual compounds and exposure mixture identified income, time spent outdoors, maternal age, country of birth, transportation type, and season as the variables most frequently predictive of exposure.

Addition of rapamycin or co-culture with cumulus cells from younger reproductive age women does not improve rescue in vitro oocyte maturation or euploidy rates in older reproductive age women.

Both spontaneously conceived pregnancies and those achieved using assisted reproduction decline with advancing maternal age. In this study, we tested if rapamycin and/or cumulus cells (CCs) from young donors could improve oocyte maturation and euploidy rates of germinal vesicle (GV) stage oocytes obtained from older women of reproductive age. A total of 498 GVs from 201 women >38 years (40.6 ± 1.8, mean ± SD) were included. GVs were randomly assigned into five groups for rescue IVM: control (with no CCs and no rapamycin); with autologous CCs; with autologous CCs and rapamycin; with CCs from young women (<35 years); and with CCs from young women and rapamycin. After 24 h of culture, the first polar body (PB) was biopsied in metaphase II oocytes, and the cytogenetic constitution was assessed using next-generation sequencing for both oocytes and PBs. Comparable maturation rates were found (56.2%, 60.0%, 46.5%, 51.7%, and 48.5% for groups 1-5, respectively; P = 0.30). Similarly, comparable euploidy rates were observed in the five groups (41.5%, 37.8%, 47.2%, 43.6%, and 47.8% for Groups 1-5, respectively; P = 0.87). Our findings indicate that rescue IVM is effective for obtaining mature euploid oocytes in older women of reproductive age, and that incubation with rapamycin or CCs obtained from young donors does not improve the maturation or euploidy rate.

Concurrent assessment of diffusive and advective PAH movement strongly affected by temporal and spatial changes.

Chemical movement influences exposure, remediation and interventions. Understanding chemical movement in addition to chemical concentrations at contaminated sites is critical to informed decision making. Using seepage meters and passive sampling devices we assessed both diffusive and advective flux of bioavailable polycyclic aromatic hydrocarbons (PAHs) at three time points, across two seasons, at a former creosote site in St. Helens, Oregon, United States. To our knowledge, this is the first time both diffusive and advective fluxes have been measured simultaneously at a contaminated site. Concentrations of 39 parent PAHs were determined by gas chromatography triple quadrupole mass spectrometry. Across both seasons and all sites, diffusive flux of PAHs was up to three orders of magnitude larger than advective flux. Release of PAHs from sediments and water were identified, likely from legacy contamination, as well as deposition from the air into the site from contemporary and other sources. The majority of PAH movement was comprised of three and four ring PAHs. Chemical movement on the site was found to be spatially and temporally variable. Volatilization decreased and atmospheric deposition increased from summer to fall. At the locations with higher levels of contamination, sum PAH release from sediments decreased by more than two orders of magnitude from summer to late fall. These data reflect the spatial heterogeneity and temporal variability of this site and demonstrate the importance of seasonality in assessing chemical movement at contaminated sites. Results from this study can inform future legacy site assessments to optimize remediation strategies and assess remediation effectiveness.

Oocyte rescue in-vitro maturation does not adversely affect chromosome segregation during the first meiotic division.

RESEARCH QUESTION: Does rescue in-vitro maturation (IVM) in the presence or absence of cumulus cells, affect the progress of meiosis I, compared with oocytes that mature in vivo? DESIGN: This prospective study was conducted in a university-affiliated fertility centre. Ninety-five young oocyte donors (mean age 25.57 ± 4.47) with a normal karyotype and no known fertility problems were included. A total of 390 oocytes (116 mature metaphase II [MII] and 274 immature oocytes) were analysed. The immature oocytes underwent rescue IVM in the presence of cumulus cells (CC; IVM+CC; n = 137) or without them (IVM-CC; n = 137), and IVM rate was calculated. Chromosome copy number analysis using next-generation sequencing (NGS) was performed on all rescue IVM oocytes reaching MII as well as those that were mature at the time of initial denudation (in-vivo-matured oocytes [IVO]). RESULTS: Maturation rates were similar in IVM+CC and IVM-CC oocytes (62.8 versus 71.5%, P = 0.16). Conclusive cytogenetic results were obtained from 65 MII oocytes from the IVM+CC group, 87 from the IVM-CC group, and 99 from the IVO group. Oocyte euploidy rates for the three groups were similar, at 75.4%, 83.9% and 80.8%, respectively (P = 0.42). CONCLUSIONS: The results suggest that culture of germinal vesicle and metaphase I oocytes in the presence of cumulus cells does not improve rates of IVM. In general, the process of rescue IVM does not appear to alter the frequency of oocytes with a normal chromosome copy number.

Analytical Validation of the PreciseDx Digital Prognostic Breast Cancer Test in Early-Stage Breast Cancer.

BACKGROUND: PreciseDx Breast (PDxBr) is a digital test that predicts early-stage breast cancer recurrence within 6-years of diagnosis. MATERIALS AND METHODS: Using hematoxylin and eosin-stained whole slide images of invasive breast cancer (IBC) and artificial intelligence-enabled morphology feature array, microanatomic features are generated. Morphometric attributes in combination with patient's age, tumor size, stage, and lymph node status predict disease free survival using a proprietary algorithm. Here, analytical validation of the automated annotation process and extracted histologic digital features of the PDxBr test, including impact of methodologic variability on the composite risk score is presented. Studies of precision, repeatability, reproducibility and interference were performed on morphology feature array-derived features. The final risk score was assessed over 20-days with 2-operators, 2-runs/day, and 2-replicates across 8-patients, allowing for calculation of within-run repeatability, between-run and within-laboratory reproducibility. RESULTS: Analytical validation of features derived from whole slide images demonstrated a high degree of precision for tumor segmentation (0.98, 0.98), lymphocyte detection (0.91, 0.93), and mitotic figures (0.85, 0.84). Correlation of variation of the assay risk score for both reproducibility and repeatability were less than 2%, and interference from variation in hematoxylin and eosin staining or tumor thickness was not observed demonstrating assay robustness across standard histopathology preparations. CONCLUSION: In summary, the analytical validation of the digital IBC risk assessment test demonstrated a strong performance across all features in the model and complimented the clinical validation of the assay previously shown to accurately predict recurrence within 6-years in early-stage invasive breast cancer patients.

Epichloë fungal endophyte interactions in perennial ryegrass (Lolium perenne L.) modified to accumulate foliar lipids for increased energy density.

BACKGROUND: Commercial cultivars of perennial ryegrass infected with selected Epichloë fungal endophytes are highly desirable in certain pastures as the resulting mutualistic association has the capacity to confer agronomic benefits (such as invertebrate pest deterrence) largely due to fungal produced secondary metabolites (e.g., alkaloids). In this study, we investigated T2 segregating populations derived from two independent transformation events expressing diacylglycerol acyltransferase (DGAT) and cysteine oleosin (CO) genes designed to increase foliar lipid and biomass accumulation. These populations were either infected with Epichloë festucae var. lolii strain AR1 or Epichloë sp. LpTG-3 strain AR37 to examine relationships between the introduced trait and the endophytic association. Here we report on experiments designed to investigate if expression of the DGAT + CO trait in foliar tissues of perennial ryegrass could negatively impact the grass-endophyte association and vice versa. Both endophyte and plant characters were measured under controlled environment and field conditions. RESULTS: Expected relative increases in total fatty acids of 17-58% accrued as a result of DGAT + CO expression with no significant difference between the endophyte-infected and non-infected progeny. Hyphal growth in association with DGAT + CO expression appeared normal when compared to control plants in a growth chamber. There was no significant difference in mycelial biomass for both strains AR1 and AR37, however, Epichloë-derived alkaloid concentrations were significantly lower on some occasions in the DGAT + CO plants compared to the corresponding null-segregant progenies, although these remained within the reported range for bioactivity. CONCLUSIONS: These results suggest that the mutualistic association formed between perennial ryegrass and selected Epichloë strains does not influence expression of the host DGAT + CO technology, but that endophyte performance may be reduced under some circumstances. Further investigation will now be required to determine the preferred genetic backgrounds for introgression of the DGAT + CO trait in combination with selected endophyte strains, as grass host genetics is a major determinant to the success of the grass-endophyte association in this species.

Neuroanatomical differences in Latinx children from rural farmworker families and urban non-farmworker families and related associations with pesticide exposure.

Exposure to pesticides in humans may lead to changes in brain structure and function and increase the likelihood of experiencing neurodevelopmental disorders. Despite the potential risks, there is limited neuroimaging research on the effects of pesticide exposure on children, particularly during the critical period of brain development. Here we used voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) from magnetic resonance images (MRI) to investigate neuroanatomical differences between Latinx children (n = 71) from rural, farmworker families (FW; n = 48) and urban, non-farmworker families (NFW; n = 23). Data presented here serves as a baseline for our ongoing study examining the longitudinal effects of living in a rural environment on neurodevelopment and cognition in children. The VBM analysis revealed that NFW children had higher volume in several distinct regions of white matter compared to FW children. Tract-based spatial statistics (TBSS) of DTI data also indicated NFW children had higher fractional anisotropy (FA) in several key white matter tracts. Although the difference was not as pronounced as white matter, the VBM analysis also found higher gray matter volume in selected regions of the frontal lobe in NFW children. Notably, white matter and gray matter findings demonstrated a high degree of overlap in the medial frontal lobe, a brain region predominantly linked to decision-making, error processing, and attention functions. To gain further insights into the underlying causes of the observed differences in brain structure between the two groups, we examined the association of organochlorine (OC) and organophosphate (OP) exposure collected from passive dosimeter wristbands with brain structure. Based on our previous findings within this data set, demonstrating higher OC exposure in children from non-farmworker families, we hypothesized OC might play a critical role in structural differences between NFW and FW children. We discovered a significant positive correlation between the number of types of OC exposure and the structure of white matter. The regions with significant association with OC exposure were in agreement with the findings from the FW-NFW groups comparison analysis. In contrast, OPs did not have a statistically significant association with brain structure. This study is among the first multimodal neuroimaging studies examining the brain structure of children exposed to agricultural pesticides, specifically OC. These findings suggest OC pesticide exposure may disrupt normal brain development in children, highlighting the need for further neuroimaging studies within this vulnerable population.

Recommendations for Developing a Telemedicine Strategy for Botswana: A Meta-Synthesis.

Botswana is developing its eHealth capacity using a National eHealth Strategy. However, that strategy overlooks telemedicine, a potential solution for many healthcare challenges. For telemedicine to benefit Botswana, a telemedicine-specific strategy is required. While establishing a national strategy is a sovereign responsibility, guidance and recommendations can be provided. Using published resources specific to Botswana, key health-related issues were identified. These issues were matched with suitable telemedicine activities and delivery approaches. Recommendations were then derived from these for use in an effective telemedicine-specific strategy for Botswana. From 28 health-related issues, 6 were prioritised. Three telemedicine activities were identified (clinical services, education, and behaviour change), and one delivery approach was chosen (store-and-forward) because they align well with current needs, infrastructure, and mobile phone user capabilities. Since telemedicine has been proven to be effective, efficient, and cost-effective when implemented correctly, this knowledge and experience, plus a recognised strategy development framework, has led to evidence-based recommendations. Specific telemedicine options were identified as examples. As confidence grows, telemedicine options can be expanded to address additional clinical needs and explore alternative activities and delivery options. The recommendations can help the government develop a telemedicine-specific strategy that aligns with the National eHealth Strategy while actively promoting and supporting the adoption and system integration of straightforward telemedicine interventions. This foundation will facilitate the future expansion of telemedicine initiatives for the benefit of all Batswana.