Window Of Opportunity Research Articles

Advances in Prehospital Management of Intracerebral Hemorrhage.

Spontaneous acute intracerebral hemorrhage (ICH) is associated with greater stroke-related disability and mortality. Hematoma expansion (HME), an important treatment target in acute ICH, is time-dependent, with a greater probability of hematoma growth occurring <3 hours from ICH onset. Promising treatment options to reduce HME include early intensive blood pressure (BP) reduction and the administration of hemostatic or anticoagulant reversal agents, yet large phase III clinical trials have so far failed to show overwhelming benefit for these interventions in acute ICH. Post-hoc analyses provide evidence, however, that the therapeutic benefit of such treatments is enhanced by rapid and ultra-early intervention, likely driven in large part by attenuation of early HME. Clinical trials assessing ultra-rapid treatments (<2 hours from ICH onset), including study procedures in the ambulance setting are currently underway, and demonstrate that the prehospital phase is a critical window for ICH management and an indispensable area of ICH research. Mobile stroke units, specialized ambulances equipped with imaging capabilities can provide confirmatory diagnosis and expedite treatments, as in acute ischemic stroke. Nevertheless, multiple barriers (financial, organisational, geographical among others) hinder worldwide implementation. Emerging portable technologies as well as point-of-care measures of blood biomarkers show promise as feasible adjunct tools to discriminate ICH from AIS in the field and have the potential for widespread accessibility. Ultra-early interventions in acute ICH are likely necessary to mitigate the risk of HME, and as such, the prehospital setting is ideal to initiate time-sensitive ICH therapies. As such, reliable prehospital acute ICH detection is essential to provide disease-specific treatments. Overall, it is imperative that "Time is brain" become the mantra not only for ischemic stroke but for ICH as well, and that the promise of ultra-early therapies for ICH be translated into concrete benefits for patients with this devastating condition.

PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women

BackgroundPyrethroids are widely used pesticides and are suspected to affect children's neurodevelopment. The characterization of pyrethroid exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of pyrethroids potential effects within the concept of Developmental Origins of Health and Disease. ObjectiveThe aim of this study was to estimate maternal exposure of French pregnant women from biomonitoring data and simulate maternal and fetal internal concentrations of 3 pyrethroids (permethrin, cypermethrin and deltamethrin) using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. The estimated maternal exposures were compared to newly proposed toxicological reference values (TRV) children specific also called draft child-specific reference value to assess pyrethroid exposure risk during pregnancy i.e. during the in utero exposure period. MethodsA pregnancy-PBPK model was developed based on an existing adult pyrethroids model. The maternal exposure to each parent compound of pregnant women of the Elfe (French Longitudinal Study since Childhood) cohort was estimated by reverse dosimetry based on urinary biomonitoring data. To identify permethrin and cypermethrin contribution to their common urinary biomarkers of exposure, an exposure ratio based on biomarkers in hair was tested. Finally, exposure estimates were compared to current and draft child-specific reference values derived from rodent prenatal and postnatal exposure studies. ResultsThe main contributor to maternal pyrethroid diet intake is cis-permethrin. In blood, total internal concentrations main contributor is deltamethrin. In brain, the major contributors to internal pyrethroid exposure are deltamethrin for fetuses and cis-permethrin for mothers. Risk is identified only for permethrin when referring to the draft child-specific reference value. 2.5% of the population exceeded permethrin draft child-specific reference value. ConclusionsA new reverse dosimetry approach using PBPK model combined with human biomonitoring data in urine and hair was proposed to estimate Elfe pregnant population exposure to a pyrethroids mixture with common metabolites.

Windows of opportunity, strategic cognition and enterprise digital transformation

Purpose The purpose of this paper is to discuss how enterprises can effectively perceive and use the digital opportunities brought about by digital technologies and dynamic environments and how they can enhance their capabilities to realize digital transformation and adapt to the development of the digital economy era. Design/methodology/approach Based on the windows of opportunity theory and strategic cognition theory, this paper conducts an empirical analysis of the questionnaire data of 268 enterprises and discusses the influence of external windows of opportunity and internal windows of opportunity on the digital transformation of enterprises, as well as the action mechanism of strategic cognition and entrepreneurship. Findings The results show that both the external windows of opportunity and the internal windows of opportunity have significant positive effects on the digital transformation of enterprises. Strategic cognition plays a partial mediating role in the external windows of opportunity and the internal windows of opportunity influencing the enterprise digital transformation process. Entrepreneurship plays a positive regulatory role in the process of external windows of opportunity and internal windows of opportunity influencing strategic cognition. Originality/value This paper deepens the relationship between internal and external windows of opportunity and enterprise digital transformation and contributes a new theoretical cognition. This paper integrates the strategic cognition theory to clarify the complex process mechanism of digital transformation using external situational opportunities and internal capabilities. This paper introduces entrepreneurship into the path mechanism of digital transformation and expands the characteristics of the study of digital transformation antecedents to the individual level within the enterprise.

Feasibility of alcohol interventions in cardiology: A qualitative study of clinician perspectives in Sweden.

To identify barriers and facilitators to implementing alcohol screening and brief interventions (SBI) in cardiology services. Qualitative study. Individual, semi-structured interviews were conducted with 24 clinical cardiology staff (doctors, nurses, assistant nurses) of varying experience levels, and from various clinical settings (high dependency unit, ward, outpatient clinic), in three regions of Sweden. Reflexive thematic analysis was used, with deductive coding applying the Capability, Opportunity, Motivation (COM-B) theoretical framework. A total of 41 barriers and facilitators were identified, including twelve related to capability, nine to opportunity, and 20 to motivation. Four themes were developed: 1. Uncharted territory, where clinicians expressed a need to address alcohol use but lacked knowledge and a roadmap for implementing SBI; 2. Cardiology as a cardiovascular specialty, where tasks were prioritized according to established roles; 3. Alcohol stigma, where alcohol was reported to be a sensitive topic that staff avoid discussing with patients; 4. Window of opportunity, where staff expressed potential for implementing SBI in routine cardiology care. Findings suggest that opportunities exist for early identification and follow-up of hazardous alcohol use within routine cardiology care. Several barriers, including low knowledge, stigma, a lack of ownership, and a greater focus on other risk factors must be addressed prior to the implementation of SBI in cardiology. To meet current clinical guidelines, there is a need to increase awareness and to improve pathways to addiction care. In addition, there may be a need for clinicians dedicated to alcohol interventions within cardiology services. OSF (osf.io/hx3ts).

Maternal-driven immune education in offspring.

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal-offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota-derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue-specific immune education to offspring. We propose a "maternal-driven immune education" hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.

Prehospital stroke care in Singapore.

Due to the narrow window of opportunity for stroke therapeutics to be employed, effectiveness of stroke care systems is predicated on the efficiency of prehospital stroke systems. A robust prehospital stroke system of care that provides a rapid and well-coordinated response maximises favourable poststroke outcomes, but achieving this presents a unique set of challenges dependent on demographic and geographical circumstances. Set in the context of a highly urbanised first-world nation with a rising burden of stroke, Singapore's prehospital stroke system has evolved to reflect the environment in which it operates. This review aims to characterise the current state of prehospital stroke care in Singapore, covering prehospital aspects of the stroke survival chain from symptom onset till arrival at the emergency department. We identify areas for improvement and innovation, as well as provide insights into the possible future of prehospital stroke care in Singapore.

Nano-graphene oxide particles induce inheritable anomalies through altered gene expressions involved in oocyte maturation

The inheritable impact of exposure to graphene oxide nanoparticles (GO NPs) on vertebrate germline during critical windows of gamete development remain undetermined to date. Here, we analyzed the transgenerational effects of exposure to nano-graphene oxide particles (nGO) synthesized in house with lateral dimensions 300–600 nm and surface charge of −36.8 mV on different developmental stages of germ cells (GCs): (1) during GCs undergoing early development and differentiation, and (2) during GCs undergoing gametogenesis and maturation in adulthood. Biocompatibility analyses in Japanese medaka embryos showed lethality above 1 µg/ml and also an aberrant increase in germ cell count of both males and females at doses below the lethal dose. However, no lethality or anomalies were evident in adults up to 45 µg/ml. Long term exposure of embryos and adults for 21 days resulted in reduced fecundity. This effect was transmitted to subsequent generations, F1 and F2. Importantly, the inheritable effects of nGO in adults were pronounced at a high dose of 10 µg/ml, while 1 µg/ml showed no impact on the germline indicating lower doses used in this study to be safe. Further, expressions of selected genes that adversely affected oocyte maturation were enhanced in F1 and F2 individuals. Interestingly, the inheritance patterns differed corresponding to the stage at which the fish received the exposure.

Overnight neuronal plasticity and adaptation to emotional distress.

Expressions such as 'sleep on it' refer to the resolution of distressing experiences across a night of sound sleep. Sleep is an active state during which the brain reorganizes thesynaptic connections that form memories. This Perspective proposes a model of how sleep modifies emotional memory traces. Sleep-dependent reorganization occurs through neurophysiological events in neurochemical contexts that determine the fates of synapses to grow, to survive or to be pruned. We discuss how low levels of acetylcholine during non-rapid eye movement sleep and low levels of noradrenaline during rapid eye movement sleep provide a unique window of opportunity for plasticity in neuronal representations of emotional memories that resolves the associated distress. We integrate sleep-facilitated adaptation over three levels: experience and behaviour, neuronal circuits, and synaptic events. The model generates testable hypotheses for how failed sleep-dependent adaptation to emotional distress is key to mental disorders, notably disorders of anxiety, depression and post-traumatic stress with the common aetiology of insomnia.

An improved finegrained ciphertext policy based temporary keyword search on encrypted data for secure cloud storage

We present a temporary keyword search over sensitive and confidential health data in a cloud environment. The cloud constitutes a semi-trusted domain, making it necessary for data owners to secure their data before outsourcing it through techniques like encryption. Attribute-based keyword search techniques tend to perform a search operation using a search token generated by an authorized user. These search tokens can lead to serious privacy threats, as they can extract all ciphertexts that may have been generated along with their keyword. Therefore, restricting search tokens to extract ciphertexts generated within a time interval is a more promising solution. In this paper, we present a novel ciphertext policy fine-grained temporary keyword that prevents the misuse of these search tokens. Further, it mitigates the risk of insider threats within healthcare organizations by limiting the window of opportunity for unauthorized access to minimum. To assess the security, our proposed scheme is formally proven to be secure against Selectively Chosen Keyword Attacks in the generic bilinear group model. Additionally, we demonstrate that the encryption algorithm’s complexity is linear in relation to the number of attributes. Our scheme’s significance and practicality are revealed by the performance evaluation.

(015) Comparison of Penile Arterial Doppler-Ultrasound and Coronary Computed Tomography Angiography (CCTA) to Improve Cardiovascular Risk Assessment in Patients with Erectile Dysfunction

Abstract Introduction Erectile dysfunction (ED) has been shown to be an independent and early marker of future cardiovascular events, providing an important window of opportunity for cardiovascular preventive measures. However, there are several etiologies for ED (arterial, venous, hormonal, neurological, psychological), and earlier studies have not taken etiology into account when assessing cardiovascular risk. Arterial ED etiology share risk factors and pathophysiologic mechanisms with coronary and neurovascular diseases. Therefore, it can be assumed that patients with ED with arterial (atherosclerotic) etiology have a higher risk of future cardiovascular events than the general ED population. Objective To evaluate the predictive value of penile artery Doppler ultrasound (DUS) in cardiovascular risk assessment by comparing it with coronary atheroma screening by Coronary computed tomography angiography (CCTA) in patients with erectile dysfunction. Methods Men under 70 years of age, with ED and at least 1 cardiovascular risk factor (hypertension, dyslipidemia, diabetes, smoking, metabolic syndrome, obesity) were included. Patients with a primary cardiovascular event were excluded. Every patient had a penile DUS to assess penile arterial disease based on the maximum systolic velocity of the carvernous arteries after stimulation by intracavernous injection (A-Score), and a CCTA to assess coronary atheromatous arterial disease (CAD-RADS score). Results From October 2022 to June 2023, 72 consecutive patients were included. Mean age was 55 +/- 8.6 years. Mean IIEF5 score was 11 +/-5.3. N=34 (30%) were smokers, n=24 (33%) had hypertension, n=27 (37.5%) had diabetes, n=9 (11.1%) had obesity, n=10 (13.9%) had dyslipidemia. On penile artery DUS assessment n=62 (86%) patients had a positive A-Score. On CCTA, CAD-RADS scores were 0 in n=13 (18%) patients, 1 in n=18 (25%), 2 in n=19 (26%), 3 in n=17 (24%), and 4 in n=5 (7%) patients. We then analyzed the predictive value of A-Score as follows: 1. patients with coronary atheromatous plaques on CCTA (CAD-RADS ≥1, n=59), were significantly more likely to have a positive A-Score (n=56, 94.9%) than negative A-Score (n=13, 18%, p&amp;lt;.001, Chi2-test). The positive predictive value of the A-Score indicating penile arterial disease for the presence of coronary plaque, was 90.3%. 2. Patients with significant coronary stenosis (CAD-RADS ≥3, n=22) all patients n=22 (100%), had a positive A-Score and none a negative test (p=.026). The positive predictive value of the A-Score for the presence of significant coronary stenosis on CCTA was 100%. Conclusions The penile artery Doppler ultrasound A-Score has a good predictive value for coronary atheromatous artery disease in patients with erectile dysfunction, and allowed us to identify a sub-population at higher cardiovascular risk. When the A-Score is positive, the presence of coronary plaque is highly probable; when it is negative, the presence of significant coronary stenosis is highly unlikely. Disclosure No.

Effect of Enhanced Recovery after Surgery (ERAS) protocol on maternal outcomes following emergency caesarean delivery: A randomized controlled trial

BackgroundWith ever increasing rates of emergency caesarean deliveries (CD),incorporating the ERAS protocol might provide a perfect window of opportunity to increase maternal comfort during the postsurgical period, but also improve outcomes and facilitate optimal return of physiological function. ObjectiveTo determine whether an ERAS pathway at emergency caesarean birth would permit a reduction in postoperative length of stay and improve postoperative patient satisfaction. Material & methodsPatients undergoing emergent caesarean delivery at ≥ 34 weeks of gestation were randomized to ERAS or conventional care. The primary outcome was to compare postoperative length of hospital stay. Secondary outcome variables included first oral intake, passage of flatus/defecation, first ambulation, first urination after catheter removal and postoperative pain scores in both groups. ResultsWe randomized 142 women (71 each in ERAS versus Conventional arm) undergoing emergency cesarean delivery. Incorporation of ERAS protocol resulted in shorter length of hospital stay (73.92 ± 8.96 in conventional arm vs 53.87 ± 15.02 in ERAS arm; p value <.0001). Significant difference was seen in visual analogue scoring during initial ambulation and rest on day 0 and day 1 between ERAS and conventional arms with mean scores being lower in ERAS arm compared to Conventional arm (p value <.05). In terms of quality of life, ERAS arm had better quality of life compared to conventional arm ConclusionIncorporation of ERAS protocol in emergency caesarean definitely improves patient outcome in terms of early resumption of activities with better quality of life.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

FIGO Preconception Checklist: Preconception care for mother and baby.

The preconception period is a unique and opportunistic time in a woman's life when she is motivated to adopt healthy behaviors that will benefit her and her child, making this time period a critical "window of opportunity" to improve short- and long-term health. Improving preconception health can ultimately improve both fetal and maternal outcomes. Promoting health before conception has several beneficial effects, including an increase in seeking antenatal care and a reduction in neonatal mortality. Preconception health is a broad concept that encompasses the management of chronic diseases, including optimal nutrition, adequate consumption of folic acid, control of body weight, adoption of healthy lifestyles, and receipt of appropriate vaccinations. Use of the FIGO Preconception Checklist, which includes the key elements of optimal preconception care, will empower women and their healthcare providers to better prepare women and their families for pregnancy.

Abstract A021: Pilot study of daily exemestane in patients with Endometrial Intraepithelial Neoplasia (EIN) or grade 1 endometrial cancer

Abstract Introduction: The purpose of this study is to evaluate exemestane, an aromatase inhibitor, as a potential agent for the chemoprevention of endometrial cancer. Experimental procedures: This is a multi-center, phase IIA, single arm ‘window of opportunity’ pilot study of 25 mg per day of exemestane for 21-42 days in postmenopausal patients undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine if there is a decrease in proliferation index, measured by percent Ki-67 expression in endometrial tissue, from pre-treatment to post-exposure. Results of Ki-67 are compared with a historic control cohort of tumors from patients matched by preoperative histologic diagnosis, age, BMI category. Specimens from the historic control cohort included a preoperative endometrial biopsy as well as a surgical specimen, separated in time by less than 42 days. Secondary outcomes include comparison of Ki67 to historic controls, circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety and adverse effects. Summary of Data: Forty patients accrued to the study between January of 2018 and March of 2021. The mean age was 63 (range 52-75). Thirty-nine patients (97.5%) self identifiedself-identified as white; 1 patient (2.5%) identified as Asian. The mean BMI was 40.3 (SD 9.75, range 22.8-60.5). Preoperative diagnoses included EIN, grade 1 endometrial adenocarcinoma, and grade 2 endometrial adenocarcinoma in 11 (27.5%), 26 (65%), and 3 (7.5%) patients respectively. Thirty-nine patients (97.5%) were compliant with exemestane dosing. All patients completed the study and no patients discontinued or interrupted therapy due to treatment related adverse events. Thirty-eight patients had evaluable specimens for both pre and post-treatment Ki-67 analysis. Median Ki-67 score decreased from 40.7% [IQR (33.9%, 50.3] at baseline to 18.1% [IQR (8.8%, 31.8%)]. This represents a median absolute change from baseline of -20.4% [IQR (-29.9, -6.7), p&amp;lt;0.001]. In total, percentage of Ki-67 in tumor cells declined in 31 patients and increased in 7 patients. In the historic control cohort, patients also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7%, -1.3%), p&amp;lt;0.001]. However, the decrease in Ki-67 was greater in the study patients than the matched historic controls, with a median difference between the groups of -13.4% [IQR= (-23.3%, 6.9%), p=0.0095]. Serum estradiol levels did not change significantly between baseline and post-treatment (p=0.16). There was a small but significant increase from baseline to post-treatment in serum progesterone (0.14 ng/mL vs 0.37 ng/mL, p&amp;lt;0.001). Conclusion: In this pilot window of opportunity study, exemestane demonstrates anti-proliferative effects in endometrial intraepithelial neoplasia and low-grade endometrial cancer. This agent warrants further evaluation for the chemoprevention of endometrial cancer. Citation Format: Britt K. Erickson, Lisa Barrioullet, Rebecca C. Arend, Dina El-Rayes, Mahmoud Khalifa, Amy Skubitz, Kristin Boylan, Andrew Nelson, Bharat Thyagarajan, Thomas Havighurst, Richard Chappell, Eileen Dimond, Katina Deshong, Goli Samimi, Eva Szabo, Howard Bailey. Pilot study of daily exemestane in patients with Endometrial Intraepithelial Neoplasia (EIN) or grade 1 endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A021.

Moving beyond COVID-19: Break or continuity in the urban mobility regime?

Upon its irruption in early 2020, the COVID-19 pandemic spurred a flurry of reflection on its potential long-term effects on urban mobility. Despite widespread speculation about the likely permanent impacts of the pandemic on urban mobility, few academic accounts have re-examined the extent to which these speculations were warranted once the pandemic is over. To this end, the present article explores the retrospective perceptions of key stakeholders regarding the long-term impacts of the pandemic on the urban mobility regime, through a qualitative case study of the Barcelona Metropolitan Region, involving 22 semi-structured interviews. Approaching urban mobility through the lens of sociotechnical regimes and the multilevel perspective (MLP), we identify key perceived changes to the urban mobility regime in the aftermath of the pandemic, as well as four main obstacles to effecting transformative change towards sustainable urban mobility during the “window of opportunity” created by the pandemic. Our findings suggest that the pandemic has generally not led to significant changes in the urban mobility regime, with two key exceptions: the normalisation of teleworking, and the consolidation of tactical urbanism approaches to street redesign. These findings confirm the obduracy of the existing urban mobility regime, while pointing to promising inroads which might result in the transformation or destabilization of the current regime.

Euclid: The search for primordial features

Primordial features, in particular oscillatory signals, imprinted in the primordial power spectrum of density perturbations represent a clear window of opportunity for detecting new physics at high-energy scales. Future spectroscopic and photometric measurements from the Euclid space mission will provide unique constraints on the primordial power spectrum, thanks to the redshift coverage and high-accuracy measurement of nonlinear scales, thus allowing us to investigate deviations from the standard power-law primordial power spectrum. We consider two models with primordial undamped oscillations superimposed on the matter power spectrum described by 1 + 𝒜X sin (ωXΞX + 2 πϕX), one linearly spaced in k space with Ξlin ≡ k/k* where k* = 0.05 Mpc−1 and the other logarithmically spaced in k space with Ξlog ≡ ln(k/k*). We note that 𝒜X is the amplitude of the primordial feature, ωX is the dimensionless frequency, and ϕX is the normalised phase, where X = {lin, log}. We provide forecasts from spectroscopic and photometric primary Euclid probes on the standard cosmological parameters Ωm, 0, Ωb, 0, h, ns, and σ8, and the primordial feature parameters 𝒜X, ωX, and ϕX. We focus on the uncertainties of the primordial feature amplitude 𝒜X and on the capability of Euclid to detect primordial features at a given frequency. We also study a nonlinear density reconstruction method in order to retrieve the oscillatory signals in the primordial power spectrum, which are damped on small scales in the late-time Universe due to cosmic structure formation. Finally, we also include the expected measurements from Euclid’s galaxy-clustering bispectrum and from observations of the cosmic microwave background (CMB). We forecast uncertainties in estimated values of the cosmological parameters with a Fisher matrix method applied to spectroscopic galaxy clustering (GCsp), weak lensing (WL), photometric galaxy clustering (GCph), the cross correlation (XC) between GCph and WL, the spectroscopic galaxy clustering bispectrum, the CMB temperature and E-mode polarisation, the temperature-polarisation cross correlation, and CMB weak lensing. We consider two sets of specifications for the Euclid probes (pessimistic and optimistic) and three different CMB experiment configurations, that is, Planck, Simons Observatory (SO), and CMB Stage-4 (CMB-S4). We find the following percentage relative errors in the feature amplitude with Euclid primary probes: for the linear (logarithmic) feature model, with a fiducial value of 𝒜X = 0.01, ωX = 10, and ϕX = 0: 21% (22%) in the pessimistic settings and 18% (18%) in the optimistic settings at a 68.3% confidence level (CL) using GCsp+WL+GCph+XC. While the uncertainties on the feature amplitude are strongly dependent on the frequency value when single Euclid probes are considered, we find robust constraints on 𝒜X from the combination of spectroscopic and photometric measurements over the frequency range of (1,  102.1). Due to the inclusion of numerical reconstruction, the GCsp bispectrum, SO-like CMB reduces the uncertainty on the primordial feature amplitude by 32%–48%, 50%–65%, and 15%–50%, respectively. Combining all the sources of information explored expected from Euclid in combination with the future SO-like CMB experiment, we forecast 𝒜lin ≃ 0.010 ± 0.001 at a 68.3% CL and 𝒜log ≃ 0.010 ± 0.001 for GCsp(PS rec + BS)+WL+GCph+XC+SO-like for both the optimistic and pessimistic settings over the frequency range (1,  102.1).

Role of skin management in the prevention of atopic dermatitis and food allergy.

Food allergy is postulated to originate from cutaneous sensitization through a disrupted skin barrier, particularly in atopic dermatitis (AD). Strategies for food allergy prevention currently centre around early allergic food introduction, but there is now increasing evidence for the role of early skin barrier restoration in the form of prophylactic emollient therapy and early aggressive, proactive treatment of established AD for food allergy prevention. Research gaps that remain to be addressed include the type of emollient or anti-inflammatory medication, which confers the greatest efficacy in preventive or proactive skin treatment, respectively, the duration of therapy, and the window of opportunity for these interventions.

Abstract IA005: New directions in prevention and early detection of endometrial cancers

Abstract Most endometrial cancers and precursor lesions are preceded by postmenopausal bleeding (PMB), offering a window of opportunity for early detection and improved survival. Clinical guidelines recommend prompt evaluation of PMB to rule out endometrial cancer. Current diagnostic approaches including transvaginal ultrasound and endometrial biopsy are invasive and can be associated with discomfort and procedural pain, and we have shown that recommendations may not be consistent with underlying risk of endometrial cancer. Access to these procedures may be challenging for patients who live in rural areas or who experience other barriers to care. Current strategies may also have limited accuracy for detecting non-endometrioid cancers which are clinically aggressive, more common in Black women, and increasing in incidence and mortality in the U.S. Black women experience significant racial disparities in endometrial cancer survival and are more likely to experience diagnostic delays compared to their White counterparts. Because of the anatomical continuity of the lower genital tract, we and others have demonstrated the feasibility of pairing molecular assays with minimally invasive self-sampling approaches, such as vaginal tampons, for the detection of tumor DNA. In a recent study led by our colleagues at the Mayo Clinic, we identified over 28 methylation markers that were tested in self-collected tampon samples that showed good clinical performance for endometrial cancer detection. Such approaches can mitigate cancer disparities by offering an at-home early detection strategy to increase coverage and expand access to care. To date, few endometrial cancer studies have been conducted within diverse clinical populations. To address this gap, we designed the Discovery and Evaluation of Tests for Endometrial Cancer in Tampons (DETECT) study. DETECT is a case control study that includes patients undergoing hysterectomy for endometrial cancer and benign conditions at the University of Alabama at Birmingham (UAB). DETECT has enrolled over 700 patients to date, including over 360 with endometrial cancer (approximately 30% with non-endometrioid tumors). In this study, we collect extensive questionnaire data including information about symptoms, and novel risk factors such as feminine hygiene and hair product use. We obtain clinical information on diagnostic procedures, surgery, and treatment information from electronic medical records, and collect tampon, tissue, and blood samples from enrolled patients. In preliminary analyses, over two-thirds of participants self-collected a vaginal tampon sample, with collection varying by race (57% in Black vs. 76% in White patients). Next steps include pilot testing to compare the performance of biomarkers (somatic mutations and methylation markers) measured from tampon samples to tissue for endometrial cancer detection. Future goals of DETECT include the evaluation of endometrial cancer risk factors, biomarkers, outcomes, and disparities across the cancer continuum. Citation Format: Megan A. Clarke. New directions in prevention and early detection of endometrial cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA005.

Effectiveness of Yijinjing exercise in the treatment of early-stage knee osteoarthritis: a randomized controlled trial protocol

IntroductionKnee osteoarthritis (KOA) is still a challenging degenerative joint disease with high morbidity and disease burden. Early-stage KOA, the focus of this study, could present a Window of Opportunity to...

Type-I-interferon-responsive microglia shape cortical development and behavior

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.