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This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention. Clinical Trial Registration:NCT05577416 (ClinicalTrials.gov) Plain Language Summary Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in IDH1 or IDH2. When the IDH gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant IDH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG. Article highlights Introduction Background & rationale Adult low-grade gliomas (aLGGs) are defined by IDH1/2 mutations which lead to accumulation of 2-HG, an oncometabolite affecting tumorigenesis. 2-HG inhibits α-KG-dependent enzymes, affecting epigenetic regulation, collagen synthesis and cell signaling, hindering progenitor cell differentiation and promoting cancer. In addition, 2-HG promotes angiogenesis, an immunosuppressive tumor microenvironment and oxidative damage. aLGGs grow slowly, diffusely infiltrating the brain and are difficult to cure. Emergence of targeted mutant IDH inhibitors has shifted focus toward identifying prognostic markers and future combination studies. Current treatment of aLGG Treatment includes maximal safe surgical resection, radiation therapy and sequential chemotherapy. Early, extensive surgery improves overall survival. Active surveillance with MRI is suitable for some patients to delay side effects. Mutant IDH inhibitors for glioma Multiple mutant IDH inhibitors have shown promise in glioma. Vorasidenib (IDH1/2 inhibitor) improved progression-free survival in the INDIGO Phase III trial. Safusidenib (DS-1001b, AB-218) is an orally available small molecule inhibitor of mutant IDH1 with demonstrated brain penetration and clinical activity in Phase I trials. Perioperative trials There have been few therapeutic advances in glioma due to challenges in measuring drug penetration and pharmacodynamic (PD) evaluation. Perioperative trials, including biopsy to obtain pre-treatment tissue, are feasible and offer a means to examine the direct effects of new drugs. These studies allow evaluation of drug pharmacokinetics (PK) and PD outcomes. Objectives Hypothesis: Treatment with safusidenib following biopsy and prior to resection in newly diagnosed IDH1 mutated glioma is feasible. Estimate: >60% of screened patients completing planned investigations and procedures. Primary objective: Assess feasibility and acceptability of a perioperative study in IDH1 mutated aLGG patients. Secondary end points: Determine safusidenib toxicity, safety of two-stage surgery and biological activity by changes in 2-HG levels. Methods Participants, interventions, & outcomes Key inclusion: Adults ≥18 years with aLGG diagnosis not requiring urgent resection. Key exclusion: prior chemotherapy/radiation, cerebellar/brainstem tumors. Procedures: Open biopsy, oral safusidenib, second-stage resection, continued safusidenib post-resection. Data collection: tumor tissue, CSF and blood samples processed per protocols. PK/PD relationships: Evaluated by blood, tumor and CSF samples. Biological activity: Assessed by changes in 2-HG levels and IDH1 ctDNA. Data collection, management, & analysis Tumor tissue, CSF and blood samples collected for research. Safusidenib PK will be investigated to evaluate PK/PD relationships. Translational end points include paired whole-genome transcriptome profiling, single nuclei RNA sequencing, bulk metabolomics and DNA methylation. Spatial transcriptomics using in situ digital sequencing and spatial metabolomics on sections pre- and post-safusidenib treatment. Descriptive statistics for demographics, safety, PK, PD, efficacy and biomarker data by dose and time. Monitoring Toxicity: Monitored by adverse events, clinical tests and vital signs. Safety of surgery: 30-day morbidity and mortality recorded post-biopsy and resection. Radiological response: Determined by MRI changes and LGG-RANO criteria. Progression-free survival and time to treatment failure: Calculated from biopsy date. Conclusion Perioperative studies in aLGG offer a unique opportunity to study drug effects and are feasible, ethical and acceptable to patients. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of type-1 diabetes is on the rise, particularly in developed nations, and predominantly affects the youth. While genetic predisposition plays a substantial role, environmental factors, including alterations in the gut microbiota, are increasingly recognized as significant contributors to the disease. Methods: In this study, we utilized germ-free non-obese diabetic mice to explore the effects of microbiota colonization during early life on type-1 diabetes susceptibility. Results: Our findings reveal that microbiota introduction at birth, rather than at weaning, significantly reduces the risk of type-1 diabetes, indicating a crucial window for microbiota-mediated modulation of immune responses. This protective effect was independent of alterations in intestinal barrier function but correlated with testosterone levels in male mice. Additionally, early life colonization modulated T cell subset frequencies, particularly T helper cells and regulatory T cells, in the intestine, potentially shaping type-1 diabetes predisposition. Discussion: Our findings underscore the pivotal role of early-life microbial interactions in immune regulation and the development of autoimmune diseases. [ABSTRACT FROM AUTHOR]

It has become increasingly apparent that even mature forests are susceptible to plant invasions. However, invasive plants are often more abundant in younger forest stands. It is difficult to disentangle possible mechanisms that would explain this pattern due to the scarcity of long-term studies in successional forests. Several mechanisms have been proposed to explain patterns of invasions as forests age, including biotic resistance, window of opportunity, historical legacies, and invasion debt. We explored patterns and potential mechanisms of plant invasions over 70 years in a regenerating forest with different land-use histories in the Bolleswood Natural Area, Connecticut, USA. We examined how environmental factors related to colonization patterns of invasive and non-invasive introduced species over time, and whether these patterns were consistent with the proposed mechanisms. Non-invasive introduced species declined rapidly with canopy closure, while many invasive plants persisted or even increased over time as the forest aged. Colonization was focused in younger post-agricultural areas, although this declined with time. Dispersal distance, soil conditions, and land-use history played important roles in patterns of colonization, while the effect of shading was less clear. There was some evidence for each mechanism, but the relative importance of each mechanism was species-dependent, making generalizations about how invasive plants invade forests difficult. We found that land-use history impacted invasion more strongly than forest age, but over time even mature forests were slowly being invaded by some species. Thus, invasive species management may be required even in mature forests. [ABSTRACT FROM AUTHOR]

Background: The importance of timely diagnosis of rheumatic diseases is beyond any doubt. However, in the real practice the time from manifestation of the first symptoms to the assessment by a rheumatologist and treatment administration often exceeds the window of opportunity for disease control. At the moment, there has been no Russian-language questionnaire that would allow a primary care physician to suspect a rheumatic disease manifesting with an articular syndrome. Aim: To develop, validate and test a questionnaire to identify risk factors for joint disorders and related conditions. Methods: From November 2022 to April 2024, we performed the study on the image-based questionnaire on identification of the risk factors for joint syndromes and associated conditions (ARTROVIS), which we have developed for early detection of both joint syndromes, as well as comorbid conditions associated with elevated serum uric acid levels (hyperuricemia). The initial test version of the questionnaire was tested in a focus group of respondents (n = 20) who came for regular medical examination. Based on the results of this face validity assessment, we corrected the wording of 10 questionnaire items. At the second study step, we assessed the primary validity and reliability of the questionnaire in a group of 41 rheumatology patients. The third study step involved 828 respondents (408 men and 420 women, median age 19 [18,0; 20,0] years; 21% with joint syndromes), who came for routine medical examination. The reliability of the questionnaire, its face and discriminant validity, as well as sensitivity and specificity (the ROC analysis) were assessed from 827 questionnaires included in the final processing (one was excluded due to questionnaire completion defects). Results: The self-report questionnaire for patients (ARTROVIS) has 24 items aimed at collecting social and demographic data, identifying risk factors for non-communicable diseases, assessing genetic aspects, identifying complaints from various organ systems, providing information on medical treatments taken by the patient (non-steroid anti-inflammatory agents, diuretics, antihypertensives, glucocorticosteroids, chemotherapy and radiation therapy), as well as an additional question for women on current pregnancy pathology. The questionnaire contains visual aids (colored photos) that facilitate the detection of clinical signs of autoimmune (psoriatic arthritis, Reynolds’s syndrome) and inflammatory rheumatic disease (gout), as well as the differential diagnosis of the joint syndrome. The assessment of face validity of the questionnaire showed the total number of missed answers of 3.42%; 62.85% of the respondents gave their full answers to all items. Good discriminant validity was demonstrated. The ROC analysis showed high correlation between the questionnaire score and the presence of a joint syndrome: the area under the curve was 0.884. The Cronbach’s alfa was 0.798, which is sufficient for a medical questionnaire. Conclusion: We have performed the approbation and standardization of the questionnaire to identify risk factors for the joint syndrome and related comorbidities by assessing its validity and reliability. The ARTROVIS as a self-report questionnaire can be used in primary care as a tool enabling general practitioners and internists to decide on further patient routing to corresponding specialists.

Abstract Introducion The concept of a window of opportunity in hidradenitis suppurativa (HS) management suggests that early initiation of biological therapy leads to better outcomes, though its timing remains uncertain. Methods We conducted a retrospective observational multicenter study, including consecutive patients with moderate to severe HS who initiated secukinumab treatment following prior failure with systemic antibiotics or adalimumab. Therapeutic burden was defined as the sum of previous systemic treatment cycles and previous major surgical interventions for HS. Patients were followed up for 24 weeks. Main outcomes were safety and effectiveness, assessed through the proportion of patients achieving HS Clinical Response (HiSCR) and a 55% reduction in International HS Severity Score System (IHS4-55). Additionally, potential predictors of response to secukinumab were studied. Analysis was performed on an intention-to-treat basis. Results A total of 67 patients (33 men, 34 women) were included, with a mean age of 41.55 (11.94) years and a mean baseline IHS4 of 17.88 (11.13). The mean therapeutic burden was 6.06 (3.49). At week 24, 10.45% (7/67) of patients experienced adverse events, with three leading to treatment discontinuation. At week 24, 41.79% (28/67) of patients achieved HiSCR, and 44.78% (30/67) of patients achieved IHS4-55. HiSCR could not be calculated in 12 patients with a baseline AN count

The COVID-19 pandemic, originating as a health crisis but quickly expanding to other social spheres, had significant and asymmetric impacts across Europe, which potentially undermine territorial cohesion. Much has been written about the overall impact of the pandemic on the underlying thematic and budgetary focus of European Union-level policies with respect to territorial cohesion. However, it remains unclear to what extent policies implemented at regional and local levels in response to the crisis also contribute to territorial cohesion. To address this, we investigated the extent to which the pandemic constituted a 'window of opportunity' for developing innovative policies furthering territorial cohesion policy goals and objectives within member states, and assessed whether the crisis led to more collaborative, integrative and holistic policymaking. To this end, the research examined policy responses across 14 European regions by means of a mixed-method case study approach, including the analysis of relevant policy documents and over 100 semi-structured interviews with key stakeholders. We show that the pandemic led to the introduction of new short-term social policies to reduce socio-economic disparities produced by COVID-19 and accelerated the implementation of green and smart policies. Additionally, the crisis fostered greater collaboration between public authorities and key stakeholders, and between regional and municipal public authorities, although the long-term impact is uncertain. These findings could have policy implications for other crisis situations. Moreover, they suggest that territorial cohesion policies should be tailored to empower regions and local governments to use systemic shocks to draft and implement proactive social, economic and environmental policies. [ABSTRACT FROM AUTHOR]

Social contracts have recently re-emerged as a field of research. They can stabilize the relationship between state and society by establishing some predictability about the mutual deliverables between actors - especially if they are flexible for modifications to take account of changes in the framework conditions, the positions and preferences of their parties, and prevailing norms, values and ideologies. The question is, thus, when, why and how social contracts change. We argue that they change more continuously in countries with institutionalized mechanisms of renegotiation, such as parliamentary debates, open public discourse and interest group lobbying. These are more often democratic countries even if changes in democratic countries can also happen suddenly and unexpectedly. Autocratic countries, though, tend to be more resistant to regular change because they lack the procedures and mechanisms. This includes most countries in the Middle East and North Africa. Here, significant changes usually only take place if something unforeseen happens, such as a price shock, a pandemic, an earthquake or an invasion by a foreign country. At these ‘critical junctures’, at least one key actor in a country – often but not always the government – must react. This actor can, but does not have to, change its previous course. [ABSTRACT FROM AUTHOR]

Introducion: The concept of a window of opportunity in hidradenitis suppurativa (HS) management suggests that early initiation of biological therapy leads to better outcomes, though its timing remains uncertain. Methods: We conducted a retrospective observational multicenter study, including consecutive patients with moderate to severe HS who initiated secukinumab treatment following prior failure with systemic antibiotics or adalimumab. Therapeutic burden was defined as the sum of previous systemic treatment cycles and previous major surgical interventions for HS. Patients were followed up for 24 weeks. Main outcomes were safety and effectiveness, assessed through the proportion of patients achieving HS Clinical Response (HiSCR) and a 55% reduction in International HS Severity Score System (IHS4-55). Additionally, potential predictors of response to secukinumab were studied. Analysis was performed on an intention-to-treat basis. Results: A total of 67 patients (33 men, 34 women) were included, with a mean age of 41.55 (11.94) years and a mean baseline IHS4 of 17.88 (11.13). The mean therapeutic burden was 6.06 (3.49). At week 24, 10.45% (7/67) of patients experienced adverse events, with three leading to treatment discontinuation. At week 24, 41.79% (28/67) of patients achieved HiSCR, and 44.78% (30/67) of patients achieved IHS4-55. HiSCR could not be calculated in 12 patients with a baseline AN count < 3. A lower therapeutic burden was significantly associated with a higher likelihood of achieving HiSCR and IHS4-55 at week 24. Conclusions: Secukinumab showed safety and efficacy in real-world patients with HS, and the inverse correlation found between therapeutic burden and treatment response supports the concept of a window of opportunity, offering insights into its timing. [ABSTRACT FROM AUTHOR]

Many river reaches have transitioned to heavily vegetated systems following the regulation of their flow regime. Vegetation recruitment and survival are key to these transformations. We propose a novel predictive approach to detect how changes in the flow regime may affect conditions for successful vegetation recruitment and survival in channelized rivers with alternate bars. Our approach combines elements of existing vegetation recruitment models (Recruitment Box and Window of Opportunity) with simplified morphodynamic predictions of alternate bar migration. The approach is illustrated by applying it to a reach of the regulated Isère river, SE France, which has transitioned from migrating, unvegetated to steady, vegetated alternate bars over two decades following flow regulation associated with hydropower development. Our modelling approach identifies a strong impact of modified summer flows on vegetation recruitment since 1950 when major flow regulation began. An increase of up to 1 cm year−1 (after 1990) has occurred in the vertical extent of vegetation recruitment bands on the bars. This has been accompanied by an almost 20 m total increase (since 1950) in the horizontal extent of the recruitment bands, and a 1.5 times reduction in the frequency of high flows capable of promoting bar migration. Our modelling also suggests viable flow restoration options to limit widespread vegetation colonisation. Comparing outcomes from our modelling approach with those from the Bertagni et al. (2018) model suggests that the Isère may have been highly prone to vegetation colonisation even before flow regulation and close to some threshold for a shift from an unvegetated to a vegetated state. [ABSTRACT FROM AUTHOR]

In statistical process control, accurately estimating in-control (IC) parameters is crucial for effective monitoring. This typically requires a Phase I analysis to obtain estimates before monitoring commences. The traditional "fixed" estimate (FE) approach uses these estimates exclusively, while the "adaptive" estimate (AE) approach updates the estimates with each new observation. Such extreme criteria reflect the traditional bias-variance tradeoff in the framework of the sequential parameter learning schemes. This paper proposes an intermediate update rule that generalizes two ad hoc criteria for monitoring univariate Gaussian data, by giving a lower probability to parameter updates when an out-of-control (OC) situation is likely, therefore updating more frequently when there is no evidence of an OC scenario. The simulation study shows that this approach improves the detection power for small and early shifts, which are commonly regarded as a weakness of control charts based on fully online adaptive estimation. The paper also shows that the proposed method performs similarly to the fully adaptive procedure for larger or later shifts. The proposed method is illustrated by monitoring the sudden increase in ICU counts during the 2020 COVID outbreak in New York. [ABSTRACT FROM AUTHOR]

IntroductionThe incidence of type-1 diabetes is on the rise, particularly in developed nations, and predominantly affects the youth. While genetic predisposition plays a substantial role, environmental factors, including alterations in the gut microbiota, are increasingly recognized as significant contributors to the disease.MethodsIn this study, we utilized germ-free non-obese diabetic mice to explore the effects of microbiota colonization during early life on type-1 diabetes susceptibility.ResultsOur findings reveal that microbiota introduction at birth, rather than at weaning, significantly reduces the risk of type-1 diabetes, indicating a crucial window for microbiota-mediated modulation of immune responses. This protective effect was independent of alterations in intestinal barrier function but correlated with testosterone levels in male mice. Additionally, early life colonization modulated T cell subset frequencies, particularly T helper cells and regulatory T cells, in the intestine, potentially shaping type-1 diabetes predisposition.DiscussionOur findings underscore the pivotal role of early-life microbial interactions in immune regulation and the development of autoimmune diseases.

The document discusses the use of anakinra as a first-line monotherapy for new-onset steroid-naïve systemic juvenile idiopathic arthritis (sJIA) patients. It highlights the effectiveness of anakinra in achieving inactive disease status and prolonged remission without the need for glucocorticoids. The text emphasizes the importance of early initiation of anakinra as monotherapy in newly diagnosed sJIA patients to improve treatment outcomes and prognosis. Additionally, it mentions the need for further studies to compare anakinra monotherapy with combined treatment in sJIA patients. [Extracted from the article]

Abstract Background Children with sensitization against foods have to be orally food-challenged before eating these foods for the first time. However, the waiting time for an oral food challenge (OFC) in Germany is about 3–6 months. In contrast, there are hints that an early introduction of allergenic foods might be protective regarding the development of food allergy. The aim of this clinical trial is therefore to investigate, whether an introduction and regular consumption of small amounts of food allergens is safe and will result in an increase of tolerance in children with sensitization against food allergens with unknown clinical relevance. Methods In this randomized, placebo-controlled, double-blind, single-center trial, 138 children (8 months to 4 years of age) sensitized to the target allergen(s) hen’s egg, cow’s milk, peanuts, and/or hazelnuts with unknown clinical relevance will be randomized in a 1:1 ratio to either an active or a placebo group, daily receiving a rusk-like biscuit powder with or without the target allergen(s) for 3–6 months until an OFC will be performed in routine diagnostics. The primary endpoint is an IgE-mediated food allergy to the primary target allergen, after the interventional period. Discussion Children with sensitization against food allergens with unknown clinical relevance often have to avoid the corresponding foods for several months until an OFC is performed. Therefore, the “window of opportunity” for an early preventive introduction of allergenic foods might be missed. This trial will assess whether an introduction of small allergen amounts will favor tolerance development in these children. Trial registration German Clinical Trials Register DRKS00032769. Registered on 02 October 2023.

In this article, we analyse how different governments have dealt with situations, labelled as 'crises' in the international and national discourses. More specifically, we analyse how the Czech, Hungarian and Slovak governments framed and dealt with their social policies during the 2008 'financial crisis', the 2015 'refugee crisis', and the 2020 'Covid crisis'. We argue that sometimes governments and the mass media frame the situation as a crisis, when objectively it would be hard to argue empirically that there really was a crisis. At other times, according to objective criteria, there is ample evidence that there is indeed a crisis, but the government tries to deny it for political reasons. Despite differences in objective conditions and differences in political constellations, none of the policymakers in the three countries took advantage of the windows of opportunity that the alleged crises presented to carry out path‐changing social policy? changes. Instead, the changes we rather small and usually only temporary; thus, showing the importance of path dependency even during crisis situations. [ABSTRACT FROM AUTHOR]

La spondyloarthrite axiale est une maladie inflammatoire chronique qui touche le rachis et les articulations sacro-iliaques et peut entraîner des dommages structuraux irréversibles. Il est extrêmement important de la diagnostiquer et de démarrer un traitement rapidement pour prévenir ces lésions dans le temps, améliorer la qualité de vie et atténuer le fardeau de la maladie. Le concept de « fenêtre d'opportunité » suggère qu'une intervention précoce dans la phase réversible de la maladie peut améliorer les résultats à long terme. Cependant, on ne sait pas si ce concept peut être appliqué à la spondyloarthrite axiale. Des progrès récents dans la prise en charge de cette forme de la maladie, notamment le recours à l'IRM diagnostique ou à des thérapies avancées, semblent capables d'améliorer les résultats. Or, les conclusions des études sur l'éventualité d'une fenêtre d'opportunité dans la spondyloarthrite axiale évaluant l'impact d'un traitement précoce sur les résultats cliniques ne sont pas concluantes. L'une des raisons est l'absence de définition standardisée de la spondyloarthrite axiale débutante. Le projet ASAS (Assessment of Spondyloarthritis International Society)-SPEAR (SPondyloarthritis EARly) travaille à l'élaboration d'une définition consensuelle. Des essais comparatifs randomisés ont spécifiquement comparé un traitement mis en place dans les phases débutante et tardive de la maladie, et une définition standardisée de la spondyloarthrite axiale débutante est indispensable pour mieux comprendre les possibles bénéfices d'un traitement précoce sur l'issue clinique. De plus, il serait intéressant d'évaluer les résultats à long terme d'un traitement intervenant dans la phase débutante, notamment en ce qui concerne les dommages structuraux, pour mieux circonscrire la notion de fenêtre d'opportunité dans la spondyloarthrite axiale. Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that affects the spine and sacroiliac joints, that can lead to irreversible structural damage. Early detection and timely intervention are crucial for preventing long-term structural damage, improving quality of life, and reducing the burden of the disease. The concept of a window of opportunity suggests that an early intervention in the reversible stage of the disease can lead to improved long-term outcomes. However, it is unclear whether this concept applies in axSpA. Recent advances in axSpA management, including the use of diagnostic techniques such as magnetic resonance imaging as well as the use of advanced therapies, have shown promise in improving outcomes. However, studies investigating the potential window of opportunity in axSpA by assessing the impact of an early treatment on clinical outcomes have yielded inconclusive results. One of the reasons behind this is the lack of a standardized definition of early axSpA. The Assessment of Spondyloarthritis International Society (ASAS)-SPEAR (SPondyloarthritis EARly) project has set the ground for it by working on a consensus definition of early axSpA. Randomized controlled trials specifically focused on the comparison between treating axSpA in the early and late stages of the disease and using the standardised definition of early axSpA are essential to understand better the potential benefits of an early treatment on clinical outcomes. Additionally, it would be relevant to assess the long-term outcomes of early axSpA treatment, especially regarding structural damage, to better grasp the concept of the window of opportunity in axSpA. [ABSTRACT FROM AUTHOR]

Transplantations of organisms in aquatic ecosystems play an important role in ecological restoration and commercial practices. However, success rates of these transplantations, especially when ecosystem engineers are involved, are often low. To enhance transplantation success, the promotion of self‐facilitation between transplants that mitigate environmental stressors is crucial. Besides, spatial patterns resulting from self‐facilitation can enhance ecosystem resilience. Using blue mussels as a model organism, we explored the possibility of increasing transplantation success in a subtidal ecosystem. We used biodegradable structures ("BioShell‐SMCs") to ameliorate self‐facilitating feedback mechanisms to overcome environmental stressors in the initial post‐transplantation phase, and to increase transplantation success by implementing large‐scale spatial configurations, mimicking natural mussel bed patterns. The structures are an innovation of traditional seed mussel collectors (SMCs) used in mussel cultivation. They consist of a biodegradable net based on a compound of aliphatic polyesters, filled with empty cockle shells around a coconut fiber rope. We tested whether different spatial configurations could increase transplantation success of mussel seed: low versus high density labyrinth pattern and banded pattern. The results of this experiment showed high losses (approximately 75%), with no significant variation between configurations. The lack of migration due to unexpected retention of the biodegradable net hindered the initiation of natural aggregations, resulting in increased competition among mussels. Besides, factors such as hydrodynamic dislodgement, burial and interannual variation likely contributed to the observed losses. While the BioShell‐SMC has not demonstrated large‐scale success, this research contributes to understanding the mechanisms that underlie successful transplantation strategies in aquatic ecosystems. [ABSTRACT FROM AUTHOR]

Introduction: Vulvar lichen sclerosus (VLS) is characterized by progressive anatomical changes which become increasingly severe and irreversible. The objective of this study was to investigate if a "window of opportunity" exists in VLS, i.e., to assess if an early treatment may prevent disease progression and facilitate clearance of symptoms and/or signs. Methods: This retrospective, cohort study included VLS patients treated for the first time with a topical corticosteroid, namely with mometasone furoate 0.1% ointment, for 12 weeks (2016–2021). Scoring of subjective symptoms (global subjective score, GSS, and dyspareunia) and clinical features (global objective score [GOS] and sclerosis-scarring-atrophy) was performed at baseline (T0) and at the control visit (T1). We assessed if the achievement of clearance in GSS, GOS, sclerosis-scarring-atrophy, or dyspareunia depended on the time elapsed between VLS onset and treatment initiation. Results: Among the 168 patients (59.2 ± 13.2 years) included, the median time between VLS onset and first treatment was 14.0 months. At T1, 48.8% of patients achieved clearance of GSS, 28% of GOS and 11.9% of both GSS and GOS, 57.9% of dyspareunia, and 19.2% of sclerosis-scarring-atrophy. The logistic regression model showed that each 10-month increase in treatment initiation adversely affected the clearance of GSS while starting treatment within 6 months of disease onset was significantly associated with clearance of GOS and sclerosis-scarring-atrophy. Conclusion: Early treatment is crucial in determining a complete healing of VLS-related symptoms and signs, especially of tissue sclerosis-scarring-atrophy, which appear poorly responsive, or even unresponsive, after the earliest stages of the disease. Thus our findings provide evidence for a "window of opportunity" in VLS treatment. [ABSTRACT FROM AUTHOR]

Purpose: Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC). Methods: In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy. Results: Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53–2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant. Conclusion: No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials. [ABSTRACT FROM AUTHOR]

This document is an editorial published in Frontiers in Immunology titled "The early life window of opportunity: role of the microbiome on immune system imprinting." The editorial discusses the critical role of the developing microbiome in shaping the immune system during early life, which has long-lasting effects on health and disease. It highlights five articles that provide insights into the complex interactions between the early-life microbiome and immune system development. The articles discuss topics such as the influence of perinatal factors on microbiome composition, the effects of maternal antibiotic treatment on immune function, the impact of the microbiome on intestinal innate immune development, the consequences of neonatal antibiotic exposure on the gut-brain-immune axis, and the potential of leveraging the early-life microbiome to enhance vaccine efficacy. The editorial emphasizes the need for further research to fully understand the microbiome-immune system interaction and develop targeted interventions for optimal immune development and disease prevention. [Extracted from the article]

With the emergence of new and advanced information and telecommunication technologies, Chinese cities are encountering significant changes in their development dynamics. This study examines the spatial pattern of emerging industries under the influence of new technologies within the context of China's "Internet Plus" initiative. It constructs a theoretical framework from an evolutionary economic geography (EEG) perspective and highlights the interdependence between the Internet Plus economy and urban systems. The analysis finds that the development of Internet Plus in cities intensifies the spatial agglomeration of new economic resources, and results in industrial transformation led by only a few large cities and spatial polarization within the urban system. However, advances in Internet technologies also provide a window of opportunity for smaller cities, and local industrial bases and relevant specializations play a crucial role in this process. [ABSTRACT FROM AUTHOR]

Disponibles depuis le début des années 1950, les glucocorticoïdes (GC) font aujourd'hui partie intégrante de la prise en charge de la polyarthrite rhumatoïde (PR). Leur rapidité d'action les rend particulièrement intéressants pour le traitement des poussées ou comme agents relais dans la PR débutante. L'efficacité des GC dans la PR a été établie, à la fois pour contrôler l'activité de la maladie et pour retarder la progression des dégradations articulaires. Parallèlement à ces bénéfices, les GC ont également des effets indésirables bien identifiés. Il est généralement déconseillé d'utiliser les GC sur de longues périodes, surtout à forte dose, et les directives récentes pour la prise en charge de la PR préconisent de ne pas recourir à ces agents, ou suggèrent de ne les utiliser qu'à titre de thérapie relais. Les perceptions relatives aux effets néfastes des GC, essentiellement fondées sur des études observationnelles, demeurent. Les corticothérapies prolongées à faible dose restent très prévalentes dans la pratique clinique, et des données récentes semblent indiquer que cette stratégie présente un rapport bénéfice–risque plutôt favorable, même chez les patients âgés. Ainsi, l'objectif de parvenir à équilibrer les bénéfices et les risques du traitement de la PR par des GC est toujours quelque peu controversé. Cette revue narrative met en avant la place, historique et actuelle, des GC dans la prise en charge de la PR, et résume les éléments récents étayant leurs effets bénéfiques et néfastes. De plus, des stratégies pratiques pour l'utilisation et la diminution des GC dans la PR sont proposées. Glucocorticoids have been available since the early 1950s and have since become an integral part of the management of rheumatoid arthritis (RA). Due to their rapid effect, glucocorticoids have an appealing profile for treating flares or as ''bridging'' agents in early RA. The efficacy of glucocorticoids to treat RA has been well established, both to control disease activity and to delay the progression of joint damage. However, despite their benefits, glucocorticoids have equally well-known adverse effects. It is generally accepted that long-term use of glucocorticoids, particularly at higher doses, is not advisable, and recent guidelines for the management of RA therefore either recommend against the use of glucocorticoids or suggest using them only as bridging therapy. Perceptions on the harmful effects of glucocorticoids remain, mainly based on observational studies. Prolonged glucocorticoid therapy at low doses is still highly prevalent in clinical practice, but recent data suggested a rather favourable risk-benefit balance for this strategy, even in senior patients. Balancing the benefits and risks of treating RA with glucocorticoids thus remains a somewhat controversial topic. Therefore, this narrative review outlines the historical and current position of glucocorticoids in the management of RA, while summarising recent evidence on their beneficial and detrimental effects. Furthermore, practical strategies for the current use and tapering of glucocorticoids in RA were formulated. [ABSTRACT FROM AUTHOR]

What is addressed as growing season in terrestrial ecosystems is one of the main determinants of annual plant biomass production globally. However, there is no well‐defined concept behind. Here, we show different facets of what might be termed growing season, each with a distinct meaning: (1) the time period during which a plant or a part of it actually grows and produces new tissue, irrespective of net carbon gain (growing season sensu stricto). (2) The period defined by developmental, that is, phenological markers (phenological season). (3) The period during which vegetation as a whole achieves its annual net primary production (NPP) or a net ecosystem production (NEP), expressed as net carbon gain (productive season) and (4) the period during which plants could potentially grow based on meteorological criteria (meteorological season). We hypothesize that the duration of such a 'window of opportunity' is a strong predictor for NPP at a global scale, especially for forests. These different definitions have implications for the understanding and modelling of plant growth and biomass production. The common view that variation in phenology is a proxy for variation in productivity is misleading, often resulting in unfounded statements on potential consequences of climatic warming such as carbon sequestration. [ABSTRACT FROM AUTHOR]

Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn's response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus in utero and to the newborn via milk. But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring's response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach. [ABSTRACT FROM AUTHOR]

Abstract Background Although patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation of important information in consent forms for these trials. Methods The study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial’s consent form. The location of information in the consent forms was compared to the participants’ suggestions for placement. Results 34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the “Risks” section. 3/5(60%) consents did this. Conclusions Designing consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding.

The article considers the problem of identifying windows of opportunity for the sustainable development of the Russian industrial sector. The relevance of this article is due to the need to improve the mechanism of communication between the innovative and practical environments of the domestic industry, to identify the optimal terms and conditions for the implementation of new technical and technological solutions. Based on the analysis of the factors affecting the prospects for the practical implementation of innovations, it is shown that changing over time, they at certain times create technological windows of opportunity for enterprises with the most favorable combination of needs, readiness and capabilities of an economic entity to use the innovations proposed by developers. Their timely identification will help to improve targeting and reduce the timing of innovation. The article presents concept map of the formation of a mechanism for identifying windows of opportunity, which provides for its decomposition into three consecutive hierarchical levels – the level of analysis of influencing indicators, the level of identification of compliance of the innovation with the needs of the enterprise and its capabilities. The purpose of this work is to determine approaches to the creation of a preventive assessment mechanism and to establish the most favorable combinations of factors of technical and technological development of industrial organizations in the most appropriate, but critically short time.

We analyse how the COVID-19 pandemic crisis created the window of opportunity (WOP) in the digital industry and digital applications. These led to the leapfrogging of digital transformation in China. This was considered a major contribution to the pandemic recovery in early to mid-2020. By exploring this phenomenon, we examine alternatives for sustainable development during such turbulent circumstances mediating the destruction arisen from the crisis. We unveil the mechanisms that reveal the large-scale digitalisation that emerged as part of the response to managing the crisis. We find that during this crisis in China, the WOPs from policy, technology and demand perspectives facilitated the leapfrogging of the digital transformation in numerous social and economic areas. More importantly, we also discover that the WOPs are unevenly distributed among firms, time, and locations. Based on these results, we put forth that the COVID-19 pandemic brings a relative window of opportunity (RWOP) to society, impacting industries and firms. However, these impacts are disproportionately distributed. To the best of our knowledge, this is one of the first studies to illustrate how a social crisis leads to WOPs enhancing digital transformation. Furthermore, this also ultimately provided a coping mechanism to deal with the pandemic. [ABSTRACT FROM AUTHOR]

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Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn’s response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus in utero and to the newborn via milk. But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring’s response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach.

This study deals with the European Commission and Communication Europe 2020, which was a result of the global economic crisis of 2007–2008 and forward. Europe 2020 was an initiative to deal with the crisis by promoting smart, sustainable, and inclusive growth. The Commission addressed the crisis as an existential threat to Europe, but also as a window of opportunity to build a new prosperous region. This study explores the political entrepreneurial efforts taken by the Commission as well as assesses the outcome of reforms implemented. The Commission has achieved many targets, although some challenges remain unsolved.

Background: Although patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation of important information in consent forms for these trials. Methods: The study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial's consent form. The location of information in the consent forms was compared to the participants' suggestions for placement. Results: 34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the "Risks" section. 3/5(60%) consents did this. Conclusions: Designing consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding. [ABSTRACT FROM AUTHOR]

Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related symptoms and restoration of normal functioning. However, there is currently no consensus if an optimal strategy, upon the initiation of treatment to the proper drugs withdrawal, is enough to induce it, or whether it is a predetermined condition related to patients' intrinsic characteristics. This review focuses on two key concepts around DFR. First, we analyze patients' intrinsic factors that may increase the chance of DFR, regardless of therapeutic choices. Second, we discuss on the evidence that it can be induced thanks to adequate, extrinsic disease management. Finally, we provide a glimpse into consequences of drugs discontinuation. The early initiation of DMARD and the subsequent strict monitoring and drug adjustments are of primary importance to allow patients to achieve DFR, irrespective of initial treatment strategy. Once remission is obtained and maintained, it is possible to gradually taper and discontinue drugs with no dramatic consequences on the disease course. Among those who stop medication, ACPA-negative patients more often maintain the remission. Thus, DFR might depend on a combination of intrinsic and extrinsic factors. [ABSTRACT FROM AUTHOR]

This article describes and discusses the cooperation between police and social services when working in accordance with the so-called Icelandic model. The aim of this article is to explore what cooperation within the Icelandic model during the “window of opportunity” means for police officers and social workers discretion and their possibility to perform their work in acute cases of domestic violence in families with children. Empirical data consists of interviews with police officers and social workers. Theories of new institutionalism and street level bureaucrats are used in the analysis. Results show that the Icelandic model has led to increased cooperation between police and social workers at the crime scene. The police and social workers state that they can focus to a greater extent on carrying out what they regard as their own tasks in acute cases of domestic violence when they work according to the model. At the same time, the model has entailed increased control of their work, which has reduced the degree of discretion and possibility for professional assessments and priorities. The perception that there is a “window of opportunity” is shared by the police and the social services and they believe that coordinated efforts in the acute phase are important. [ABSTRACT FROM AUTHOR]

The coronavirus epidemic has left a deep damage on economic and social life. In the fight against the epidemic, governance at the national and international level has been proposed. The success of countries such as South Korea with governance has reinforced this proposal. In this study, the coronavirus epidemic was examined from the perspective of Kingdon's 'Multi-Stream Model', and it was discussed how the crisis was a window of opportunity for 'governance' and to what extent Turkey was able to seize this opportunity. Scientific committees, social support groups and information management, which are the main activities in the fight against coronavirus in Turkey, have been analyzed with the principles of multi-actor, participation and transparency of governance. As a result, (1) scientific committees constitute a limited example of multi-actor and participation due to the advisory board nature, the superior benefits provided by social support groups, as well as the fact that they are predominantly composed of public officials and both institutions lost their effectiveness after the crisis, (2) information management based on the ministry of health and health is an important factor in terms of transparency and participation, but the trust in transparency has weakened over time. As a result, it was concluded that the window of opportunity for the consolidation of governance in Turkey could only be evaluated in a limited way. [ABSTRACT FROM AUTHOR]

The research is aimed at building a functional model ofmarket launch process of innovative mechanical engineering products. The subject of the study was the innovative process of a machine-building enterprise. The research methodology includes a comparative analysis and analysis of dynamic series, the concept of DCOR modeling, and IDEF0 methodology. As a result of the study, the patterns of innovative development of machine-building industries in Russia have revealed. The decomposition of the DCOR model of market launch process of innovative products adapted to the machine-building industry has proposed. The levers of successful market launch of innovative products have offered. A functional model of market launch process of innovative mechanical engineering products has developed. The model has formalised in the IDEF0 notation, which in general can contribute to the opening and use of a “window of opportunity” for the implementation of breakthrough innovation. The formulated conclusions contribute to the development of the theory of innovation in the context of machine-building industry and can be applied in planning and forecasting the innovative development of industrial enterprises.

Estrogen produces several beneficial effects in healthy neurological tissues and exhibits cardioprotective effects. Hormone therapy has been widely used to treat menopausal estrogen deficiency for more than 80 years. Despite high initial expectations of cardioprotective effects, there has been substantial distrust following important randomized clinical trials, such as the Women’s Health Initiative. Subsequently, the timing of treatment in relation to the onset of menopause came under consideration and led to the proposal of the timing hypothesis, that early initial treatment is important, and benefits are lost as the timing since menopause becomes prolonged. Subsequent analyses of the Women’s Health Initiative data, together with more recent data from randomized and observational trials, consistently show reductions in coronary heart disease and mortality in younger menopausal women. Regarding cognitive function, the timing hypothesis is consistent with observations from basic and animal studies. There is some clinical evidence to support the benefits of hormonal therapy in this context, though skepticism remains due to the paucity of clinical trials of substantial length in younger menopausal women. It is likely that the effects of estrogens on cognitive performance are due to rapid mechanisms, including mechanisms that influence Ca2+ homeostasis dynamics, provide protection in a hostile environment and reduce inflammatory signals from neural tissues. In the future, inflammatory profiles accounting for early signs of pathological inflammation might help identify the ‘window of opportunity’ to use estrogen therapy for successful cognitive protection.

This paper examines whether natural disasters open a policy window of opportunity for sustainable transition in lagging regions. Bridging disaster studies and the transition management approach, the authors define the Post-Disaster Policy Window of Opportunity (PPWO) concept, as a heuristic tool to assess the acceleration of a sustainable transition generated by a shock. The paper applies PPWO to the case study of the Central Italy earthquake (2016) deploying both primary and secondary data concerning public policies designed to pursue societal challenges at regional levels. The authors examine (i) the governance scheme, (ii) the objectives, and (iii) the policy implementation strategy of the transition as agreed in a pre-disaster phase, and whether they changed during the disaster and in its aftermath. The findings highlight natural disasters per se cannot prompt a radical change to territorial development patterns in lagging regions. However, disasters' potential to spur sustainable transitiońs acceleration can be enabled through a place-based approach with a coherent vertical and horizontal policy coordination. [ABSTRACT FROM AUTHOR]

Simple Summary: Window of opportunity (WoO) trials allow the opportunity to assess the use of drugs in breast cancer research before treatment has commenced. The aim of this review of the literature is to review WoO trials in patients with oestrogen receptor-positive (ER+) breast cancer to help guide treatment. This will be useful for patients who receive drug treatment before surgery, or as an alternative to surgery in older, more frail adults. Window of opportunity (WoO) trials create the opportunity to demonstrate pharmacodynamic parameters of a drug in vivo and have increasing use in breast cancer research. Most breast cancer tumours are oestrogen receptor-positive (ER+), leading to the development of multiple treatment options tailored towards this particular tumour subtype. The aim of this literature review is to review WoO trials pertaining to the pharmacodynamic activity of drugs available for use in ER+ breast cancer in order to help guide treatment for patients receiving neoadjuvant and primary endocrine therapy. Five databases (EMBASE, Cochrane, MEDLINE, PubMed, Web of Science) were searched for eligible studies. Studies performed in treatment-naïve patients with histologically confirmed ER+ breast cancer were included if they acquired pre- and post-treatment biopsies, compared measurement of a proteomic biomarker between these two biopsies and delivered treatment for a maximum mean duration of 31 days. Fifteen studies were eligible for inclusion and covered six different drug classes: three endocrine therapies (ETs) including aromatase inhibitors (AIs), selective oestrogen receptor modulators (SERMs), selective oestrogen receptor degraders (SERDs) and three non-ETs including mTOR inhibitors, AKT inhibitors and synthetic oestrogens. Ki67 was the most frequently measured marker, appearing in all studies. Progesterone receptor (PR) and ER were the next most frequently measured markers, appearing five and four studies, respectively. All three of these markers were significantly downregulated in both AIs and SERDs; Ki67 alone was downregulated in SERMs. Less commonly assessed markers including pS6, pGSH3B, FSH and IGF1 were downregulated while CD34, pAKT and SHBG were significantly upregulated. There were no significant changes in the other biomarkers measured such as phosphate and tensin homolog (PTEN), Bax and Bcl-2.WoO studies have been widely utilised within the ER+ breast cancer subtype, demonstrating their worth in pharmacodynamic research. However, research remains focused upon routinely measured biomarkers such ER PR and Ki67, with an array of less common markers sporadically used. [ABSTRACT FROM AUTHOR]

Patients with triple-negative breast cancer (TNBC) have a relatively poor clinical outcome. The immune checkpoint inhibitor (ICI) pembrolizumab combined with chemotherapy is the current standard of care in TNBC patients with stage II and III. Monotherapy with ICIs has not been comprehensively assessed in the neoadjuvant setting in TNBC patients, given unfavorable results in metastatic trials. ICIs, however, have been tested in the window of opportunity (WOO) before surgery or standard chemotherapy-based neoadjuvant treatment. The WOO design is well suited to assess an ICI alone or in combination with other ICIs, targeted therapy, radiotherapy or cryotherapy, and measure their pharmacodynamic and clinical effect in this treatment-naive population. Some patients show a good response to ICIs in WOO studies. Biomarkers like tumor-infiltrating lymphocytes, programmed death ligand-1, and interferon-γ signature may predict activity and may identify patients likely to benefit from ICIs. Moreover, an increase in tumor-infiltrating lymphocytes, programmed death ligand-1 expression or T cell receptor expansion following administration of ICIs in the WOO setting could potentially inform of immunotherapy benefit, which would allow tailoring further treatment. This article reviews WOO trials that assessed immunotherapy in the early-stage TNBC population, and how these results could be translated to test de-escalation strategies of neoadjuvant chemotherapy and immunotherapy without compromising a patient's prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The incidence of type-1 diabetes is on the rise, particularly in developed nations, and predominantly affects the youth. While genetic predisposition plays a substantial role, environmental factors, including alterations in the gut microbiota, are increasingly recognized as significant contributors to the disease., Methods: In this study, we utilized germ-free non-obese diabetic mice to explore the effects of microbiota colonization during early life on type-1 diabetes susceptibility., Results: Our findings reveal that microbiota introduction at birth, rather than at weaning, significantly reduces the risk of type-1 diabetes, indicating a crucial window for microbiota-mediated modulation of immune responses. This protective effect was independent of alterations in intestinal barrier function but correlated with testosterone levels in male mice. Additionally, early life colonization modulated T cell subset frequencies, particularly T helper cells and regulatory T cells, in the intestine, potentially shaping type-1 diabetes predisposition., Discussion: Our findings underscore the pivotal role of early-life microbial interactions in immune regulation and the development of autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fernandez Trigo, Kalbermatter, Yilmaz and Ganal-Vonarburg.)