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PurposeTo evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy.MethodsCases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis.ResultsThree hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09).ConclusionWomen with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery.Trial registrationClinical trial registration number: NCT03354793.

Abstract A network of endometriosis experts from 16 Italian academic departments and teaching hospitals distributed all over the country made a critical appraisal of the available evidence and definition of 10 suggestions regarding measures to be de-implemented. Strong suggestions were made only when high-quality evidence was available. The aim was to select 10 low-value medical interventions, characterized by an unfavorable balance between potential benefits, potential harms, and costs, which should be discouraged in women with endometriosis. The following suggestions were agreed by all experts: do not suggest laparoscopy to detect and treat superficial peritoneal endometriosis in infertile women without pelvic pain symptoms; do not recommend controlled ovarian stimulation and IUI in infertile women with endometriosis at any stage; do not remove small ovarian endometriomas (diameter <4 cm) with the sole objective of improving the likelihood of conception in infertile patients scheduled for IVF; do not remove uncomplicated deep endometriotic lesions in asymptomatic women, and also in symptomatic women not seeking conception when medical treatment is effective and well tolerated; do not systematically request second-level diagnostic investigations in women with known or suspected non-subocclusive colorectal endometriosis or with symptoms responding to medical treatment; do not recommend repeated follow-up serum CA-125 (or other currently available biomarkers) measurements in women successfully using medical treatments for uncomplicated endometriosis in the absence of suspicious ovarian cysts; do not leave women undergoing surgery for ovarian endometriomas and not seeking immediate conception without post-operative long-term treatment with estrogen–progestins or progestins; do not perform laparoscopy in adolescent women (<20 years) with moderate–severe dysmenorrhea and clinically suspected early endometriosis without prior attempting to relieve symptoms with estrogen–progestins or progestins; do not prescribe drugs that cannot be used for prolonged periods of time because of safety or cost issues as first-line medical treatment, unless estrogen–progestins or progestins have been proven ineffective, not tolerated, or contraindicated; do not use robotic-assisted laparoscopic surgery for endometriosis outside research settings. Our proposal is to better address medical and surgical approaches to endometriosis de-implementing low-value interventions, with the aim to prevent unnecessary morbidity, limit psychological distress, and reduce the burden of treatment avoiding medical overuse and allowing a more equitable distribution of healthcare resources.

Neutron detection is nowadays mostly based on 3 He gas detectors, but its shortage and the continuous upgrades of the neutron facilities require new devices to perform experiments with maximum performances. This work presents a new detector based on the Gas Electron Multiplier (GEM) combined with several boron layers. This detector combines the features of GEM technology with the properties of boron as a neutron converter and the device is produced to sustain high neutron fluxes with high detection efficiency. The detector has been characterised at the ISIS Pulsed Neutron and Muon Source (UK). Based on the analysis of our results, the detector has shown a good response to thermal and epithermal neutrons reaching a detection efficiency of 16% at 1.8 Å (25 meV). The good detection efficiency (even increasable with the addition of further boron GEM foils) and the good time resolution, make the detector a unique device for the neutron techniques. In particular, its use can easily be envisaged in techniques involving neutron transmission measurements, that require high fluxes impinging on the detectors, with the added bonus of a 2D-resolved capability due to the padded anode.

The RFX-mod2 device, the upgraded version of the previous RFX-mod with a modified magnetic boundary, is presently under realization and will start to be operated in 2025. Significant upgrades of the diagnostic capabilities have been proposed and are under development. These include a largely increased number of in-vessel magnetic and electrostatic sensors, a new fast reciprocating manipulator for the exploration of the edge plasma in a wide range of experimental conditions, the improved Thomson scattering and soft x-ray diagnostics system for a detailed determination of the behavior of the electron temperature profile, new dedicated systems for the space and time resolved analysis of x-ray spectra and neutron rate, a reflectometric diagnostic for real-time determination of plasma position, two diagnostics devoted to the imaging of light impurities and influxes behavior along with arrays of halo current sensors. These diagnostic upgrades will be accompanied by a significant effort to improve the control of the electron density and of the impurity influxes by means of proper treatment of plasma facing components with in-vessel fixed electrodes distributed over the first wall. The described advancements will allow a deeper understanding of physics phenomena in the wide variety of magnetic configurations, including the tokamak, the reversed-field pinch and the Ultra-low q, which can be produced in RFX-mod2 thanks to its flexibility and unique MHD control capabilities.

Purpose: The aim of part one of this EU-US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programmes, non-operative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures will be presented in a part II article. Methods: This consensus followed the European Society for Sports Traumatology and Arthroscopy (ESSKA)’s “formal consensus” methodology. For this combined ESSKA, American Orthopedic Society for Sports Medicine and American Academy of Sports Physical Therapy initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (US and 13 European countries), including orthopaedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature and proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations, reaching a final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to address the geographical adaptability. Results: The overall level of evidence in the literature was low. Of the 19 questions (leading to 29 statements), 1 received a Grade A of recommendation, 2 a Grade B, 9 a Grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1–9). The global mean rating was 8.4 ± 0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion-based rehabilitation protocol, based on milestones rather than a time-based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion-based milestones. Conclusion: Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence: Level I, consensus.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial 1 , 2 , 3 , 4 – 5 . The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer. Malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division.

Purpose: Part II of this consensus aimed to provide recommendations for the prevention of meniscus injuries, nonoperative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures. Methods: This consensus followed the European Society of Knee Surgery, Sports Traumatology and Arthroscopy (ESSKA) formal consensus methodology. For this combined ESSKA—American Orthopedic Society for Sports Medicine (AOSSM)—American Academy of Sports Physical Therapy (AASPT) initiative, 67 experts from 14 countries, including orthopedic surgeons and physiotherapists, were involved. The 26 Steering Group members established guiding questions, screened the existing evidence, and proposed statements, and provided Grades of recommendations. The 41 Rating Group members assessed the statements according to a Likert scale (1–9). Final documents were assessed by an international peer review group for geographical adaptability. Results: Low to moderate scientific level of evidence was available, so that grades of recommendations were low (3 Grade A ratings, 4 Grade B, 3 Grade C and 13 Grade D), underlining the relevance of this consensus. One strong and 17 relative agreements with overall median of 8 (8–9) and a mean of 7.92 ± 0.37 were achieved for 23 statements on 18 questions. Prevention of meniscus injuries is possible with general knee injury reduction programs and through avoidance of certain activities. Non-operative treatment including physical therapy is the first line approach for degenerative meniscus lesions and may be an option for some acute tears. Return to sports after meniscus tear surgery should be both criterion-based and timebased. Patient reported outcomes in combination with performance-based measures are recommended to evaluate the rehabilitation process. Conclusion: This international EU–US consensus established recommendations for prevention strategies, describes rehabilitation of nonoperated patients and of patients after partial meniscectomy, meniscus repair and meniscus reconstruction, and establishes return to sport criteria. These updated and structured recommendations may be applied by surgeons and physiotherapists. Level of Evidence: Level I, consensus.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

A new position-sensitive thermal neutron detector based on boron-coated converters has been developed as an alternative to today’s standard 3 He -based technology for application to thermal neutron scattering. The key elements of the development are the boron-coated GEM foils (Sauli in Nucl Instrum Methods Phys Res Sect A Accel Spectrom Detect Assoc Equip 386:531, 1997) that are used as a multi-layer neutron converter via the 10 B ( n , α ) 7 Li reaction together with an efficient collection of the produced secondary electrons. This paper reports the test performed on a 3 layers converter prototype coupled to a GEMPix detector (Murtas in Radiat Meas 138:106421, 2020), carried out in order to study the possibility to produce a large-scale multi-layer neutron detector capable to reach high detection efficiency with high spatial resolution and able to sustain the high neutron flux expected in the new neutron spallation source under development like the ESS.

BackgroundUveal melanoma (UM) is a rare tumor characterized by mutually exclusive activating mutations in GNAQ in GNA11, followed by secondary events in BAP1, SF3B1 and EIF1AX. Notably, a large subset of patients presents with copy-loss of chromosome 3 (monosomy 3), which is highly associated with metastatic progression in late-stage disease. Monosomy 3 tumors demonstrate a marked resistance to chemotherapy, targeted therapeutics, and immunotherapy, despite successes observed in cutaneous melanoma.Informing on the biology underlying chromosome 3 copy-loss, and its impact on the tumor microenvironment, is critical towards directing future efforts in targeted therapeutics and immunotherapy. Current limited insight can be attributed to both lack of: (a) preclinical models, and (b) in-depth characterization of paired primary and metastatic tumors in patients.MethodsTo address this, we first induced chromosome 3 copy-loss through CRISPR-based centromere targeting in a well characterized Disomy 3 UM cell line. Disomy 3 (D3) and Monosomy 3 (M3) clones derived from these efforts have enabled us to develop patient derived xenograft (PDX) models to compare D3 and M3 behavior in paired primary and metastatic settings.Additionally, we identified and collected a range of match-paired (primary and metastatic) clinical UM samples across multiple patients.Leveraging these unique samples, we applied spatial transcriptomics to inform on tumor intrinsic and extrinsic features of progressive UM, identifying gene signatures of disease advancement and deconvoluting the evolving tumor microenvironment.ResultsInvestigation of metastatic UM tumor heterogeneity in our models enables us to characterize unique features of phenotypically transformed clones (e.g. depigmentation and growth advantage) (figure 1). We also adapted existing methodology to infer chromosomal copy number events from spatial transcriptomics data to our PDX system, overcoming the lack of same-species microenvironment controls. We complement our preclinical analyses with an investigation of spatial heterogeneity in a patient cohort of paired primary and metastatic tumors (figure 2). Leveraging single-cell deconvolution in this paired dataset, we captured unique immune microenvironments in primary vs. metastatic tumors. Additionally, we integrated our preclinical tumor intrinsic signatures to pair differential gene expression signatures of tumor sub-clones with differential immune cell populations.ConclusionsOur methodology allows for deep characterization of sub-clonal heterogeneity in primary and metastatic settings and informs on the unique microenvironmental heterogeneity underlying invasiveness and outgrowth of M3 tumors. More broadly, comparing these preclinical and patient tumors provides an opportunity to expand on our knowledge of metastatic disease drivers and derive prognostic signatures associated with poor survival and lack of response to immunotherapy.Abstract 1498 Figure 1Spatial Transcriptomics Informs on Liver Outgrowth Phenotypes in Engineered UM Preclinical Models. (A) Spatial slides of two Disomy 3 tumors in the mouse liver and matched clustering following the removal of mouse background demonstrated with differential pigrnentahon and tumor size. (B) Corresponding copy number inference of the D3.5_2 slide demonstrates our ability to identify subclones based on copy number heterogeneity. (C) Spatial slides of two Monosomy 3 tumors in the mouse liver and matched clustering following the removal of mouse background. (D) Corresponding copy number inference of the M3.8_2 slide unable to accurately capture copy number in the absence of microenvironment as a normal control demonstrated by chromosome 3 being inferred as copy neutralAbstract 1498 Figure 2Spatial Transcriptomics on Uveal Melanoma Clinical Samples — Paired Primary Eye and Liver Metastases. (A) Spatial slide with matched primary eye and liver sections from Patient #1. (B) Spatial slide with matched primary eye and liver sections from Patient #2. (C) Predicted cell types observed in matched primary and liver tumors of Patient #1. (D) Predicted cell types in matched primary and liver tumors of Patient #2