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In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform. NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Reptiles in the wild or as pets may act as spreaders of bacteria, viruses, fungi and parasites. However, studies on the mycobiota of these animals are scanty. This study investigates the occurrence of yeasts from the cloacal swabs of snakes of different origins and the antifungal profile of the isolated strains. A total of 180 cloacal samples of snakes were collected from Morocco (Group I: n = 68) and Italy (Group II: n = 112). Yeast species were biochemically and molecularly identified. A total of 72 yeast strains belonging to 13 genera, 8 from snakes in Group I and five from snakes in Group II were identified. The most frequently isolated species were Trichosporon asahii (22.2%) and Candida tropicalis (15.3%) from snakes in Group I and Debaryomyces spp. (16.7%) and Metahyphopichia silvanorum (11.1%) from snakes in Group II. Multiple azole and amphotericin B (AmB) resistance phenomena were detected among isolated yeasts. Azole multi drug resistance phenomena were detected among yeasts from Group I and Rhodotorula mucilaginosa from Group II, whereas AmB resistance phenomena among those from Group II. Data suggest that snakes may harbor pathogenetic yeasts, being potential reservoirs and spreaders of these organisms in the environment. Since the yeast species community from different groups of animals as well as their antifungal profile reflects the epidemiology of human yeast infections in the same geographical areas, the results indicate that snakes may be considered as sentinels for human/animal pathogenic microorganisms and bio-indicators of environmental quality., (© 2024. The Author(s).)

Background: Solitary fibrous tumors of the liver (SFTL) are rare neoplasms, whose identification and definition of malignant potential are challenging., Case Presentation: A 62-year-old patient underwent conventional imaging and CEUS to characterize an indeterminate liver lesion after other imaging techniques were inconclusive. In fact, all diagnostic techniques concluded that it was a partially fibrotic lesion, while CEUS determined its extra-hepatocellular origin and malignant potential, initially hypothesized to be a cholangiocarcinoma. Due to the possible risk of seeding following a biopsy procedure, the patient was a candidate for surgery. Subsequently, histopathological examination revealed SFTL., Conclusion: CEUS confidently characterized the malignancy and hypothesized the origin of the liver lesion, thus aiding in treatment planning., (© 2024. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Background: Whether ticagrelor may reduce periprocedural myocardial necrosis after elective percutaneous coronary intervention (PCI) in patients with and without chronic clopidogrel therapy is unclear., Objectives: This study sought to compare ticagrelor vs clopidogrel in patients with and without chronic clopidogrel therapy before undergoing elective PCI., Methods: In this prespecified analysis of the ALPHEUS (Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial, patients were defined as clopidogrel(+) and clopidogrel(-) according to the presence and absence of clopidogrel treatment for ≥7 days before PCI, respectively. The primary endpoint was the composite of PCI-related myocardial infarction and major injury as defined by the third and fourth universal definition 48 hours after PCI., Results: A total of 1,882 patients were included, 805 (42.7%) of whom were clopidogrel(+). These patients were older, had more comorbidities, and had more frequent features of complex PCI. The primary endpoint was less frequently present in clopidogrel(-) compared to clopidogrel(+) patients (32.8% vs 40.0%; OR: 0.73; 95% CI: 0.60-0.88), but no significant differences were reported for the risk of death, myocardial infarction, stroke, or transient ischemic attack at 48 hours or 30 days. Ticagrelor did not reduce periprocedural myocardial necrosis or the risk of adverse outcomes, and there was no significant interaction regarding the presence of chronic clopidogrel treatment., Conclusions: Clopidogrel-naive patients presented less periprocedural complications compared to clopidogrel(+) patients, a difference related to a lower risk profile and less complex PCI. The absence of clopidogrel at baseline did not affect the absence of a difference between ticagrelor and clopidogrel in terms of PCI-related complications supporting the use of clopidogrel as the standard of care in elective PCI in patients with or without chronic clopidogrel treatment., Competing Interests: Funding Support and Author Disclosures This trial was led by the Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION) Study Group, an Academic Research Organization based at Pitié-Salpêtrière Hospital in Paris, France. It was sponsored by Assistance Publique-Hôpitaux de Paris and was funded by an unrestricted grant from AstraZeneca. AstraZeneca was not involved in the data collection, analysis, or in the writing of the manuscript. The Steering Committee oversaw the conduct of the trial in collaboration with representatives of the study sponsor. The trial was monitored by an independent Data and Safety Monitoring Board. Data were collected and analyzed according to the predefined statistical analysis plan by academic statisticians of the ACTION group. Drs Silvain and Montalescot had full access to the data and final responsibility for the decision to submit for publication. There was no medical writing support. Dr Manzo-Silberman has received consulting fees from Bayer, Organon, and Exeltis; has received lecture fees from Bayer, BMS, Exeltis Organon, and Terumo; and has served on the adjudication board for a study for Biotronik. Dr Beygui has received consulting and lecture fees from AstraZeneca, Bristol Myers Squibb, Medtronic, Biosensors, Boston Scientific; and has received institutional research grants from Medtronic, Biosensors, Acist, and Boston Scientific. Dr Cayla has received speaker or congress fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Microport CRM, Pfizer, and Sanofi; and has received research grants/consultant fees/lectures fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Microport CRM, Pfizer, and Sanofi. Dr Rangé has received speaker and/or consulting fees from Abbott, Biotronik, and Microport. Dr Motovska has received consulting, speaker, investigator and advisory board fees from AstraZeneca, Boehringer Ingelheim, and Idorsia. Dr Zeitouni has received research grants from Federation Française de Cardiologie and Institut Servier; and has received honoraria from BMS/Pfizer, Bayer, AstraZeneca, and Novo Nordisk. Dr Vicaut has received consulting or speaker fees from Abbott, Bristol Myers Squibb, Celgene, Edwards Lifesciences, Pfizer, Sanofi, and Novartis. Dr Montalescot has received consulting or speaker fees from Abbott, Amgen, AstraZeneca, Axis, Bayer, BMS, Boehringer-Ingelheim, Boston Scientific, Cell Prothera, CSL Behring, Idorsia, Leo-Pharma, Lilly, Medtronic, Novartis, Pfizer, Quantum Genomics, Sanofi, and Terumo. Dr Silvain has received consulting and lecture or travel support from AstraZeneca, Bayer HealthCare SAS, Biotronik, Sanofi Aventis France, Abbott Medical France, SAS, and Zoll; and is a stockholder of 4P-Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and study aims Artificial Intelligence (AI) systems could make the optical diagnosis (OD) of diminutive colorectal polyps (DCPs) more reliable and objective. This study was aimed at prospectively evaluating feasibility and diagnostic performance of AI-standalone and AI-assisted OD of DCPs in a real-life setting by using a white light-based system (GI Genius, Medtronic Co, Minneapolis, Minnesota, United States). Patients and methods Consecutive colonoscopy outpatients with at least one DCP were evaluated by 11 endoscopists (5 experts and 6 non-experts in OD). DCPs were classified in real time by AI (AI-standalone OD) and by the endoscopist with the assistance of AI (AI-assisted OD), with histopathology as the reference standard. Results Of the 480 DCPs, AI provided the outcome "adenoma" or "non-adenoma" in 81.4% (95% confidence interval [CI]: 77.5-84.6). Sensitivity, specificity, positive and negative predictive value, and accuracy of AI-standalone OD were 97.0% (95% CI 94.0-98.6), 38.1% (95% CI 28.9-48.1), 80.1% (95% CI 75.2-84.2), 83.3% (95% CI 69.2-92.0), and 80.5% (95% CI 68.7-82.8%), respectively. Compared with AI-standalone, the specificity of AI-assisted OD was significantly higher (58.9%, 95% CI 49.7-67.5) and a trend toward an increase was observed for other diagnostic performance measures. Overall accuracy and negative predictive value of AI-assisted OD for experts and non-experts were 85.8% (95% CI 80.0-90.4) vs. 80.1% (95% CI 73.6-85.6) and 89.1% (95% CI 75.6-95.9) vs. 80.0% (95% CI 63.9-90.4), respectively. Conclusions Standalone AI is able to provide an OD of adenoma/non-adenoma in more than 80% of DCPs, with a high sensitivity but low specificity. The human-machine interaction improved diagnostic performance, especially when experts were involved., Competing Interests: Conflict of Interest Paggi S and Amato A: speaker honoraria from Fujifilm Co. Rondonotti E: speaker honoraria from Fujifilm Co., Medtronic Co. consultancy. Radaelli F: Speaker honoraria from Fujifilm Co; research grant from Fujifilm Co; endoscopy equipment loan from Medtronic Co. Hassan C: Medtronic Co, Fujifilm Co and Odin Co. consultancy. All the other authors declare no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values., Objective: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings., Study Design: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm 2 ]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm 2 ]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy., Results: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02)., Conclusion: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline-directed heart failure (HF) medical therapy (GDMT) and one-year survival rate in patients who are post-CS., Methods and Results: FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in-hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P <0.001 and 29% versus 37%, P <0.001, respectively). In the overall cohort, the one-year mortality rate was 23%. Triple GDMT prescription was significantly associated with a lower one-year all-cause mortality compared with non-triple GDMT (adjusted hazard ratio 0.44 [95% CI, 0.19-0.80]; P =0.007). Similarly, 2:1 propensity score matching and inverse probability treatment weighting based on the propensity score demonstrated a lower incidence of one-year mortality in the triple GDMT group. As the number of HF drugs increased, a stepwise decrease in mortality was observed (log rank; P <0.001)., Conclusions: In survivors of CS, the one-year mortality rate was significantly lower in those with triple GDMT. Therefore, this study suggests that intensive HF therapy should be considered in patients following CS.

Background and Aims: Endoscopic activity is associated with an increased risk of surgery in patients with ulcerative colitis [UC]. Transmural activity, as defined by Milan Ultrasound Criteria [MUC] > 6.2, reliably detects endoscopic activity in patients with UC. The present study aimed to assess in UC patients whether transmural severity is a better predictor of colectomy as compared to endoscopy., Methods: Consecutive adult UC patients were recruited in two IBD Referral Centres and underwent colonoscopy and intestinal ultrasound in a blinded fashion. The need for colectomy was assessed at follow-up. Univariable and multivariable logistic and Cox regression analyses were performed. Receiver operating characteristic [ROC] analysis was used to compare MUC baseline values and Mayo Endoscopic Scores [MES] in predicting colectomy risk., Results: Overall, 141 patients were enrolled, and 13 underwent colectomy in the follow-up period. Both MES (hazard ratio [HR]: 3.15, 95% confidence interval [CI]: 1.18-8.37, p = 0.02) and MUC [HR: 1.48, 95% CI: 1.19-1.76, p < 0.001] were associated with colectomy risk, but only MUC was independently associated with this event on multivariable analysis [HR: 1.46, 95% CI: 1.06-2.02, p = 0.02]. MUC was the only independent variable associated with colectomy risk in patients with clinically active disease (odds ratio [OR]: 1.53 [1.03-2.27], p = 0.03). MUC demonstrated higher accuracy than MES (area under ROC curve [AUROC] 0.83, 95% CI: 0.75-0.92 vs 0.71, 95% CI: 0.62-0.80) and better performance for predicting colectomy [p = 0.02]. The optimal MUC score cut-off value for predicting colectomy, as assessed by the Youden index, was 7.7., Conclusions: A superior predictive value was found for transmural vs endoscopic severity for colectomy risk in UC patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

While in much of the Western world snakes are feared, in the small, rural, mountainous town of Cocullo, in the middle of central Italy, snakes are annually collected and celebrated in a sacro-profane ritual. Every 1st of May, Serpari (snake catchers) capture and showcase dozens of non-venomous snakes to celebrate the ritual of San Domenico. In order to detect potential zoonotic pathogens within this unique epidemiological context, parasites and microorganisms of snakes harvested for the "festa dei serpari" ritual were investigated. Snakes (n = 112) were examined and ectoparasites collected, as well as blood and feces sampled. Ectoparasites were identified morpho-molecularly, and coprological examination conducted through direct smear and flotation. Molecular screenings were performed to identify parasites and microorganisms in collected samples (i.e., Mesostigmata mites, Anaplasma/Ehrlichia spp., Rickettsia spp., Borrelia burgdorferi sensu lato, Coxiella burnetii, Babesia/Theileria spp., Cryptosporidium spp., Giardia spp., Leishmania spp. and helminths). Overall, 28.5% (32/112) of snakes were molecularly positive for at least one parasite and/or microorganism. Endosymbiont Wolbachia bacteria were identified from Macronyssidae mites and zoonotic vector-borne pathogens (e.g., Rickettsia, Leishmania), as well as orally transmitted pathogens (i.e., Cryptosporidium, Giardia, Proteus vulgaris, Pseudomonas), were detected from blood and feces. Thus, given the central role of the snakes in the tradition of Cocullo, surveys of their parasitic fauna and associated zoonotic pathogens may aid to generate conservation policies to benefit the human-snake interactions, whilst preserving the cultural patrimony of this event., Competing Interests: The authors report there are no competing interests to declare., (Copyright: © 2024 Mendoza-Roldan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Idiopathic dilated cardiomyopathy (IDCM) is one of the most common forms of nonischemic cardiomyopathy worldwide, possibly leading to cardiogenic shock (CS). Despite this heavy burden, the outcomes of CS in IDCM are poorly reported. Based on a large registry of unselected CS, our aim was to shed light on the 1-year outcomes after CS in patients with and without IDCM. FRENSHOCK was a prospective registry including 772 patients with CS from 49 centers. The 1-year outcomes (rehospitalizations, mortality, heart transplantation [HTx], ventricular assist devices [VAD]) were analyzed and adjusted on independent predictive factors. Within 772 CS included, 78 occurred in IDCM (10.1%). Patients with IDCM had more frequent history of chronic kidney failure and implantable cardioverter-defibrillator implantation. No difference was found in 1-month all-cause mortality between groups (28.2 vs 25.8%for IDCM and others, respectively; adjusted hazard ratio 1.14 [0.73 to 1.77], p = 0.57). Patients without IDCM were more frequently treated with noninvasive ventilation and intra-aortic balloon pump. At 1 year, IDCM led to higher rates of death or cardiovascular rehospitalizations (adjusted odds ratio 4.77 [95% confidence interval 1.13 to 20.1], p = 0.03) and higher rates of HTx or VAD for patients aged <65 years (adjusted odds ratio 2.68 [1.21 to 5.91], p = 0.02). In conclusion, CS in IDCM is a very common scenario and is associated with a higher rate of 1-year death or cardiovascular rehospitalizations and a more frequent recourse to HTx or VAD for patients aged <65 years, encouraging the consideration of it as a red flag for myocardial decline and urging for a closer follow-up and earlier evaluation for advanced heart failure therapies., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aim: Celiac disease is a risk factor for osteopenia and osteoporosis. Our aim was to evaluate the possible correlation between villous atrophy extension and dual-energy X-ray absorptiometry (DXA)-derived parameters of bone status., Methods: We have retrospectively analyzed data of 47 celiac patients (36 women, 52 ± 14 years of age) who underwent video capsule endoscopy and DXA scans within 1 year of interval from 2006 to 2019. Quantitative, qualitative and geometric DXA parameters were collected only from the most recent DXA measurements., Results: . Patients were divided into three categories; the first included those with no lesions at video capsule endoscopy (23 patients), the second those with typical lesions (mucosal atrophy, mosaicism and scalloping) in less than one-third of the small bowel (SB) (16 patients) and the third those with typical lesions in more than one-third of the SB (7 patients). In the third group, bone mineral density seemed to be lower in both the lumbar spine and the hip ( P  = 0.026 and P  = 0.011, respectively). The deterioration of bone structure in patients with severe and extended SB atrophy was statistically significant ( P  = 0.032). Furthermore, bone density, structure and geometry did not correlate with the duration of the gluten-free diet. Notably, autoimmune comorbidities did not affect DXA results., Conclusion: Neither endoscopic nor histological atrophy itself can explain the deterioration of bone mineralization and structure, whereas atrophy extension appeared to be responsible for bone impairment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Prenatal ultrasound diagnosis of anorectal malformations (ARMs) is challenging and often missed as direct visualization of the anal sphincter is not routinely performed, plus the technique is operator-dependent and inaccurate, also in expert hands. Other indirect signs, such as rectosigmoid overdistension or intraluminal calcifications, are occasionally present in late pregnancy. The detection of a cyst of the lower abdomen in the first trimester may be an early sign of ARM. Here we reported our experience and a review of the literature of such cases., Material and Methods: Isolated cases of lower abdomen cysts encountered in the first trimester at the Prenatal Diagnosis Unit during the last 5 years were retrieved and compared with those found in literature. Post-natal clinical data were analyzed to check the presence and type of malformations., Results: A total of three cases of lower abdomen cysts were found in our center and 13 in literature. In our case series all the cysts spontaneously regressed and were no longer visible since the second trimester of pregnancy, while in literature this was reported in only 4 out of 13 cases. ARM was confirmed in all patients at birth or post-mortem., Conclusions: The finding of a lower abdomen cyst during the first trimester of pregnancy could be an early predictive sign of ARM, even if it disappears during pregnancy. In these cases, we suggest mentioning to the parents the possibility of an ARM during the counseling and to refer the couple to a Colorectal Center., (© 2022. The Author(s).)

Introduction: The objective of this study was to describe a cohort of fetuses with an ultrasound prenatal diagnosis of obliterated cavum septi pellucidi (oCSP) with the aim to explore the rate of associated malformations, the progression during pregnancy and the role of fetal magnetic resonance imaging (MRI)., Material and Methods: This was a retrospective multicenter international study of fetuses diagnosed with oCSP in the second trimester with available fetal MRI and subsequent ultrasound and/or fetal MRI follow-up in the third trimester. Where available, postnatal data were collected to obtain information on neurodevelopment., Results: We identified 45 fetuses with oCSP at 20.5 weeks (interquartile range 20.1-21.1). oCSP was apparently isolated at ultrasound in 89% (40/45) and fetal MRI found additional findings in 5% (2/40) of cases, including polymicrogyria and microencephaly. In the remaining 38 fetuses, fetal MRI found a variable amount of fluid in CSP in 74% (28/38) and no fluid in 26% (10/38). Ultrasound follow-up at or after 30 weeks confirmed the diagnosis of oCSP in 32% (12/38) while fluid was visible in 68% (26/38). At follow-up MRI, performed in eight pregnancies, there were periventricular cysts and delayed sulcation with persistent oCSP in one case. Among the remaining cases with normal follow-up ultrasound and fetal MRI findings, the postnatal outcome was normal in 89% of cases (33/37) and abnormal in 11% (4/37): two with isolated speech delay, and two with neurodevelopmental delay secondary to postnatal diagnosis of Noonan syndrome at 5 years in one case and microcephaly with delayed cortical maturation at 5 months in the other., Conclusions: Apparently isolated oCSP at mid-pregnancy is a transient finding with the visualization of the fluid later in pregnancy in up to 70% of cases. At referral, associated defects can be found in around 11% of cases at ultrasound and 8% at fetal MRI indicating the need for a detailed evaluation by expert physicians when oCSP is suspected., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy., Summary: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays., Key Messages: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy., (© 2023 S. Karger AG, Basel.)

How the brain represents gender identity is largely unknown, but some neural differences have recently been discovered. We used an intrinsic ignition framework to investigate whether there are gender differences in the propagation of neural activity across the whole-brain and within resting-state networks. Studying 29 trans men and 17 trans women with gender incongruence, 22 cis women, and 19 cis men, we computed the capability of a given brain area in space to propagate activity to other areas (mean-ignition), and the variability across time for each brain area (node-metastability). We found that both measurements differentiated all groups across the whole brain. At the network level, we found that compared to the other groups, cis men showed higher mean-ignition of the dorsal attention network and node-metastability of the dorsal and ventral attention, executive control, and temporal parietal networks. We also found higher mean-ignition values in cis men than in cis women within the executive control network, but higher mean-ignition in cis women than cis men and trans men for the default mode. Node-metastability was higher in cis men than cis women in the somatomotor network, while both mean-ignition and node-metastability were higher for cis men than trans men in the limbic network. Finally, we computed correlations between these measurements and a body image satisfaction score. Trans men's dissatisfaction as well as cis men's and cis women's satisfaction toward their own body image were distinctively associated with specific networks in each group. Overall, the study of the whole-brain network dynamical complexity discriminates gender identity groups, functional dynamic approaches could help disentangle the complex nature of the gender dimension in the brain., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Despite the Haber-Bosch process being more than 100 years old, only incremental improvements have been achieved until recently. Now, by combining the catalyst expertise of CLARIANT and the engineering knowledge of CASALE, a breakthrough has been realized. AmoMax®-Casale is a new ammonia synthesis catalyst jointly developed by Casale and Clariant particularly for use in Casale ammonia converters. AmoMax®-Casale is a customized evolution of the well-known, wustite-based catalyst, AmoMax® 10. While retaining the same superior resistance to ageing, poisoning and mechanical strength, AmoMax®-Casale is significantly more active. This feature allows to reduce the loop recycle rate and the loop pressure and/or to increase the ammonia production. The higher activity of AmoMax®-Casale contributes to improve the overall operating efficiency either by saving energy, or by increasing significantly the plant capacity. This article will describe in detail the successful development of AmoMax®-Casale, explain advantages and commercial benefits based on concrete plant simulations and share the start-up experience of the first commercial reference., (Copyright 2022 John D'Alessandri, Ermanno Filippi, Sergio Panza, Marvin Estenfelder, Stephan J. Reitmeier, Andreas Reitzmann, Pierdomenico Biasi, Rene Eckert. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

In the past decade, several studies have shown that Neurofeedback (NFB) by functional magnetic resonance imaging can alter the functional coupling of targeted and non-targeted areas. However, the causal mechanisms underlying these changes remain uncertain. Here, we applied a whole-brain dynamical model to estimate Effective Connectivity (EC) profiles of resting-state data acquired before and immediately after a single-session NFB training for 17 participants who underwent motor imagery NFB training and 16 healthy controls who received sham feedback. Within-group and between-group classification analyses revealed that only for the NFB group it was possible to accurately discriminate between the 2 resting-state sessions. NFB training-related signatures were reflected in a support network of direct connections between areas involved in reward processing and implicit learning, together with regions belonging to the somatomotor, control, attention, and default mode networks, identified through a recursive-feature elimination procedure. By applying a data-driven approach to explore NFB-induced changes in spatiotemporal dynamics, we demonstrated that these regions also showed decreased switching between different brain states (i.e. metastability) only following real NFB training. Overall, our findings contribute to the understanding of NFB impact on the whole brain's structure and function by shedding light on the direct connections between brain areas affected by NFB training., (© The Author(s) 2022. Published by Oxford University Press.)

Spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD) are pathologies that appear to be closely related. This study compares the characteristics of the FMD population to the non-FMD population in a SCAD cohort. It thus assesses the involvement of the FMD phenotype in a SCAD population. From the data of the French DISCO registry, we included patients with a diagnosis of SCAD and in whom a search for FMD was performed. We collected the following characteristics of this population: the clinical and angiographic presentation, the data concerning the management, and the events occurring during the follow-up. In the 373 SCADs confirmed in the DISCO registry, we obtained imaging data for 340 of them. FMD was found in 45% of cases. The mean age was higher in the FMD group, 53.2 ± 8.8 years, versus 50.1 ± 11 years in the non-FMD group. High blood pressure and postmenopausal status were significantly higher in the FMD group. Clinical presentation, angiographic data, and management were comparable. The major adverse cardiac event rate and recurrence rate were not different between the 2 groups after 1 year of follow-up. In conclusion, we confirmed a 45% prevalence of FMD in the SCAD population. The median age was higher in the FMD group, suggesting that FMD may develop over time. The rate of major adverse cardiac events and recurrence were similar in the FMD group versus the non-FMD group after 1 year of follow-up., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In the past decades, there has been a growing scientific interest in characterizing neural correlates of meditation training. Nonetheless, the mechanisms underlying meditation remain elusive. In the present work, we investigated meditation-related changes in functional dynamics and structural connectivity (SC). For this purpose, we scanned experienced meditators and control (naive) subjects using magnetic resonance imaging (MRI) to acquire structural and functional data during two conditions, resting-state and meditation (focused attention on breathing). In this way, we aimed to characterize and distinguish both short-term and long-term modifications in the brain's structure and function. First, to analyze the fMRI data, we calculated whole-brain effective connectivity (EC) estimates, relying on a dynamical network model to replicate BOLD signals' spatio-temporal structure, akin to functional connectivity (FC) with lagged correlations. We compared the estimated EC, FC, and SC links as features to train classifiers to predict behavioral conditions and group identity. Then, we performed a network-based analysis of anatomical connectivity. We demonstrated through a machine-learning approach that EC features were more informative than FC and SC solely. We showed that the most informative EC links that discriminated between meditators and controls involved several large-scale networks mainly within the left hemisphere. Moreover, we found that differences in the functional domain were reflected to a smaller extent in changes at the anatomical level as well. The network-based analysis of anatomical pathways revealed strengthened connectivity for meditators compared to controls between four areas in the left hemisphere belonging to the somatomotor, dorsal attention, subcortical and visual networks. Overall, the results of our whole-brain model-based approach revealed a mechanism underlying meditation by providing causal relationships at the structure-function level., (© 2022. The Author(s).)

Introduction: Real-world pharmacoutilization analysis of biological drugs in psoriatic arthritis (PsA) patients with the aim to evaluate biologic treatment patterns and pharmacoutilization among patients with PsA in Italy., Methods: A retrospective study was conducted using administrative databases of Italian Entities. PsA patients were included and diagnosed by hospitalization and/or an active exemption code. Two analyses were performed: a cross-sectional for treatment patterns in patients enrolled among 2017-2020, and a longitudinal study during 2015 to investigate the pharmacoutilization, in terms of persistence and monthly maintenance dosage of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Patients with or without b/tsDMARDs prescriptions before inclusion were defined as bioexperienced or naïve, respectively. An analysis on ixekizumab-treated patients (IXE patients) from the 2017-to study ending was performed., Results: PsA was diagnosed in 24,786 (2017), 27,221 (2018), 28,889 (2019), and 29,292 (2020) patients. Across 2017-2020, 31.1-40.5% of PsA patients were untreated with systemic medications, and 16.4-18.8% were under biological therapies. Among b/tsDMARD-treated patients, decreasing use of TNF-inhibitors (77.6-57.1%) and increasing IL-inhibitors (19.6-33.2%) was found across 2017-2020, respectively. Persistence to TNF-inhibitors and IL inhibitors as first-line ranged, respectively, 74.9-83.0% and 73.0-84.6%; specifically, 73.1-76.9% and 73.0-83.8% among bio-naïve, 83.3-90.0%, and 87.0% among bio-experienced. Among IXE-patients (N = 178), 55.6% were bio-naïve, while 21.9% previously used secukinumab, 12.9% adalimumab, 10.1% etanercept. During a 1-year follow-up, 6.8% of IXE patients switched therapy., Conclusions: This real-world study of PsA pharmacoutilization in Italy showed that more than one-third of patients were systemically untreated, and almost 20% were receiving biological medications. Among biological users, increasing use of IL-inhibitors and a decrease in TNF-inhibitors prescriptions over the years were found. A rather-high extent of persistency in treatment was observed. A focused analysis on IXE patients revealed over half of them to be bio-naïve, while around one-fourth were bio-experienced to IL inhibitors., (© 2022. The Author(s).)

Objectives: To evaluate the prevalence of ankylosing spondylitis (AS) and associated treatment patterns and drug utilization in real-world clinical practice in Italy., Methods: This observational study used data from administrative databases of selected Italian entities and included patients with AS diagnosis identified by ICD-9-CM and/or exemption codes. Patients without biologic disease-modifying antirheumatic drug (bDMARD) prescriptions prior to inclusion were defined bio-naïve. A cross-sectional analysis identified treatment patterns from 2016 to 2018. A longitudinal analysis investigated bDMARD utilization (persistence, switch, discontinuing treatment) among bio-naïve patients, with 2014 and 2017 as inclusion periods. Follow-up extended from first bDMARD prescription (index date) to end of data availability., Results: The prevalence of AS was 75.5 per 100,000 (88.3 per 100,000 in adults) in 2018. In total, 5,942 AS patients were identified in 2016, 6,554 in 2017, and 7,146 in 2018. bDMARDs were prescribed to 21.4% (2016), 22.0% (2017), and 16.9% (2018) of the patients. Among the 349 patients included in 2014, 9.5% switched therapies, 13.8% discontinued treatment. In 2017, 12.2% of the 262 patients included switched therapies, 27.1% discontinued treatment., Conclusions: This study provided an up-to-date prevalence of AS diagnosis in Italy. Bio-naïve patients showed an increasing tendency toward switch of therapy and discontinuation.

Background: Ventricular arrhythmias can be life-threatening complications of ST-segment elevation myocardial infarction (STEMI)., Aims: To describe the incidence, predictors and in-hospital impact of early ventricular arrhythmia (EVA, occurring

Brain dynamics have recently been shown to be modulated by rhythmic changes in female sex hormone concentrations across an entire menstrual cycle. However, many questions remain regarding the specific differences in information processing across spacetime between the two main follicular and luteal phases in the menstrual cycle. Using a novel turbulent dynamic framework, we studied whole-brain information processing across spacetime scales (i.e., across long and short distances in the brain) in two open-source, dense-sampled resting-state datasets. A healthy naturally cycling woman in her early twenties was scanned over 30 consecutive days during a naturally occurring menstrual cycle and under a hormonal contraceptive regime. Our results indicated that the luteal phase is characterized by significantly higher information transmission across spatial scales than the follicular phase. Furthermore, we found significant differences in turbulence levels between the two phases in brain regions belonging to the default mode, salience/ventral attention, somatomotor, control, and dorsal attention networks. Finally, we found that changes in estradiol and progesterone concentrations modulate whole-brain turbulent dynamics in long distances. In contrast, we reported no significant differences in information processing measures between the active and placebo phases in the hormonal contraceptive study. Overall, the results demonstrate that the turbulence framework is able to capture differences in whole-brain turbulent dynamics related to ovarian hormones and menstrual cycle stages., 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 © 2021 De Filippi, Uribe, Avila-Varela, Martínez-Molina, Gashaj, Pritschet, Santander, Jacobs, Kringelbach, Sanz Perl, Deco and Escrichs.)

During the last decades, neurofeedback training for emotional self-regulation has received significant attention from scientific and clinical communities. Most studies have investigated emotions using functional magnetic resonance imaging (fMRI), including the real-time application in neurofeedback training. However, the electroencephalogram (EEG) is a more suitable tool for therapeutic application. Our study aims at establishing a method to classify discrete complex emotions (e.g., tenderness and anguish) elicited through a near-immersive scenario that can be later used for EEG-neurofeedback. EEG-based affective computing studies have mainly focused on emotion classification based on dimensions, commonly using passive elicitation through single-modality stimuli. Here, we integrated both passive and active elicitation methods. We recorded electrophysiological data during emotion-evoking trials, combining emotional self-induction with a multimodal virtual environment. We extracted correlational and time-frequency features, including frontal-alpha asymmetry (FAA), using Complex Morlet Wavelet convolution. Thinking about future real-time applications, we performed within-subject classification using 1-s windows as samples and we applied trial-specific cross-validation. We opted for a traditional machine-learning classifier with low computational complexity and sufficient validation in online settings, the Support Vector Machine. Results of individual-based cross-validation using the whole feature sets showed considerable between-subject variability. The individual accuracies ranged from 59.2 to 92.9% using time-frequency/FAA and 62.4 to 92.4% using correlational features. We found that features of the temporal, occipital, and left-frontal channels were the most discriminative between the two emotions. Our results show that the suggested pipeline is suitable for individual-based classification of discrete emotions, paving the way for future personalized EEG-neurofeedback training., 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 © 2021 De Filippi, Wolter, Melo, Tierra-Criollo, Bortolini, Deco and Moll.)