Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

Three-Dimensional Geometric Analysis of Viabahn VBX Bridging Stent Grafts in Fenestrated Endovascular Aortic Repair: A Multicenter, Retrospective Cohort Study.

PURPOSE: The primary aim of this study was to assess the 3-dimensional flare geometry of the Gore Viabahn VBX balloon-expandable covered stent (BECS) after fenestrated endovascular aortic repair (FEVAR) and to determine and visualize BECS-associated complications. METHODS: This multicenter retrospective study included patients who underwent FEVAR between 2018 and 2022 in 3 vascular centers participating in the VBX Expand Registry. Patients with at least one visceral artery treated with the VBX and with availability of 2 post-FEVAR computed tomography angiography (CTA) scans (follow-up [FU] 1: 0-6 months; FU2: 9-24 months) were included. The flare geometry of the VBX, including flare-to-fenestration distance, flare-to-fenestration diameter ratio, flare angle, and apposition with the target artery were assessed using a vascular workstation and dedicated CTA applied software. RESULTS: In total, 90 VBX BECS were analyzed in 43 FEVAR patients. The median CTA FU for FU1 and FU2 was 35 days (interquartile range [IQR], 29-51 days) and 14 months (IQR, 13-15 months), respectively. The mean flare-to-fenestration distance was 5.6±2.0 mm on FU1 and remained unchanged at 5.7±2.0 mm on FU2 (p=.417). The flare-to-fenestration diameter ratio was 1.19±0.17 on FU1 and remained unchanged at 1.21±0.19 (p=.206). The mean apposition length was 18.6±5.3 mm on FU1 and remained 18.6±5.3 mm (p=.550). The flare angle was 31°±15° on FU1 and changed to 33°±16° (p=.009). On FU1, the BECS-associated complication rate was 1%, and the BECS-associated reintervention rate was 0%. On FU2, the BECS-associated complication rate was 3%, and the BECS-associated reintervention rate was 1%. CONCLUSIONS: The flare geometry of the VBX bridging stent did not change significantly during 14 months follow-up in this study. Three-dimensional geometric analysis of the flare may contribute to identify the origin of endoleaks and occlusions, but this should be confirmed in a larger study including enough patients and BECS to compare complicated and uncomplicated cases. CLINICAL IMPACT: The three-dimensional flare geometry of the Gore Viabahn VBX BECS was assessed on the first and second postoperative CTA scans, and geometrical changes during this period were identified. For BECS that were diagnosed with a type 3c endoleak or occlusion, the BECS geometry was analyzed to detect geometrical components that were related to the complication. Geometric analysis of the flare may help to better detect and identify the cause of such complications.

Ultrasound assessment of Achilles enthesitis: a dedicated training program.

OBJECTIVE: To describe an intensive and multimodal ultrasound (US) training program focused on Achilles enthesitis and to illustrate the learning curve of trainees without experience. METHODS: Three medical students (trainees) and two rheumatologists experienced in musculoskeletal US (trainers) were involved in the training program, which encompassed one preliminary theoretical-practical meeting and five scanning sessions (two patients per session). The students and one expert performed the US examination of the Achilles enthesis bilaterally. The trainees acquired representative images and assessed the presence of Outcome Measures in Rheumatology (OMERACT) US abnormalities of enthesitis. The experts provided feedback addressing trainees' misinterpretations, and the quality of the acquired images was evaluated. A dedicated questionnaire was used to evaluate the students' confidence. After each session, five sets of static images (total=100 images of most commonly scanned entheses) were provided and scored by the students according to OMERACT US definitions. Total agreement and prevalence and bias adjusted kappa (PABAK) were used to evaluate the concordance between the trainees and the expert sonographer. RESULTS: The total agreement and PABAK significantly improved between the first and fifth scanning sessions (76.2% versus 92.9%, p<0.01, and 0.5 versus 0.79, p<0.01) and between the first and fifth static image sets (64.5% versus 81.9%, p<0.01, and 0.29 versus 0.74, p<0.01). Image quality did not significantly improve (p=0.34). A significant increase in trainees' confidence was registered (p<0.01). CONCLUSIONS: The described training program rapidly improved the students' performance in the US assessment of Achilles enthesitis, appearing to be an effective starting model for the future development of pathology-oriented teaching programs for the US in rheumatology.

Estimating Molecular Thermal Averages with the Quantum Equation of Motion and Informationally Complete Measurements.

By leveraging the Variational Quantum Eigensolver (VQE), the "quantum equation of motion" (qEOM) method established itself as a promising tool for quantum chemistry on near-term quantum computers and has been used extensively to estimate molecular excited states. Here, we explore a novel application of this method, employing it to compute thermal averages of quantum systems, specifically molecules like ethylene and butadiene. A drawback of qEOM is that it requires measuring the expectation values of a large number of observables on the ground state of the system, and the number of necessary measurements can become a bottleneck of the method. In this work, we focus on measurements through informationally complete positive operator-valued measures (IC-POVMs) to achieve a reduction in the measurement overheads by estimating different observables of interest through the measurement of a single set of POVMs. We show with numerical simulations that the qEOM combined with IC-POVM measurements ensures satisfactory accuracy in the reconstruction of the thermal state with a reasonable number of shots.

Extracorporeal Blood Purification with CytoSorb in 359 Critically Ill Patients.

INTRODUCTION: Critically ill patients with inflammatory dysregulation and organ disfunction may benefit from blood purification, although the use of this technique has not been described in large case series. We evaluated clinical outcomes and survival in high-risk intensive care unit (ICU) patients who underwent extracorporeal blood purification. METHODS: 359 consecutive ICU patients treated with CytoSorb were included. RESULTS: Main admission diagnoses were 120 (34%) refractory cardiac arrest under mechanical chest compression; 101 (28%) profound cardiogenic shock; 81 (23%) post-cardiotomy cardiogenic shock; and 37 (10%) respiratory failure. Fifteen patients (4%) were positive for SARS-CoV-2 infection. We observed 49% 30-day mortality, 57% ICU mortality, and 62% hospital mortality, all lower than the 71% mortality predicted by SAPS II and 68% predicted by SOFA score. Parameters of shock and organ failure, above all vasoactive inotropic score, reduced during CytoSorb treatment. Multivariable analysis identified SAPS II, lactate dehydrogenase, ICU stay duration, vasoactive inotropic score, lactates, intra-aortic counterpulsation on top of VA-ECMO, and total bilirubin as predictors of mortality. No CytoSorb-related complications occurred. CONCLUSION: CytoSorb treatment was effective in reducing laboratory parameters of shock and vasoactive inotropic score with possible survival implications in a large population of critically ill patients.

Link Prediction with Continuous-Time Classical and Quantum Walks.

Protein-protein interaction (PPI) networks consist of the physical and/or functional interactions between the proteins of an organism, and they form the basis for the field of network medicine. Since the biophysical and high-throughput methods used to form PPI networks are expensive, time-consuming, and often contain inaccuracies, the resulting networks are usually incomplete. In order to infer missing interactions in these networks, we propose a novel class of link prediction methods based on continuous-time classical and quantum walks. In the case of quantum walks, we examine the usage of both the network adjacency and Laplacian matrices for specifying the walk dynamics. We define a score function based on the corresponding transition probabilities and perform tests on six real-world PPI datasets. Our results show that continuous-time classical random walks and quantum walks using the network adjacency matrix can successfully predict missing protein-protein interactions, with performance rivalling the state-of-the-art.

The molecular mechanisms mediating mammalian fertilization.

Fertilization is a key biological process in which the egg and sperm must recognize one another and fuse to form a zygote. Although the process is a continuum, mammalian fertilization has been studied as a sequence of steps: sperm bind and penetrate through the zona pellucida of the egg, adhere to the egg plasma membrane and finally fuse with the egg. Following fusion, effective blocks to polyspermy ensure monospermic fertilization. Here, we review how recent advances obtained using genetically modified mouse lines bring new insights into the molecular mechanisms regulating mammalian fertilization. We discuss models for these processes and we include studies showing that these mechanisms may be conserved across different mammalian species.

Ultrathin Durable Organic Hydrophobic Coatings Enhancing Dropwise Condensation Heat Transfer.

Organic hydrophobic layers targeting sustained dropwise condensation are highly desirable but suffer from poor chemical and mechanical stability, combined with low thermal conductivity. The requirement of such layers to remain ultrathin to minimize their inherent thermal resistance competes against durability considerations. Here, we investigate the long-term durability and enhanced heat-transfer performance of perfluorodecanethiol (PFDT) coatings compared to alternative organic coatings, namely, perfluorodecyltriethoxysilane (PFDTS) and perfluorodecyl acrylate (PFDA), the latter fabricated with initiated chemical vapor deposition (iCVD), in condensation heat transfer and under the challenging operating conditions of intense flow (up to 9 m s-1) of superheated steam (111 °C) at high pressures (1.42 bar). We find that the thiol coating clearly outperforms the silane coating in terms of both heat transfer and durability. In addition, despite being only a monolayer, it clearly also outperforms the iCVD-fabricated PFDA coating in terms of durability. Remarkably, the thiol layer exhibited dropwise condensation for at least 63 h (>2× times more than the PFDA coating, which survived for 30 h), without any visible deterioration, showcasing its hydrolytic stability. The cost of thiol functionalization per area was also the lowest as compared to all of the other surface hydrophobic treatments used in this study, thus making it the most efficient option for practical applications on copper substrates.

Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems.

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.

Emergent entanglement structures and self-similarity in quantum spin chains.

We introduce an experimentally accessible network representation for many-body quantum states based on entanglement between all pairs of its constituents. We illustrate the power of this representation by applying it to a paradigmatic spin chain model, the XX model, and showing that it brings to light new phenomena. The analysis of these entanglement networks reveals that the gradual establishment of quasi-long range order is accompanied by a symmetry regarding single-spin concurrence distributions, as well as by instabilities in the network topology. Moreover, we identify the existence of emergent entanglement structures, spatially localized communities enforced by the global symmetry of the system that can be revealed by model-agnostic community detection algorithms. The network representation further unveils the existence of structural classes and a cyclic self-similarity in the state, which we conjecture to be intimately linked to the community structure. Our results demonstrate that the use of tools and concepts from complex network theory enables the discovery, understanding and description of new physical phenomena even in models studied for decades. This article is part of the theme issue 'Emergent phenomena in complex physical and socio-technical systems: from cells to societies'.

Migraine Pharmacological Treatment and Cognitive Impairment: Risks and Benefits.

Migraine is a common neurological disorder impairing the quality of life of patients. The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs acting on the central nervous system (CNS). The long-term impact of these medications on cognition and neurodegeneration has never been consistently assessed. The paper reviews pharmacological migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits. These features should be carefully evaluated when prescribing a pharmacological treatment as many migraineurs are of scholar or working age and their performances may be affected by drug misuse. Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results have emerged in the relationship between migraine and dementia, future studies must consider present and past pharmacological regimens as potential confounding factors.

Nicotine in Combination with SARS-CoV-2 Affects Cells Viability, Inflammatory Response and Ultrastructural Integrity.

The aims of our study are to: (i) investigate the ability of nicotine to modulate the expression level of inflammatory cytokines in A549 cells infected with SARS-CoV-2; (ii) elucidate the ultrastructural features caused by the combination nicotine+SARS-CoV-2; and (iii) demonstrate the mechanism of action. In this study, A549 cells pretreated with nicotine were either exposed to LPS or poly(I:C), or infected with SARS-CoV-2. Treated and untreated cells were analyzed for cytokine production, cytotoxicity, and ultrastructural modifications. Vero E6 cells were used as a positive reference. Cells pretreated with nicotine showed a decrease of IL6 and TNFα in A549 cells induced by LPS or poly(I:C). In contrast, cells exposed to SARS-CoV-2 showed a high increase of IL6, IL8, IL10 and TNFα, high cytopathic effects that were dose- and time-dependent, and profound ultrastructural modifications. These modifications were characterized by membrane ruptures and fragmentation, the swelling of cytosol and mitochondria, the release of cytoplasmic content in extracellular spaces (including osmiophilic granules), the fragmentation of endoplasmic reticulum, and chromatin disorganization. Nicotine increased SARS-CoV-2 cytopathic effects, elevating the levels of inflammatory cytokines, and inducing severe cellular damage, with features resembling pyroptosis and necroptosis. The protective role of nicotine in COVID-19 is definitively ruled out.

The diagnostic value of conventional radiography and musculoskeletal ultrasonography in calcium pyrophosphate deposition disease: a systematic literature review and meta-analysis.

OBJECTIVE: To examine and compare the accuracy of conventional radiography (CR) and musculoskeletal ultrasonography (US) in the diagnosis of calcium pyrophosphate (CPP) crystals deposition disease (CPPD). DESIGN: A systematic search of electronic databases (PubMed, Embase, and Cochrane), conference abstracts and reference lists was undertaken. Studies which evaluated the accuracy of CR and/or US in the diagnosis of CPPD, using synovial fluid analysis (SFA), histology or classification criteria as reference tests were included. Subgroup analyses by anatomic site and by reference test were performed. RESULTS: Twenty-six studies were included. Using SFA/histology as reference test, CR and US showed an excellent (CR AUC = 0.889, 95%CI = 0.811-0.967) and an outstanding (US AUC = 0.954, 95%CI = 0.907-1.0) diagnostic accuracy (p < 0.01), respectively. Furthermore, US showed a higher sensitivity (0.85, 95%CI = 0.79-0.90 vs 0.47, 95%CI = 0.40-0.55) and only a little lower specificity (0.87, 95%CI = 0.83-0.91 vs 0.95, 95%CI = 0.92-0.97) than CR. A considerable heterogeneity between the studies was found, with adopted reference test being the main source of heterogeneity. In fact, subgroup analysis showed a significant change in the diagnostic accuracy of CR, but not of US, using Ryan and McCarty criteria or SFA/histology as reference test (CR: AUC = 0.956, 95%CI = 0.925-1.0 vs AUC = 0.889, 95%CI = 0.828-0.950, respectively, p < 0.01) (US: AUC = 0.922, 95%CI = 0.842-1.0 vs AUC = 0.957, 95%CI = 0.865-1.0, respectively, p = 0.08) CONCLUSIONS: Although US is more sensitive and a little less specific than CR for identifying CPP crystals, both these two techniques showed a great diagnostic accuracy and should be regarded as complementary to each other in the diagnostic work-up of patients with CPPD.

Social organization and the evolution of life-history traits in two queen morphs of the ant Temnothorax rugatulus.

During the evolution of social insects, not only did life-history traits diverge, with queens becoming highly fecund and long lived compared with their sterile workers, but also individual traits lost their importance compared with colony-level traits. In solitary animals, fecundity is largely influenced by female size, whereas in eusocial insects, colony size and queen number can affect the egg-laying rate. Here, we focused on the ant Temnothorax rugatulus, which exhibits two queen morphs varying in size and reproductive strategy, correlating with their colony's social organization. We experimentally tested the influence of social structure, colony and body size on queen fecundity and investigated links between body size, metabolic rate and survival under paraquat-induced oxidative stress. To gain insight into the molecular physiology underlying the alternative reproductive strategies, we analysed fat body transcriptomes. Per-queen egg production was lower in polygynous colonies when fecundity was limited by worker care. Colony size was a determinant of fecundity rather than body size or queen number, highlighting the super-organismal properties of these societies. The smaller microgynes were more frequently fed by workers and exhibited an increase in metabolic activity, yet they were similarly resistant to oxidative stress. Small queens differentially expressed metabolic genes in the fat body, indicating that shifts in molecular physiology and resource availability allow microgyne queens to compensate for their small size with a more active metabolism without paying increased mortality costs. We provide novel insights into how life-history traits and their associations were modified during social evolution and adapted to queen reproductive strategies.

Elder Mistreatment in an Italian Population: Prevalence and Correlates.

This study aimed to examine the prevalence of elder mistreatment (EM) in an Italian population and to determine the risk factors. The sample consisted of 393 older adults (Mage = 77.07; standard deviation = 9.45) of whom 60.1% were females. The prevalence of EM was of 20.1%. Older elders who were separated, divorced, with a poor state of health, and problems of autonomy were more likely to experience EM. The most common forms of EM were physical/sexual (9.9%) and emotional mistreatment (9.9%). The most common perpetrators were paid caregivers and members of the victim's family. A path analysis model suggested that limited autonomy and poor perceived health status appeared to be predictors of EM. We conclude that the results of this study have important implications in terms of reducing mistreatment of older adults. Understanding EM is essential to promoting equality, tolerance, and supportive attitudes and developing better prevention policies and practices.

Strategies for fortified sustainable food: the case of watermelon-based candy.

The aim of this research was to design a new product, in particular a watermelon-based jelly candy, without generating waste. The study was divided in two steps: (i) optimization of candy formulation in terms of amount of rind, pulp and juice; (ii) fortification of the jelly candy with different concentrations of orange by-products (albedo and flavedo flours). The fortified jelly samples were assessed for sensory quality and chemical properties, before and after digestion. The new candy product was greatly appreciated. The addition of albedo and flavedo flours significantly improved the chemical composition compared to jelly candy without by-products, before and after digestion. A whole quality index was also calculated to determine the best combination of by-products to be added. Fortification with albedo 1.2% and flavedo ranged between 0.6 and 1.2% allowed recording the most interesting jelly candy.

Noisy Quantum Metrology Enhanced by Continuous Nondemolition Measurement.

We show that continuous quantum nondemolition (QND) measurement of an atomic ensemble is able to improve the precision of frequency estimation even in the presence of independent dephasing acting on each atom. We numerically simulate the dynamics of an ensemble with up to N=150 atoms initially prepared in a (classical) spin coherent state, and we show that, thanks to the spin squeezing dynamically generated by the measurement, the information obtainable from the continuous photocurrent scales superclassically with respect to the number of atoms N. We provide evidence that such superclassical scaling holds for different values of dephasing and monitoring efficiency. We moreover calculate the extra information obtainable via a final strong measurement on the conditional states generated during the dynamics and show that the corresponding ultimate limit is nearly achieved via a projective measurement of the spin-squeezed collective spin operator. We also briefly discuss the difference between our protocol and standard estimation schemes, where the state preparation time is neglected.

Biomechanical coupling facilitates spinal neural tube closure in mouse embryos.

Neural tube (NT) formation in the spinal region of the mammalian embryo involves a wave of "zippering" that passes down the elongating spinal axis, uniting the neural fold tips in the dorsal midline. Failure of this closure process leads to open spina bifida, a common cause of severe neurologic disability in humans. Here, we combined a tissue-level strain-mapping workflow with laser ablation of live-imaged mouse embryos to investigate the biomechanics of mammalian spinal closure. Ablation of the zippering point at the embryonic dorsal midline causes far-reaching, rapid separation of the elevating neural folds. Strain analysis revealed tissue expansion around the zippering point after ablation, but predominant tissue constriction in the caudal and ventral neural plate zone. This zone is biomechanically coupled to the zippering point by a supracellular F-actin network, which includes an actin cable running along the neural fold tips. Pharmacologic inhibition of F-actin or laser ablation of the cable causes neural fold separation. At the most advanced somite stages, when completion of spinal closure is imminent, the cable forms a continuous ring around the neuropore, and simultaneously, a new caudal-to-rostral zippering point arises. Laser ablation of this new closure initiation point causes neural fold separation, demonstrating its biomechanical activity. Failure of spinal closure in pre-spina bifida Zic2Ku mutant embryos is associated with altered tissue biomechanics, as indicated by greater neuropore widening after ablation. Thus, this study identifies biomechanical coupling of the entire region of active spinal neurulation in the mouse embryo as a prerequisite for successful NT closure.

Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression.

Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1α) activation and necrosis with alarmins release. Importantly, HIF-1α also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1-2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs).

Cardiomyopathies and Adrenal Diseases.

Cardiomyopathies are myocardial disorders in which heart muscle is structurally and/or functionally abnormal. Previously, structural cardiomyocyte disorders due to adrenal diseases, such as hyperaldosteronism, hypercortisolism, and hypercatecholaminism, were misunderstood, and endomyocardial biopsy (EMB) was not performed because was considered dangerous and too invasive. Recent data confirm that, if performed in experienced centers, EMB is a safe technique and gives precious information about physiopathological processes implied in clinical abnormalities in patients with different systemic disturbances. In this review, we illustrate the most important features in patients affected by primary aldosteronism (PA), Cushing's syndrome (CS), and pheochromocytoma (PHEO). Then, we critically describe microscopic and ultrastructural aspects that have emerged from the newest EMB studies. In PA, the autonomous hypersecretion of aldosterone induces the alteration of ion and water homeostasis, intracellular vacuolization, and swelling; interstitial oedema could be a peculiar feature of myocardial toxicity. In CS, cardiomyocyte hypertrophy and myofibrillolysis could be related to higher expression of atrogin-1. Finally, in PHEO, the hypercontraction of myofilaments with the formation of contraction bands and occasional cellular necrosis has been observed. We expect to clear the role of EMB in patients with cardiomyopathies and adrenal disease, and we believe EMB is a valid tool to implement new management and therapies.