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Background: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI)., Methods: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]., Results: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1β, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged., Conclusion: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and objectives: Endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) play a pivotal role in the pathophysiology and vascular remodeling of chronic thromboembolic pulmonary hypertension (CTEPH) which is an under-diagnosed complication of acute pulmonary embolism (PE). Currently, pulmonary endarterectomy (PEA) is still the treatment of choice for selected patients suffering from CTEPH. The aim of this study was to evaluate the preoperative and postoperative circulating levels of ET-1 and TGF-β in subjects affected by CTEPH undergoing successful surgical treatment by PEA. Methods: The data from patients diagnosed with CTEPH who underwent PEA at the Foundation IRCCS Policlinico San Matteo Hospital (Pavia, Italy) were prospectively recorded in the Institutional database. Circulating ET-1 and TGF-β levels were assessed by an ELISA commercial kit before PEA, at 3 months and 1 year after PEA. The demographic data, preoperatory mean pulmonary arterial pressure (mPAP), cardiac output (CO), and pulmonary vascular resistance (PVR) were also recorded. Univariate and multivariate analyses were performed. Results: The analysis included 340 patients with complete ET-1 measurements and 206 patients with complete TGF-β measurements. ET-1 significantly decreased both at 3 months ( p < 0.001) and at 1 year ( p = 0.009) after PEA. On the other hand, preoperatory TGF-β levels did not significantly change after PEA. Furthermore, ET-1, but not TGF-β, was a good predictor for increased mPAP in multivariate analyses ( p < 0.05). Conclusions: ET-1 but not TGF β was significantly modulated by PEA in subjects affected by CTEPH up to 1 year after surgery. The mechanisms leading to prolonged elevated circulating TGF-β levels and their clinical significance have to be further elucidated.

The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Blood transfusion is one of the most common medical practices worldwide. However, current scientific literature has shown that the immunomodulatory effects of blood transfusion are associated with an increased likelihood of infection, prolonged hospitalization, and morbimortality. Also, it means high costs for healthcare systems., Methods: In this context, acknowledging that blood transfusions are essentially heterologous cell transplantations, the use of therapeutic options has gained strength and is collectively known as the patient blood management (PBM) program. PBM is an approach based on three main pillars: (1) treating anemias and coagulopathies in an optimized manner, especially in the preoperative period; (2) optimizing perioperative hemostasis and the use of blood recovery systems to avoid the loss of the patient's blood; (3) anemia tolerance, with improved oxygen delivery and reduced oxygen demand, particularly in the postoperative period., Results: Current scientific evidence supports the effectiveness of PBM by reducing the need for blood transfusions, decreasing associated complications, and promoting more efficient and safer blood management. Thus, PBM not only improves clinical outcomes for patients but also contributes to the economic sustainability of healthcare systems., Conclusion: The aim of this review was to summarize PBM strategies in a comprehensive, evidence-based approach through a systematic and structured model for PBM implementation in tertiary hospitals. The recommendations proposed herein are from researchers and experts of a high-complexity university hospital in the network of the Sistema Único de Saúde, presenting itself as a strategy that can be followed as a guideline for PBM implementation in other settings.

Objective: When developing mHealth apps with point reward systems, knowledge engineers and domain experts should define app requirements capturing quantitative reward patterns that reflect patient compliance with health behaviors. This is a difficult task, and they could be aided by an ontology that defines systematically quantitative behavior goals that address more than merely the recommended behavior but also rewards for partial compliance or practicing the behavior more than recommended. No ontology and algorithm exist for defining point rewards systematically., Methods: We developed an OWL ontology for point rewards that leverages the Basic Formal Ontology, the Behaviour Change Intervention Ontology and the Gamification Domain Ontology. This Compliance and Reward Ontology (CaRO) allows defining temporal elementary reward patterns for single and multiple sessions of practicing a behavior. These could be assembled to define more complex temporal patterns for persistence behavior over longer time intervals as well as logical combinations of simpler reward patterns. We also developed an algorithm for calculating the points that should be rewarded to users, given data regarding their actual performance. A natural language generation algorithm generates from ontology instances app requirements in the form of user stories. To assess the usefulness of the ontology and algorithms, information system students who are trained to be system analysts/knowledge engineers evaluated whether the ontology and algorithms can improve the requirement elicitation of point rewards for compliance patterns more completely and correctly., Results: For single-session rewards, the ontology improved formulation of two of the six requirements as well as the total time for specifying them. For multi-session rewards, the ontology improved formulation of five of the 11 requirements., Conclusion: CaRO is a first attempt of its kind, and it covers all of the cases of compliance and reward pattern definitions that were needed for a full-scale system that was developed as part of a large European project. The ontology and algorithm are available at https://github.com/capable-project/rewards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The evolution of socio-technological habits together with the widespread demand of post-acute and chronic treatments outside hospital boundaries drove the increased demand of medical informatics experts to develop tools for and support healthcare professionals. The recent COVID-19 pandemic further highlighted the need of physicians able to manage diseases virtually and remotely. Moreover, healthcare professionals need to access to innovative techniques and procedures to manage biomedical data, cloud-based communication, and data sharing procedures, often connected to innovative devices to support an effective precision in the health treatments. In this paper we report the experiences of the Italian Biomedical Informatics Society (SIBIM), in the definition and promotion of eHealth educational topics in medical and health professions teaching programs, as well as in bioengineering schools, showing how SIBIM members' efforts have been applied towards increasing the level of eHealth contents in medical schools.

Introduction: Differential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting. The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis., Method: Patients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers-Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona-were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols., Results: One hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants. The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy., Conclusion: The Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants., (© 2024. The Author(s).)

Background: Predominant right temporal atrophy is a radiological sign usually associated with frontotemporal dementia but this sign can also be present in Alzheimer's disease. Given the overlap of clinical symptoms between the two conditions, it is important to know which characteristics allow them to be differentiated., Objectives: To compare clinical, neuropsychological and structural magnetic resonance imaging (MRI) data of subjects with prominent right anterior temporal atrophy, depending on the status of amyloid biomarkers., Methods: Among patients followed in the dementia center of Ospedale Maggiore Policlinico, subjects with right anterior temporal atrophy, defined as grade 3 or 4 on the corresponding visual rating scale, were identified. Only subjects with both an MRI scan and amyloid status available were considered. For selected subjects, data were extracted from clinical and neuropsychological records at initial presentation and at last available follow-up. Two raters applied a protocol of eight visual rating scales to compare brain atrophy and white matter hyperintensities., Results: Of 497 subjects, 17 fulfilled the inclusion criteria: 7 amyloid-positive and 10 amyloid-negative. At initial presentation, executive dysfunction and topographical disorientation were more common in amyloid-positive patients. At follow-up, behavioral symptoms, such as social awkwardness and compulsive attitude, were more frequent in the amyloid-negative patients. Amyloid-positive patients presented an overall worse neuropsychological performance, especially in the language and visuospatial domain, and had higher scores on the right anterior cingulate visual rating scale., Conclusion: Patients with predominant right temporal atrophy showed clinical, neuropsychological and radiological differences, depending on the status of amyloid biomarkers., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: This retrospective study on patients with biopsy-proven lupus nephritis (LN) aimed to assess the probability of sustained clinical remission (sCR) and to investigate sCR effects on disease flares and impaired kidney function (IKF)., Methods: sCR was defined as clinical-Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) = 0 and estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m 2 lasting ≥1 year; IKF: eGFR <60 ml/min per 1.73 m 2 for >3 months. We analyzed the probability of achieving and maintaining sCR, and the yearly risk of flare. Cox models were used to identify predictors of sCR and IKF with variables analyzed as time-dependent covariates when appropriate., Results: Of 303 patients followed-up with for 14.8 (interquartile range: 9.8-22) years, 257 (84.8%) achieved sCR. The probability of achieving sCR progressively increased over time reaching 90% at 15 years. Baseline age (hazard ratio [HR]: 1.017; 95% confidence interval [CI]: 0.005-1.029; P  = 0.004), hydroxychloroquine intake (HR: 1.385; 95% CI: 1.051-1.825; P  = 0.021), and absence of arterial hypertension (HR: 0.699; 95% CI: 0.532-0.921; P  = 0.011) were independent predictors of sCR. Among patients who achieved sCR, 142 (55.3%) developed a lupus flare after a median time of 3.6 (2.3-5.9) years. In the remaining 115 patients, sCR persisted for 9.5 (5.8-14.5) years. The probability of sCR to persist at 15 years was 38%. SLE flare risk decreased to 10%, 5%, and 2% in patients with sCR lasting <5, 5 to 10, and >10 years, respectively. At the last observation, 57 patients (18.81%) had IKF. sCR achievement (HR: 0.18, P  < 0.001) and its duration (HR: 0.83, P  < 0.001) were protective against IKF., Conclusion: sCR is an achievable target in LN management and protects against IKF. The longer the sCR, the higher the chance of its persistence and the lower the risk of SLE flares., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood., Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI)., Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC)., Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression., Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.

Background: Since treatment with immune checkpoint inhibitors (ICIs) is becoming standard therapy for patients with high-risk and advanced melanoma, an increasing number of patients experience treatment-related adverse events such as fatigue. Until now, studies have demonstrated the benefits of using eHealth tools to provide either symptom monitoring or interventions to reduce treatment-related symptoms such as fatigue. However, an eHealth tool that facilitates the combination of both symptom monitoring and symptom management in patients with melanoma treated with ICIs is still needed., Objective: In this pilot study, we will explore the use of the CAPABLE (Cancer Patients Better Life Experience) app in providing symptom monitoring, education, and well-being interventions on health-related quality of life (HRQoL) outcomes such as fatigue and physical functioning, as well as patients' acceptance and usability of using CAPABLE., Methods: This prospective, exploratory pilot study will examine changes in fatigue over time in 36 patients with stage III or IV melanoma during treatment with ICI using CAPABLE (a smartphone app and multisensory smartwatch). This cohort will be compared to a prospectively collected cohort of patients with melanoma treated with standard ICI therapy. CAPABLE will be used for a minimum of 3 and a maximum of 6 months. The primary endpoint in this study is the change in fatigue between baseline and 3 and 6 months after the start of treatment. Secondary end points include HRQoL outcomes, usability, and feasibility parameters., Results: Study inclusion started in April 2023 and is currently ongoing., Conclusions: This pilot study will explore the effect, usability, and feasibility of CAPABLE in patients with melanoma during treatment with ICI. Adding the CAPABLE system to active treatment is hypothesized to decrease fatigue in patients with high-risk and advanced melanoma during treatment with ICIs compared to a control group receiving standard care. The Medical Ethics Committee NedMec (Amsterdam, The Netherlands) granted ethical approval for this study (reference number 22-981/NL81970.000.22)., Trial Registration: ClinicalTrials.gov NCT05827289; https://clinicaltrials.gov/study/NCT05827289., International Registered Report Identifier (irrid): DERR1-10.2196/49252., (©Itske Fraterman, Barbara M Wollersheim, Valentina Tibollo, Savannah Lucia Catherina Glaser, Stephanie Medlock, Ronald Cornet, Matteo Gabetta, Vitali Gisko, Ella Barkan, Nicola di Flora, David Glasspool, Alexandra Kogan, Giordano Lanzola, Roy Leizer, Henk Mallo, Manuel Ottaviano, Mor Peleg, Lonneke V van de Poll-Franse, Nicole Veggiotti, Konrad Śniatała, Szymon Wilk, Enea Parimbelli, Silvana Quaglini, Mimma Rizzo, Laura Deborah Locati, Annelies Boekhout, Lucia Sacchi, Sofie Wilgenhof. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.10.2023.)

Context: Implementation of pre-conception care units is still very limited in Italy. Nowadays, the population's awareness of the reproductive risks that can be reduced or prevented is very low. Purpose and main findings: We presented a new personalized multidisciplinary model of preconception care aimed at identifying and possibly reducing adverse reproductive events. We analyzed three cohorts of population: couples from the general population, infertile or subfertile couples, and couples with a previous history of adverse reproductive events. The proposal involves a deep investigation regarding family history, the personal histories of both partners, and reproductive history., Principal Conclusions: Preconception care is still neglected in Italy and under-evaluated by clinicians involved in natural or in vitro reproduction. Adequate preconception counseling will improve maternal and fetal obstetrical outcomes.

Background: There is no evidence in the current literature about the best treatment option in sacral fracture with or without neurological impairment., Materials and Methods: The Italian Pelvic Trauma Association (A.I.P.) decided to organize a consensus to define the best treatment for traumatic and insufficiency fractures according to neurological impairment., Results: Consensus has been reached for the following statements: When complete neurological examination cannot be performed, pelvic X-rays, CT scan, hip and pelvis MRI, lumbosacral MRI, and lower extremities evoked potentials are useful. Lower extremities EMG should not be used in an acute setting; a patient with cauda equina syndrome associated with a sacral fracture represents an absolute indication for sacral reduction and the correct timing for reduction is "as early as possible". An isolated and incomplete radicular neurological deficit of the lower limbs does not represent an indication for laminectomy after reduction in the case of a displaced sacral fracture in a high-energy trauma, while a worsening and progressive radicular neurological deficit represents an indication. In the case of a displaced sacral fracture and neurological deficit with imaging showing no evidence of nerve root compression, a laminectomy after reduction is not indicated. In a patient who was not initially investigated from a neurological point of view, if a clinical investigation conducted after 72 h identifies a neurological deficit in the presence of a displaced sacral fracture with nerve compression on MRI, a laminectomy after reduction may be indicated. In the case of an indication to perform a sacral decompression, a first attempt with closed reduction through external manoeuvres is not mandatory. Transcondylar traction does not represent a valid method for performing a closed decompression. Following a sacral decompression, a sacral fixation (e.g. sacroiliac screw, triangular osteosynthesis, lumbopelvic fixation) should be performed. An isolated and complete radicular neurological deficit of the lower limbs represents an indication for laminectomy after reduction in the case of a displaced sacral fracture in a low-energy trauma associated with imaging suggestive of root compression. An isolated and incomplete radicular neurological deficit of the lower limbs does not represent an absolute indication. A worsening and progressive radicular neurological deficit of the lower limbs represents an indication for laminectomy after reduction in the case of a displaced sacral fracture in a low-energy trauma associated with imaging suggestive of root compression. In the case of a displaced sacral fracture and neurological deficit in a low-energy trauma, sacral decompression followed by surgical fixation is indicated., Conclusions: This consensus collects expert opinion about this topic and may guide the surgeon in choosing the best treatment for these patients., Level of Evidence: IV., Trial Registration: not applicable (consensus paper)., (© 2023. Societa Italiana di Ortopedia e Traumatologia (Italian Society of Orthopaedics and Traumatology SIOT).)

Background: The transition from water to air is a key event in the evolution of many marine organisms to access new food sources, escape water hypoxia, and exploit the higher and temperature-independent oxygen concentration of air. Despite the importance of microorganisms in host adaptation, their contribution to overcoming the challenges posed by the lifestyle changes from water to land is not well understood. To address this, we examined how microbial association with a key multifunctional organ, the gill, is involved in the intertidal adaptation of fiddler crabs, a dual-breathing organism., Results: Electron microscopy revealed a rod-shaped bacterial layer tightly connected to the gill lamellae of the five crab species sampled across a latitudinal gradient from the central Red Sea to the southern Indian Ocean. The gill bacterial community diversity assessed with 16S rRNA gene amplicon sequencing was consistently low across crab species, and the same actinobacterial group, namely Ilumatobacter, was dominant regardless of the geographic location of the host. Using metagenomics and metatranscriptomics, we detected that these members of actinobacteria are potentially able to convert ammonia to amino acids and may help eliminate toxic sulphur compounds and carbon monoxide to which crabs are constantly exposed., Conclusions: These results indicate that bacteria selected on gills can play a role in the adaptation of animals in dynamic intertidal ecosystems. Hence, this relationship is likely to be important in the ecological and evolutionary processes of the transition from water to air and deserves further attention, including the ontogenetic onset of this association. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The gold standard for diagnosing egg allergy in children is the oral food challenge (OFC). However, OFCs are time-consuming and risky procedures. Our study aimed to evaluate the utility of the basophil activation test (BAT) and component-resolved diagnostic in the diagnostic workup of children with egg allergy., Methods: Overall, 86 children aged 6 months to 17 years, suspected of egg allergy, underwent OFC with boiled egg according to international standardized protocols. BAT and specific immunoglobulin E (sIgE) testing to component egg proteins (Gal d 1-4) were also performed., Results: Of the 22 children who reacted to boiled egg, only one experienced anaphylaxis during the challenge. BAT was performed in samples obtained by 75 of the 86 patients of our cohort. Egg white and yolk protein extracts induced CD63 upregulation in the egg-allergic (EA) children compared with sensitized children that tolerated boiled egg (we registered an overall mean of CD63 expression in the EA population of 44.4% [SD 34.1] for egg white and 34.7% [SD 31.3] for egg yolk vs. 12.5% [SD 19.1] and 10.0% [SD 16.0] in sensitized children). BAT could discriminate between true egg allergy and egg sensitization in our population. As a second-line diagnostic step, the positivity of BAT for egg white or Gal d 1-sIgE resulted in a 40.9% OFC reduction, especially for those with a positive outcome., Conclusion: The BAT may be implemented in the diagnostic workup of egg allergy in children and, in a stepwise approach, separately or combined with Gal d 1-sIgE, may predict the allergic status and reduce the number of positive OFCs in children with egg allergy at low risk for severe reactions., (© 2023 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Positive microbiological fungal culture from bronchoalveolar-lavage-fluid (BAL) for Aspergillus or tissue biopsy and the detection of high levels of Aspergillus Galactomannan (GM) are commonly considered standard for diagnosing Invasive Pulmonary Aspergillosis (IPA). However, Aspergillus infection induces both cellular and humoral immune responses, characterized by the production of specific immunoglobulins, which can be easily detected in serum and accurately measured. This study hypothesized that Aspergillus-specific IgE, IgG, including IgG4, assays could be adopted as a rapid preliminary screening tool in patients with suspected Aspergillus-related lung disease in order to help in the identification of patients who require more invasive procedures (bronchoscopy, biopsy)., Methods: We prospectively stored 447 serum specimens of patients admitted for suspected IPA from 1 January 2010 to 31 July 2021. Serum total IgE and serum IgE, IgG and IgG4 specific for Aspergillus fumigatus and Aspergillus niger were determined for each sample. In addition, bronchoscopy with BAL for microbiologic culture and Aspergillus Galactomannan (GM) antigen were performed in all patients., Results: Patients with IPA, diagnosed by detection of a positive BAL culture for Aspergillus and/or a positive GM, showed higher serum levels of specific Aspergillus fumigatus and Aspergillus niger immunoglobulins. Serum-specific Aspergillus fumigatus IgG at a cut-off of 22.6 mgA/L showed the highest sensitivity in predicting IPA, though quite moderate (AUC 0.62). Nonetheless, the simultaneous presence of values below the cut-off of Aspergillus IgE, IgG and IgG4 showed a negative predictive value greater than 90% both towards positive BAL culture and positive GM., Conclusions: In patients with suspected IPA, Aspergillus-specific immunoglobulins assay could be tested as a preliminary screening tool to support more invasive procedures, i.e. BAL.

Objectives: To investigate the normal-appearing white matter (NAWM) susceptibility in a cohort of newly diagnosed multiple sclerosis (MS) patients and to evaluate possible correlations between NAWM susceptibility and disability progression., Methods: Fifty-nine patients with a diagnosis of MS (n = 53) or clinically isolated syndrome (CIS) (n = 6) were recruited and followed up. All participants underwent neurological examination, blood sampling for serum neurofilament light chain (sNfL) level assessment, lumbar puncture for the quantification of cerebrospinal fluid (CSF) β-amyloid 1-42 (Aβ) levels, and brain MRI. T2-weighted scans were used to quantify white matter (WM) lesion loads. For each scan, we derived the NAWM volume fraction and the WM lesion volume fraction. Quantitative susceptibility mapping (QSM) of the NAWM was calculated using the susceptibility tensor imaging (STI) suite. Susceptibility maps were computed with the STAR algorithm., Results: Primary progressive patients (n = 9) showed a higher mean susceptibility value in the NAWM than relapsing-remitting (n = 44) and CIS (n = 6) (p = 0.01 and p = 0.02). Patients with a higher susceptibility in the NAWM showed increased sNfL concentration (ρ = 0.38, p = 0.004) and lower CSF Aβ levels (ρ = -0.34, p = 0.009). Mean NAWM susceptibility turned out to be a predictor of the expanded disability status scale (EDSS) worsening at follow-up (β = 0.41, t = 2.66, p = 0.01) and of the MS severity scale (MSSS) (β = 0.38, t = 2.43, p = 0.019)., Conclusions: QSM in the NAWM seems to predict the EDSS increment over time. This finding might provide evidence on the role of QSM in identifying patients with an increased risk of early disability progression., Key Points: • NAWM-QSM is higher in PPMS patients than in RRMS. • NAWM-QSM seems to be a predictor of EDSS worsening over time. • Patients with higher NAWM-QSM show increased sNfL concentration and lower CSF Aβ levels., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in cerebrospinal fluid (CSF) levels of aquaporin-4 (AQP4), a water channel expressed on PVS-bounding astrocytes, has been described in patients with neurodegenerative dementia. Our aim was to investigate the relationship between neurodegenerative diseases and two putative glymphatic system biomarkers: AQP4 and EPVS., Methods: We included 70 individuals, 54 patients with neurodegenerative diseases and 16 subjects with non-degenerative conditions. EPVS were visually quantified on MRI-scans applying Paradise's scale. All subjects underwent lumbar puncture for the measurement of AQP4 levels in the cerebrospinal fluid (CSF). CSF levels of amyloid-β-1-42, phosphorylated and total tau (tTau) were also measured. Linear regression analyses were adjusted for age, sex, education and disease duration, after excluding outliers., Results: Cerebrospinal fluid (CSF)-AQP4 levels were independent predictors of total (β = 0.28, standard error [SE] = 0.08, p = 0.001), basal ganglia (β = 0.20, SE = 0.08, p = 0.009) and centrum semiovale EPVS (β = 0.37, SE = 0.12, p = 0.003). tTau levels predicted CSO-EPVS (β = 0.30, SE = 0.15, p = 0.046). Moreover, increased levels of AQP4 were strongly associated with higher levels of tTau in the CSF (β = 0.35, SE = 0.13, p = 0.008)., Conclusion: We provide evidence that CSO-EPVS and CSF-AQP4 might be clinically meaningful biomarkers of glymphatic dysfunction and associated neurodegeneration., 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 © 2023 Sacchi, Arcaro, Carandini, Pietroboni, Fumagalli, Fenoglio, Serpente, Sorrentino, Visconte, Pintus, Conte, Contarino, Scarpini, Triulzi, Galimberti and Arighi.)

Background: Chronic cough is a common symptom, addressed in the clinical setting by empirical treatment together with some laboratory investigations. The aim of the present study was to investigate the value of testing eosinophilic cationic protein (ECP) serum levels combined with other diagnostic procedures and empirical treatment in the diagnostic workup of chronic cough., Methods: In this study, we evaluated 194 patients with chronic cough. No subject had received any anti-inflammatory treatment before clinical evaluation, and none was an active smoker. ECP was measured with a commercially available fluoroenzyme immunoassay and results were expressed as µg/L., Results: The analysis of variance showed that mean ECP level differs among the various diagnosis categories (P<0.001). Mean ECP level was significantly higher in asthmatic patients, particularly in the active disease., Conclusions: Serum ECP concentration could represent a useful biomarker in the clinical work-up of chronic cough, managing to differentiate asthma from other chronic disorders.

Allergy to natural rubber latex emerged as one of the main allergies at the beginning among some professional groups and the general population. Sensitization and development of latex allergy have been attributed to exposure to products containing residual latex proteins. The prevailing cross-reactivity of latex proteins with other food allergens is of great concern. Numerous purified allergens are currently available, which greatly help in patient management, thus determining their specific profile. We conducted a multicenter study to investigate changes, from the ROC analysis, in the characteristics of patients with latex allergy by measuring its major protein components. Sensitization to latex proteins is crucial because it highlights the cross reactivity to inhalants (pollen) and food (fruit). It is very essential in an accurate and specific clinical setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM)., Objective: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions., Methods: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n = 19) and non-AD (n = 15) groups according to their clinical profile, CSF (Aβ42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted., Results: QSM in left BANKSSTS was significantly different among groups (p = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aβ42 (rho -0.55, p = 0.005), Aβ42/40 (rho -0.66, p < 0.001), pTau (rho 0.63, p < 0.001), tTau (rho 0.56, p = 0.005), tTau/Aβ42 (rho 0.68, p < 0.001) and pTau/Aβ42 (rho 0.71, p < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95 % [0.66-0.93]). Higher QSM values were independent predictors of Aβ42 (B = 0.63, p = 0.032), Aβ42/40 (B = 0.81, p = 0.028), pTau (B = 0.96, p = 0.046), tTau (B = 0.55, p = 0.027), and tTau/Aβ42 (B = 1.13, p = 0.042) positivity., Conclusion: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

Background: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far., Objective: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene., Methods: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software., Results: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, p = 0.0037)., Conclusion: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.

The interactions between aromatase inhibitors (AI) in breast cancer (BC) and gut microbiota (GM) have not been completely established yet. The aim of the study is to evaluate the bio-diversity of GM and the relationship between GM, inflammation and tumor-infiltrating lymphocytes (TILs) in postmenopausal women with BC during adjuvant AI treatment compared to women with disease relapse during or after one year of AI therapy ("endocrine-resistant"). We conducted a monocenter observational case-control study. Eighty-four women with BC (8 cases, 76 controls) were enrolled from 2019 to 2021. We observed a significant difference in the mean microbial abundance between the two groups for the taxonomic rank of order ( p 0.035) and family ( p 0.029); specifically, the case group showed higher diversity than the control group. Veillonella reached its maximum abundance in cases ( p 0.022). Cytokine levels were compared among the groups created considering the TILs levels. We obtained a statistically significant difference ( p 0.045) in IL-17 levels among the groups, with patients with low TILs levels showing a higher median value for IL-17 (0.15 vs. 0.08 pg/mL). Further studies about the bio-diversity in women with BC may lead to the development of new biomarkers and targeted interventions.

Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis between ELISA and CLEIA methods in order to evaluate the analytical precision and the diagnostic performance of the novel CLEIA system on 111 CSF samples. Results confirmed a robust correlation between ELISA and CLEIA methods, with an improvement of the accuracy with the new CLEIA methodology in the detection of the single biomarkers and in their ratio values. For Aβ42 regression analysis with Passing−Bablok showed a Pearson correlation coefficient r = 0.867 (0.8120; 0.907% 95% CI p < 0.0001), T-tau analysis: r = 0.968 (0.954; 0.978% 95% CI p < 0.0001) and P-tau181: r = 0.946 (0.922; 0.962 5% 95% CI p < 0.0001). The overall ROC AUC comparison between ROC in ELISA and ROC in CLEIA confirmed a more accurate ROC AUC with the new automatic method: T-tau AUC ELISA = 0.94 (95% CI 0.89; 0.99 p < 0.0001) vs. AUC CLEIA = 0.95 (95% CI 0.89; 1.00 p < 0.0001), and P-tau181 AUC ELISA = 0.91 (95% CI 0.85; 0.98 p < 0.0001) vs. AUC CLEIA = 0.98 (95% CI 0.95; 1.00 p < 0.0001). The performance of the new CLEIA method in automation is comparable and, for tau and P-tau181, even better, as compared with standard ELISA. Hopefully, in the future, automation could be useful in clinical diagnosis and also in the context of clinical studies.

Aquaporin-4 (AQP4) is a channel protein that plays a fundamental role in glymphatic system, a newly described pathway for fluid exchange in the central nervous system, as well as a central figure in a fascinating new theory for the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, cerebrospinal fluid (CSF) concentration of AQP4, amyloid-β, total tau and P-tau were determined in 103 CSF samples from patients affected by neurodegenerative dementias (AD and FTD) or psychiatric diseases and 21 controls. Significantly higher levels of AQP4 were found in AD and FTD patients compared to subjects not affected by neurodegenerative diseases, and a significant, positive correlation between AQP4 and total tau levels was found. This evidence may pave the way for future studies focused on the role of this channel protein in the clinical assessment of the glymphatic function and degree of neurodegeneration., (© 2022. The Author(s).)

The digital healthcare workforce is usually composed of two major types of professionals: the healthcare workers, who are the users of eHealth, and the health informatics developers, who are usually computer scientists, biomedical engineers, or other technical experts. Health informatics educators have the responsibility to develop the appropriate skills for both, acting within their specific curricula. Here we present the experience of the Italian Society of Biomedical Informatics (SIBIM) and show that, whereas the technical curricula are widely covered with a large range of topics, the eHealth education in medical curricula is often limited to simple bioengineering and informatics skills, thus suggesting that eHealth associations and organizations at the national level should focus their efforts towards increasing the level of eHealth contents in medical schools.

Obstructive sleep apnea (OSA) is a common sleep disorder and polysomnography (PSG) is the gold standard for its diagnosis and treatment monitoring. There are nowadays several activity trackers measuring sleep quality through the detection of sleep stages. To allow an easier monitoring of the treatment efficacy at home, this work explores the possibility of using one of those commercial smart-bands. To this aim, we studied the signals provided by PSG and a Fitbit smart-band on 26 consecutive patients, admitted to the hospital after the diagnosis of OSA, and submitted to ventilation or positional treatment. They underwent monitoring for three nights (basal, titration, and control). We developed both a visualization software allowing doctors to visually compare the two hypnograms, and a set of statistics for assessing the concordance of the two methods. Results indicate that Fitbit can detect normal sleep patterns, while it is less able to detect the abnormal ones.

Online forums play an important role in connecting people who have crossed paths with cancer. These communities create networks of mutual support that cover different cancer-related topics, containing an extensive amount of heterogeneous information that can be mined to get useful insights. This work presents a case study where users' posts from an Italian cancer patient community have been classified combining both count-based and prediction-based representations to identify discussion topics, with the aim of improving message reviewing and filtering. We demonstrate that pairing simple bag-of-words representations based on keywords matching with pre-trained contextual embeddings significantly improves the overall quality of the predictions and allows the model to handle ambiguities and misspellings. By using non-English real-world data, we also investigated the reusability of pretrained multilingual models like BERT in lower data regimes like many local medical institutions.

Patient reported outcomes have been shown to be predictive of cancer patients' prognosis, and their monitoring through electronic applications have been shown to positively impact survival. On the other hand, patient apps in general show a number of criticalities that often lead patients to abandon their use. One of them is usability. A scarce attention to usability during app development leads to unsatisfactory user experience. In this work, we present an algorithm to facilitate patient symptoms reporting, by personalising the list of symptoms according to their probability of occurrence in the specific patient. This avoids searching long lists of items, thus decreasing the patients' burden in symptom reporting.

The impact of the COVID-19 pandemic involved the disruption of the processes of care and the need for immediately effective re-organizational procedures. In the context of digital health, it is of paramount importance to determine how a specific patients' population reflects into the healthcare dynamics of the hospital, to investigate how patients' sub-group/strata respond to the different care processes, in order to generate novel hypotheses regarding the most effective healthcare strategies. We present an analysis pipeline based on the heterogeneous collected data aimed at identifying the most frequent healthcare processes patterns, jointly analyzing them with demographic and physiological disease trajectories, and stratify the observed cohort on the basis of the mined patterns. This is a process-oriented pipeline which integrates process mining algorithms, and trajectory mining by topological data analyses and pseudo time approaches. Data was collected for 1,179 COVID-19 positive patients, hospitalized at the Italian Hospital "Istituti Clinici Salvatore Maugeri" in Lombardy, integrating different sources including text admission letters, EHR and hospital infrastructure data. We identified five temporal phenotypes, from laboratory values trajectories, which are characterized by statistically significant different death risk estimates. The process mining algorithms allowed splitting the data in sub-cohorts as function of the pandemic waves and of the temporal trajectories showing statistically significant differences in terms of events characteristics., 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 © 2022 Dagliati, Gatta, Malovini, Tibollo, Sacchi, Cascini, Chiovato and Bellazzi.)

Due to the chemico-physical differences between air and water, the transition from aquatic life to the land poses several challenges for animal evolution, necessitating morphological, physiological and behavioural adaptations. Microbial symbiosis is known to have played an important role in eukaryote evolution, favouring host adaptation under changing environmental conditions. We selected mangrove brachyuran crabs as a model group to investigate the prokaryotes associated with the gill of crabs dwelling at different tidal levels (subtidal, intertidal and supratidal). In these animals, the gill undergoes a high selective pressure, finely regulating multiple physiological functions during both animal submersion under and emersion from the periodical tidal events. We hypothesize that similarly to other marine animals, the gills of tidal crabs are consistently colonized by prokaryotes that may quantitatively change along the environmental gradient driven by the tides. Using electron microscopy techniques, we found a thick layer of prokaryotes over the gill surfaces of all of 12 crab species from the mangrove forests of Saudi Arabia, Kenya and South Africa. We consistently observed two distinct morphotypes (rod- and spherical-shaped), positioned horizontally and/or perpendicularly to the gill surface. The presence of replicating cells indicated that the prokaryote layer is actively growing on the gill surface. Quantitative analysis of scanning electron microscopy images and the quantification of the bacterial 16S rRNA gene by qPCR revealed a higher specific abundance of prokaryote cells per gill surface area in the subtidal species than those living in the supratidal zone. Our results revealed a correlation between prokaryote colonization of the gill surfaces and the host lifestyle. This finding indicates a possible role of prokaryote partnership within the crab gills, with potential effects on animal adaptation to different levels of the intertidal gradient present in the mangrove ecosystem., Competing Interests: The authors have declared that no competing interests exist.

Process mining techniques can be used to analyse business processes using the data logged during their execution. These techniques are leveraged in a wide range of domains, including healthcare, where it focuses mainly on the analysis of diagnostic, treatment, and organisational processes. Despite the huge amount of data generated in hospitals by staff and machinery involved in healthcare processes, there is no evidence of a systematic uptake of process mining beyond targeted case studies in a research context. When developing and using process mining in healthcare, distinguishing characteristics of healthcare processes such as their variability and patient-centred focus require targeted attention. Against this background, the Process-Oriented Data Science in Healthcare Alliance has been established to propagate the research and application of techniques targeting the data-driven improvement of healthcare processes. This paper, an initiative of the alliance, presents the distinguishing characteristics of the healthcare domain that need to be considered to successfully use process mining, as well as open challenges that need to be addressed by the community in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Developing effective digital interventions to help patients form healthy habits is a challenging goal. IDEAS is a step-by-step framework that allows developers to draw ideas from intended users and behavioral theories, and ideate implementation strategies for them, followed by rapid prototype development. Based on our long experience with developing generic knowledge-based clinical decision support systems (CDSS) and integrating them with electronic health records (EHR) to deliver patient-specific advice, we observed a challenge that IDEAS is not addressing: the semantic detailing of the clinical knowledge behind the digital intervention and relevant patient data that could be used to personalize the digital intervention. To close the gap, we augmented two steps of IDEAS with an ontology that structures the target behavior as classes, derived from HL7 Fast Healthcare Interoperability Resources standard. We exemplify the augmented IDEAS with a case study taken from the Horizon 2020 CAPABLE project, that uses Fogg's Tiny Habits behavioral model to improve the sleep of cancer patients via Tai Chi., (©2021 AMIA - All rights reserved.)

Purpose: Positron emission tomography (PET) with amyloid tracers (amy-PET) allows the quantification of pathological amyloid deposition in the brain tissues, including the white matter (WM). Here, we evaluate amy-PET uptake in WM lesions (WML) and in the normal-appearing WM (NAWM) of patients with Alzheimer's disease (AD) and non-AD type of dementia., Methods: Thirty-three cognitively impaired subjects underwent brain magnetic resonance imaging (MRI), Aβ 1-42 (Aβ) determination in the cerebrospinal fluid (CSF) and amy-PET. Twenty-three patients exhibiting concordant results in both CSF analysis and amy-PET for cortical amyloid deposition were recruited and divided into two groups, amyloid positive (A+) and negative (A-). WML quantification and brain volumes' segmentation were performed. Standardized uptake values ratios (SUVR) were calculated in the grey matter (GM), NAWM and WML on amy-PET coregistered to MRI images., Results: A+ compared to A- showed a higher WML load (p = 0.049) alongside higher SUVR in all brain tissues (p < 0.01). No correlations between CSF Aβ levels and WML and NAWM SUVR were found in A+, while, in A-, CSF Aβ levels were directly correlated to NAWM SUVR (p = 0.04). CSF Aβ concentration was the only predictor of NAWM SUVR (adj R 2  = 0.91; p = 0.04) in A-. In A+ but not in A- direct correlations were identified between WM and GM SUVR (p < 0.01)., Conclusions: Our data provide evidence on the role of amy-PET in the assessment of microstructural WM injury in non-AD dementia, whereas amy-PET seems less suitable to assess WM damage in AD patients due to a plausible amyloid accrual therein., (© 2022. The Author(s).)

Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer's disease (AD) spectrum. However, they are considered interchangeable, along with Aβ42/40 ratio, for defining 'Alzheimer's Disease pathologic change' (A+)., Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients., Methods: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ42 within a 365-days interval. Thresholds used for dichotomization were: Aβ42 < 640 pg/mL (Aβ42+); pTau > 61 pg/mL (pTau+); and Aβ42/40 < 0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC)., Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93-0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aβ42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = -0.56, p = 0.0058; rho = -0.52, p = 0.0117 respectively). No correlations between CSF-Aβ42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55-0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ42 or using Aβ42/40, instead of Aβ42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids., Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ42/40 and secondarily pTau rather than Aβ42 levels.

Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones., Competing Interests: Declaration of interests A.C., M.P., L.G., C.P., M.F., M.F., J.C., and C.R. are full-time employees of Igenomix. L.R. is the Scientific Director of GeneraLife IVF. She is editor of reproductive biomedicine online and has been associate editor of human reproduction update. She has been the principal investigator of a study sponsored by Merck KGaA. She has received honoraria and consultation fees from Merck, MSD, Ferring, Ibsa, Cooper Surgical, Cook, Nterilizer, Fujifilm-Irvine Scientific, Medea, and Universal Clinics. She is a partner and shareholder of Global Investment Clinics, Genera Health Care, and Nterilizer and has been affiliated with Flam. D.C. is a full-time employee of GeneraLife IVF, where he is the science and research manager. He received paid lectures from Fujifilm-Irvine Scientific. He received paid consultations from Merck. F.B. reports personal fees from Fujifilm-Irvine Scientific, outside the submitted work. A.V. reports personal fees from Gedeon Richter, personal fees from Merck, and personal fees from MSD, outside the submitted work. E.H. and I.V. are supported by an ERC consolidator grant (724718-ReCAP), the Novo Nordisk Foundation Young Investigator Award (NNF15OC0016662), ReproUnion, and the Danish National Research Foundation (center grant 6110-00344B). The views expressed in this article are those of the authors and not necessarily those of the sponsors. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of this article. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. E.H. is the executive board member and chair of the scientific advisory board of ReproUnion, which is co-funded by Ferring Pharmaceuticals. F.M.U. is the scientific director of GeneraLife IVF. He is the president of the Italian Society of Fertility and Sterility (SIFES). He has been the principal investigator of a study sponsored by Merck and by S&R Farmaceutici. He has received honoraria and consultation fees from Merck, Merck Sharp and Dohnme Corporation, Ferring, Institut Biochimique, Cooper Surgical, Cook, Nterilizer, Fujifilm-Irvine Scientific, Medea, and Universal Clinics. He is partner/shareholder of Global Investment Clinics, Genera Health Care, and Nterilizer, and has been of Flam. C.S. is the head of the scientific advisory board of Igenomix. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A renewed interest for activity and chronicity indices as predictors of lupus nephritis (LN) outcome has emerged. Revised National Institutes of Health activity and chronicity indices have been proposed to classify LN lesions, but they should be validated by future studies. The aims of this study were ( 1 ) to detect the histologic features associated with the development of kidney function impairment (KFI), and ( 2 ) to identify the best clinical-histologic model to predict KFI at time of kidney biopsy., Methods: Patients with LN who had more than ten glomeruli per kidney biopsy specimen were admitted to the study. Univariate and multivariate logistic regression and Cox proportional hazards models were used to investigate whether activity and chronicity indices could predict KFI development., Results: Among 203 participants with LN followed for 14 years, correlations were found between the activity index, and its components, and clinical-laboratory signs of active LN at baseline. The chronicity index was correlated with serum creatinine. Thus, serum creatinine was significantly and directly correlated with both activity and chronicity indices. In the multivariate analysis, glomerulosclerosis (OR, 3.05; 95% CI, 1.17 to 7.91; P =0.02) and fibrous crescents (OR, 6.84; 95% CI, 3.22 to 14.52; P <0.001) associated with either moderate/severe tubular atrophy (OR, 3.17; 95% CI, 1.04 to 9.64; P =0.04), or with interstitial fibrosis (OR, 2.36; 95% CI, 1.05 to 5.32; P =0.04), predicted KFI. Considering both clinical and histologic features, serum creatinine (OR, 1.68; 95% CI, 1.31 to 2.15; P <0.001), arterial hypertension (OR, 4.64; 95% CI, 1.90 to 11.32; P <0.001), glomerulosclerosis (OR, 2.12; 95% CI, 1.00 to 4.50; P =0.05), and fibrous crescents (OR, 5.18; 95% CI, 2.43 to 11.04; P <0.001) independently predicted KFI. Older age ( P <0.001) and longer delay between clinical onset of LN and kidney biopsy ( P <0.001) were significantly correlated with baseline chronicity index., Conclusions: The chronicity index and its components, but not the activity index, were significantly associated with an impairment of kidney function. The Cox model showed that serum creatinine, arterial hypertension, chronic glomerular lesions, and delay in kidney biopsy predicted KFI. These data reinforce the importance of timely kidney biopsy in LN., Competing Interests: G. Moroni reports having consultancy agreements with GlaxoSmithKline. L. Sacchi reports serving on the editorial boards of Artificial Intelligence in Medicine, BMC Medical Informatics and Decision Making, Journal of Biomedical Informatics, and PLOS One (as academic editor); and serving as chair for Società Scientifica Italiana di Informatica BioMedica (Italian Society of Biomedical Informatics). All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Lockdowns during the COVID-19 pandemic have put people in stressful situations. Recent research showed elevated levels of anxiety and depression during this period, but no study has so far evaluated to what extent emotions and regulation difficulties were perceived by people as having changed with the lockdown. This was the major aim of the present study, together with investigating whether the emotion regulation strategy of "Refocus on planning" could be an effective strategy in this context. With a 1 time-point online survey, 635 French-, Italian-, and English- speaking participants (57.6% males, mean age of 48.48 years, SD = 15.7) evaluated (a) emotion changes, (b) anxiety, depression, and difficulties in emotion regulation, and (c) use of planning. Participants retrospectively indicated their state when thinking about the period of the Spring 2020 COVID-19 lockdown, as well as their state when thinking about the period just before. Results show that the lockdown period was associated with a perceived increase in negative and positive feelings, as well as a perceived increase in anxiety, depression, and regulation difficulties. Despite people used less planning during the lockdown, absolute and heightened use of planning was associated with more positive emotions, as well as less negative emotions, depression symptoms and difficulties in emotion regulation, whereas anxiety symptoms were lower only when more planning was adopted. This study suggests that planning is an effective emotion regulation strategy. More importantly, planning works as soon as implemented, suggesting it is never too late to start planning to alleviate emotion-related symptoms and difficulties. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: the distinct MRI features of MOG-antibody disease (MOG-AD) and AQP4-NMOSD are still poorly defined. We performed a systematic review and meta-analysis to identify specific patterns of MRI abnormalities able to discriminate between MOG-AD and AQP4-NMOSD., Methods: fourteen case-series (1028 patients) were included. Outcomes were MRI lesion patterns in optic nerve (ON), brain and spinal cord (SC) that were selected after a systematic literature review and analysed separately as the event rate for individual MRI lesions in MOG-AD (experimental group) and AQP4-NMOSD (control group) by using a random effect model., Results: MOG-AD showed a higher number of MRI lesions than AQP4-NMOSD patients in the retrobulbar ON (OR=5.67; 95%CI=2.11-15.24; p=0.0006) with ON head swelling (OR=8.20; 95%CI=4.13-16.28; p<0.00001), corpus callosum (OR=2.30; 95%CI=1.11-4.76; p=0.02), pons (OR=2.87; 95%CI=1.45-5.67; p=0.002), and lumbar/conus SC (OR=3.47; 95%CI=1.66-7.24; p=0.0009). Conversely, lesions in the canalicular (OR=0.42; 95%CI=0.18-0.98; p=0.05) and intracranial ON (OR=0.30; 95%CI=0.11=0.84; p=0.02), area postrema (OR=0.12; 95%CI=0.02-0.61; p=0.01), medulla (OR=0.40; 95%CI=0.20-0.78; p=0.007), and cervical SC (OR=0.29; 95%CI=0.09-0.92; p=0.04) were prominent in patients with AQP4-NMOSD. Participants' age was found to be a source of heterogeneity across studies., Conclusion: our study provides further evidence that MOG-AD and AQP4-NMOSD have distinct MRI features that may help clinicians for an early differential diagnosis., (Copyright © 2021. Published by Elsevier B.V.)

Background: Zygomatic implants alone or in combination with conventional implants have been used for severe atrophic maxillary arches. Long-term outcomes of extramaxillary technique need validations., Purpose: To retrospectively assess the clinical outcomes and the prevalence of surgical, biological, and prosthetic complications of implant-fixed complete dental prostheses (IFCDPs) supported by zygomatic implants up to 11 years of follow-up., Materials and Methods: Dental records of 34 subjects treated between October 2008 and June 2019 were reviewed. Patients received an immediate fixed full-arch prosthesis supported solely by zygomatic implants or by a combination of zygomatic and conventional implants., Results: A total of 90 zygomatic implants and 53 standard implants were placed. Up to 11 years of follow-up, two conventional implants were lost, leading to 96.2% success rate for conventional implants and 100% for zygomatic implants. Marginal bone loss for conventional implants averaged 0.85 ± 0.17 mm after the first year and 1.36 ± 0.12 mm after 10 years, resulting in full implant success. No prosthesis was lost. The main surgical complication was the perforations of the Schneiderian membrane, occurring in five patients and in seven sinus cavities. Considering the biological complications, mucositis for standard and zygomatic implants ranged between 21%-35% and 26%-40%, respectively. No peri-implantitis were reported. Soft tissue hypertrophy ranged between 1.8% and 30% for conventional implants and 1.1%-35% for zygomatic implants. Inflammation under the prosthesis ranged between 33% and 50%. For the mechanical complications, abutment loosening was recorded in 5.8% of cases (two patients), tooth debonding and fracture of the prosthesis happened in five subjects (14.7%), and loosening of the prosthetic screws was reported in one patient (2.9%)., Conclusions: Immediate rehabilitation of the severely atrophic maxilla with zygomatic implants alone or in combination with standard implants could be considered a viable treatment modality., (© 2021 Wiley Periodicals LLC.)

Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19., (© 2021. Società Italiana di Medicina Interna (SIMI).)

" Candidatus Midichloria mitochondrii" is a Gram-negative bacterium that lives in strict intracellular symbiosis with the hard tick Ixodes ricinus, forming one of the most intriguing endosymbiosis described to date. The bacterium is capable of durably colonizing the host mitochondria, a peculiar tropism that makes " Ca . Midichloria mitochondrii" a very interesting tool to study the physiology of these cellular organelles. The interaction between the symbiont and the organelle has, however, been difficult to characterize. A parallelism with the predatory bacterium Bdellovibrio bacteriovorus has been drawn, suggesting the hypothesis that " Ca . Midichloria mitochondrii" could prey on mitochondria and consume them to multiply. We studied the life cycle of the bacterium within the host oocytes using a multidisciplinary approach, including electron microscopy, molecular biology, statistics, and systems biology. Our results were not coherent with a predatory-like behavior by " Ca . Midichloria mitochondrii" leading us to propose a novel hypothesis for its life cycle. Based on our results, we here present a novel model called the "mitochondrion-to-mitochondrion hypothesis." Under this model, the bacterium would be able to move from mitochondrion to mitochondrion, possibly within a mitochondrial network. We show that this model presents a good fit with quantitative electron microscopy data. IMPORTANCE Our results suggest that " Candidatus Midichloria mitochondrii," the intramitochondrial bacterium, does not invade mitochondria like predatory bacteria do but instead moves from mitochondrion to mitochondrion within the oocytes of Ixodes ricinus. A better understanding of the lifestyle of " Ca . Midichloria mitochondrii" will allow us to better define the role of this bacterial symbiont in the host physiology.

An interaction between metabolic glucose impairment and coronavirus disease 2019 is reported. The development of a severe multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 infection has been described. We evaluated the impact of MIS-C on glycemic patterns in pediatric patients. A group of 30 children and adolescents affected by MIS-C were considered; all patients were normal weight. Clinical and biochemical assessments, including surrogate markers of insulin resistance (IR) such as homeostasis model analysis-IR (HOMA-IR) and triglyceride-glucose (TyG) indexes, were recorded. Patients were also invited to undergo an intermittently scanned continuous glucose monitoring (isCGM). HOMA-IR index was calculated in 18 patients (60%), of which 17 (94%) revealed a pathological value. TyG index was computed for all patients and pathological values were detected in all cases. In 15 patients, isCGM data were recorded on average for 9 days (±3 days). Overall, average glucose was 105 mg/dL (±16 mg/dL) and average time spent in the 70-180 mg/dL range (TIR) was 93.76%, with nearly 10% of glucose readings in the 141-180 mg/dL range; glycemic fluctuations over the hyperglycemic threshold were detected in four patients. Regular glucose monitoring may be useful to prevent metabolic imbalance and obtain a better outcome.

Objectives: Despite the widespread diffusion of continuous glucose monitoring (CGM) systems, which includes both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), an effective application of CGM technology in clinical practice is still limited. The study aimed to investigate the relationship between isCGM-derived glycemic metrics and glycated hemoglobin (HbA1c), identifying overall CGM targets and exploring the inter-subject variability., Methods: A group of 27 children and adolescents with type 1 diabetes under multiple daily injection insulin-therapy was enrolled. All participants used the isCGM Abbott's FreeStyle Libre system on average for eight months, and clinical data were collected from the Advanced Intelligent Distant-Glucose Monitoring platform. Starting from each HbA1c exam date, windows of past 30, 60, and 90 days were considered to compute several CGM metrics. The relationships between HbA1c and each metric were explored through linear mixed models, adopting an HbA1c target of 7%., Results: Time in Range and Time in Target Range show a negative relationship with HbA1c (R 2 >0.88) whereas Time Above Range and Time Severely Above Range show a positive relationship (R 2 >0.75). Focusing on Time in Range in 30-day windows, random effect represented by the patient's specific intercept reveals a high variability compared to the overall population intercept., Conclusions: This study confirms the relationship between several CGM metrics and HbA1c; it also highlights the importance of an individualized interpretation of the CGM data., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Bacterial species able to produce proteins that are toxic against insects have been discovered at the beginning of the last century. However, up to date only two of them have been used as pesticides in mosquito control strategies targeting larval breeding sites: Bacillus thuringensis var. israelensis and Lysinibacillus sphaericus . Aiming to expand the arsenal of biopesticides, bacterial cultures from 44 soil samples were assayed for their ability to kill larvae of Aedes albopictus . A method to select, grow and test the larvicidal capability of spore-forming bacteria from each soil sample was developed. This allowed identifying 13 soil samples containing strains capable of killing Ae. albopictus larvae. Among the active isolates, one strain with high toxicity was identified as Brevibacillus laterosporus by 16S rRNA gene sequencing and by morphological characterization using transmission electron microscopy. The new isolate showed a larvicidal activity significantly higher than the B. laterosporus LMG 15441 reference strain. Its genome was phylogenomically characterized and compared to the available Brevibacillus genomes. Thus, the new isolate can be considered as a candidate adjuvant to biopesticides formulations that would help preventing the insurgence of resistance., 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 Barbieri, Ferrari, Mamberti, Gabrieli, Castelli, Sassera, Ursino, Scoffone, Radaelli, Clementi, Sacchi, Ferrari, Gasperi and Albertini.)

Background: Diogenes syndrome is a neurobehavioural syndrome characterised by domestic squalor, hoarding and lack of insight. It is an uncommon but high-mortality condition, often associated with dementia., Aims: To describe the clinical features and treatment of Diogenes syndrome secondary to behavioural variant frontotemporal dementia (bvFTD)., Method: We describe a case of bvFTD in a 77-year-old man presenting with Diogenes syndrome., Results: The patient's medical and psychiatric histories were unremarkable, but in recent years he had begun packing his flat with 'art pieces'. Mental state examination revealed confabulation and more structured delusions. Neuropsychological evaluation outlined an impairment in selective attention and letter verbal fluency, but no semantic impairment, in the context of an overall preserved mental functioning. Brain magnetic resonance imaging and positron emission tomography (PET) with fluorodeoxyglucose showed mild bilateral temporo-insular atrophy and hypometabolism in the left-superior temporal gyrus respectively. An amyloid PET scan and genetic analysis covering the dementia spectrum were normal. A diagnosis of bvFTD was made., Conclusions: The clinical framing of behavioural symptoms of dementia such as hoarding poses a diagnostic challenge. This case illustrates the importance of a deeper understanding of Diogenes syndrome, leading to timelier diagnosis and effective therapeutic strategies.

Genetics has a major role in early-onset dementia, but the correspondence between genotype and phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1. The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer's disease-but biomarkers were not-and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1, which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report suggests that the clinical spectrum of SQSTM1 variants is wider.