Publications by authors named "Valentina Mancini"

62 Publications

Altered developmental trajectories of verbal learning skills in 22q11.2DS: associations with hippocampal development and psychosis.

Psychol Med 2022 Jul 1:1-10. Epub 2022 Jul 1.

Developmental Imaging and Psychopathology Lab, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland.

Background: The cognitive profile in 22q11.2 deletion syndrome (22q11.2DS) is often characterized by a discrepancy between nonverbal verbal reasoning skills, in favor of the latter skills. This dissociation has also been observed in memory, with verbal learning skills described as a relative strength. Yet the development of these skills is still to be investigated. We thus aimed to explore verbal learning longitudinally. Furthermore, we explored verbal learning and its respective associations with hippocampal alterations and psychosis, which remain largely unknown despite their high prevalence in 22q11.2DS.

Methods: In total, 332 individuals (173 with 22q11.2DS) aged 5-30 years completed a verbal-paired associates task. Mixed-models regression analyses were conducted to explore developmental trajectories with threefold objectives. First, verbal learning and retention trajectories were compared between 22q11.2DS HC. Second, we examined hippocampal volume development in 22q11.2DS participants with lower higher verbal learning performance. Third, we explored verbal learning trajectories in 22q11.2DS participants with without positive psychotic symptoms and with without a psychotic spectrum disorder (PSD).

Results: Our findings first reveal lower verbal learning performance in 22q11.2DS, with a developmental plateau emerging from adolescence. Second, participants with lower verbal learning scores displayed a reduced left hippocampal tail volume. Third, participants with PSD showed a deterioration of verbal learning performance, independently of verbal reasoning skills.

Conclusion: Our study challenges the current view of preserved verbal learning skills in 22q11.2DS and highlights associations with specific hippocampal alterations. We further identify verbal learning as a novel cognitive marker for psychosis in 22q11.2DS.
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http://dx.doi.org/10.1017/S0033291722001842DOI Listing
July 2022

Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.

Mol Psychiatry 2022 Jun 29. Epub 2022 Jun 29.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (β = -0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (β = -0.28, P = 0.005; β = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.
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http://dx.doi.org/10.1038/s41380-022-01674-9DOI Listing
June 2022

Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol.

Cancers (Basel) 2022 Jun 18;14(12). Epub 2022 Jun 18.

GIMEMA Foundation, 00182 Roma, Italy.

/ mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of / mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19-86). Of these, 38 (14%) harbored and 51 (18%) mutations. mutations were significantly associated with WHO PS >2 ( < 0.001) and non-complex karyotype ( = 0.021) when compared to -WT. Furthermore, patients with mutations were more frequently -mutated ( = 0.007) and had a higher platelet count ( = 0.036). At relapse, /2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of -mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to /-WT. In /-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that / mutations are frequently detected at diagnosis and underlines the importance of recognizing /-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors.
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http://dx.doi.org/10.3390/cancers14123012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221405PMC
June 2022

Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome.

Neuroimage Clin 2022 Jun 8;35:103075. Epub 2022 Jun 8.

Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland. Electronic address:

Background: Dysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis.

Methods: 58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old,underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS.

Results: In line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately.

Conclusions: Our findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.
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http://dx.doi.org/10.1016/j.nicl.2022.103075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218553PMC
June 2022

Oscillatory Neural Signatures of Visual Perception Across Developmental Stages in Individuals With 22q11.2 Deletion Syndrome.

Biol Psychiatry 2022 09 7;92(5):407-418. Epub 2022 Mar 7.

Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland.

Background: Numerous behavioral studies have highlighted the contribution of visual perceptual deficits to the nonverbal cognitive profile of individuals with 22q11.2 deletion syndrome. However, the neurobiological processes underlying these widespread behavioral alterations are yet to be fully understood. Thus, in this paper, we investigated the role of neural oscillations toward visuoperceptual deficits to elucidate the neurobiology of sensory impairments in deletion carriers.

Methods: We acquired 125 high-density electroencephalography recordings during a visual grating task in a group of 62 deletion carriers and 63 control subjects. Stimulus-elicited oscillatory responses were analyzed with 1) time-frequency analysis using wavelets decomposition at sensor and source level, 2) intertrial phase coherence, and 3) Granger causality connectivity in source space. Additional analyses examined the development of neural oscillations across age bins.

Results: Deletion carriers had decreased theta-band (4-8 Hz) and gamma-band (58-68 Hz) spectral power compared with control subjects in response to the visual stimuli, with an absence of age-related increase of theta- and gamma-band responses. Moreover, adult deletion carriers had decreased gamma- and theta-band responses but increased alpha/beta desynchronization (10-25 Hz) that correlated with behavioral performance. Granger causality estimates reflected an increased frontal-occipital connectivity in the beta range (22-40 Hz).

Conclusions: Deletion carriers exhibited decreased theta- and gamma-band responses to visual stimuli, while alpha/beta desynchronization was preserved. Overall, the lack of age-related changes in deletion carriers implicates developmental impairments in circuit mechanisms underlying neural oscillations. The dissociation between the maturation of theta/gamma- and alpha/beta-band responses may indicate a selective impairment in supragranular cortical layers, leading to compensatory top-down connectivity.
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http://dx.doi.org/10.1016/j.biopsych.2022.02.961DOI Listing
September 2022

Hematemesis in Infants: The First Evidence-Based Score to Predict the Need for Timely Endoscopy.

Pediatr Emerg Care 2022 May 23;38(5):e1245-e1250. Epub 2021 Dec 23.

Division of Neurogastroenterology and Motility, Department of Paediatric Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.

Objectives: Infantile acute upper gastrointestinal bleeding involves a decision for therapeutic intervention that most pediatricians first coming into contact with the patient are, not unreasonably, unable to objectively provide. Therefore, some objective tools of individual risk assessment would seem to be crucial. The principal aim of the present study was to investigate the anamnestic and clinical parameters of infants with hematemesis, together with laboratory and instrumental findings, to create a scoring system that may help identify those infants requiring an appropriate and timely application of upper gastrointestinal (GI) endoscopy.

Methods: Clinical data of infants admitted for hematemesis to the participating centers over the study period were systematically collected. According to the outcome dealing with rebleeding, need for blood transfusion, mortality, finding of GI bleeding lesions, or need for surgical intervention, patients were blindly divided into a group with major clinical severity and a group with minor clinical severity. Univariate and multivariate logistic regressions were conducted to investigate significant prognostic factors for clinical severity.

Results: According to our findings, we drafted a practical diagnostic algorithm and a clinical score able to predict the need for timely upper GI endoscopy (BLOVO infant score). Our clinical scoring system was created by incorporating anamnestic factors, clinical parameters, and laboratory findings that emerged as predictors of a worst outcome.

Conclusions: We provided the first objective tool of individual risk assessment for infants with hematemesis, which could be very useful for pediatricians first coming into contact with the patient in the emergency department.
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http://dx.doi.org/10.1097/PEC.0000000000002579DOI Listing
May 2022

Aberrant Developmental Patterns of Gamma-Band Response and Long-Range Communication Disruption in Youths With 22q11.2 Deletion Syndrome.

Am J Psychiatry 2022 Mar;179(3):204-215

Developmental Imaging and Psychopathology Laboratory (Mancini, Schneider, Eliez) and Department of Genetic Medicine and Development (Eliez), University of Geneva School of Medicine, Geneva; Functional Brain Mapping Laboratory, Department of Basic Neurosciences, University of Geneva, Geneva (Rochas, Seeber, Roehri, Rihs, Ferat, Michel); Clinical Psychology Unit for Intellectual and Developmental Disabilities, Faculty of Psychology and Educational Sciences, University of Geneva, Geneva (Schneider); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, Scotland (Uhlhaas); Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Charité Universitätsmedizin, Berlin (Uhlhaas); Center for Biomedical Imaging (CIBM) of Lausanne and Geneva (Michel).

Objective: Brain oscillations play a pivotal role in synchronizing responses of local and global ensembles of neurons. Patients with schizophrenia exhibit impairments in oscillatory response, which are thought to stem from abnormal maturation during critical developmental stages. Studying individuals at genetic risk for psychosis, such as 22q11.2 deletion carriers, from childhood to adulthood may provide insights into developmental abnormalities.

Methods: The authors acquired 106 consecutive T-weighted MR images and 40-Hz auditory steady-state responses (ASSRs) with high-density (256 channel) EEG in a group of 58 22q11.2 deletion carriers and 48 healthy control subjects. ASSRs were analyzed with 1) time-frequency analysis using Morlet wavelet decomposition, 2) intertrial phase coherence (ITPC), and 3) theta-gamma phase-amplitude coupling estimated in the source space between brain regions activated by the ASSRs. Additionally, volumetric analyses were performed with FreeSurfer. Subanalyses were conducted in deletion carriers who endorsed psychotic symptoms and in subgroups with different age bins.

Results: Deletion carriers had decreased theta and late-latency 40-Hz ASSRs and phase synchronization compared with control subjects. Deletion carriers with psychotic symptoms displayed a further reduction of gamma-band response, decreased ITPC, and decreased top-down modulation of gamma-band response in the auditory cortex. Reduced gamma-band response was correlated with the atrophy of auditory cortex in individuals with psychotic symptoms. In addition, a linear increase of theta and gamma power from childhood to adulthood was found in control subjects but not in deletion carriers.

Conclusions: The results suggest that while all deletion carriers exhibit decreased gamma-band response, more severe local and long-range communication abnormalities are associated with the emergence of psychotic symptoms and gray matter loss. Additionally, the lack of age-related changes in deletion carriers indexes a potential developmental impairment in circuits underlying the maturation of neural oscillations during adolescence. The progressive disruption of gamma-band response in 22q11.2 deletion syndrome supports a developmental perspective toward understanding and treating psychotic disorders.
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http://dx.doi.org/10.1176/appi.ajp.2021.21020190DOI Listing
March 2022

Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey.

Mycoses 2022 Feb 3;65(2):171-177. Epub 2021 Dec 3.

Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Background: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy.

Results: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p < .033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate.

Conclusion: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.
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http://dx.doi.org/10.1111/myc.13384DOI Listing
February 2022

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA).

J Hematol Oncol 2021 10 14;14(1):168. Epub 2021 Oct 14.

Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar.

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality.

Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020.

Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases.

Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.
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http://dx.doi.org/10.1186/s13045-021-01177-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515781PMC
October 2021

Long-term quality of life of patients with acute promyelocytic leukemia treated with arsenic trioxide vs chemotherapy.

Blood Adv 2021 11;5(21):4370-4379

Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy.

The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA chemotherapy. The median time since diagnosis of the study sample was 8 years. The 2 largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ = 8.4; 95% confidence interval [CI], 0.5 to 16.3) and dyspnea (Δ = -8.5; 95% CI, -16.4 to -0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ = 4.6; 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The 2 groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA chemotherapy. This study was registered at www.clinicaltrials.gov as #NCT03096496.
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http://dx.doi.org/10.1182/bloodadvances.2021004649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579253PMC
November 2021

Selective Effects of Methylphenidate on Attention and Inhibition in 22q11.2 Deletion Syndrome: Results From a Clinical Trial.

Int J Neuropsychopharmacol 2022 03;25(3):215-225

Developmental Imaging and Psychopathology Laboratory, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland.

Background: Attention deficit and/or hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2 deletion syndrome (22q11DS) and frequently persists into adulthood. Although medication with stimulant has been demonstrated to be highly effective in idiopathic ADHD, evidence in 22q11DS is still scarce. Previous studies have shown safety and effectiveness of methylphenidate (MPH) on core symptoms of ADHD as well as improvement of associated cognitive deficits. However, only a limited number of cognitive domains have been explored.

Methods: Twenty-three participants with 22q11DS and attention difficulties, aged 8-24 years, entered a clinical trial aiming to specify the effects of MPH on clinical symptoms, cognition, and daily-life behavior. The effects of treatment were compared with/without medication in a within-subject design. The trial included both participants naïve to the molecule and chronic users.

Results: Benefit from the treatment was demonstrated through a decrease in core ADHD symptoms, specifically inattention symptoms, and improvement of cognitive measures of attention and inhibition. Conversely, no significant change was found for other executive functions (such as cognitive flexibility, working memory, initiation), learning, or memory. Moreover, no significant improvement on ecological measures of daily-life executive functioning was found, possibly because of the short treatment period. We replicated safety, and although very frequent, side effects were of mild intensity and comparable with previous findings.

Conclusions: This study extends the current knowledge on the effects of MPH in patients with 22q11DS. Treatment was found to be effective for core ADHD symptoms and cognitive measures of attention and inhibition.
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http://dx.doi.org/10.1093/ijnp/pyab057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8929751PMC
March 2022

Monitoring the manufacturing and quality of medicines: a fundamental task of pharmacovigilance.

Ther Adv Drug Saf 2021 5;12:20420986211038436. Epub 2021 Aug 5.

Uppsala Monitoring Centre, Uppsala, Sweden.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed.

Plain Language Summary: Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring, and prevention of adverse reactions with pharmaceutical products. The collection and assessment of adverse reactions are particularly important in the first decade after marketing authorisation of a drug as the information gathered in this period could help, for example, to identify complications from its use which were unknown before its commercialization. However, when it comes to medicines that have been on the market for a long time there is general acceptance that their safety profile is already well-established and unknown adverse reactions unlikely to occur. Nevertheless, even older medicines, such as generic drugs, can generate new risks. For these drugs a change in the safety profile could be the result of inadequate control of their quality, manufacturing and distribution systems. To overcome such an obstacle, it is necessary to fully integrate manufacturing and pharmacovigilance quality systems in the medicine life-cycle. This could help detect safety hazards and prevent the development of new complications which may arise due to the poor quality of a drug. Pharmacovigilance activities should indeed be included in all phases of the drugs' manufacturing and distribution process, regardless of their chemical complexity to detect quality-related matters in good time and reduce the risk of safety concerns to a minimum.
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http://dx.doi.org/10.1177/20420986211038436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361554PMC
August 2021

Commentary: A new little piece for a great puzzle.

JTCVS Tech 2021 Feb 18;5:20. Epub 2020 Nov 18.

Cardiothoracic Surgery Department, Heart & Vascular Center, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1016/j.xjtc.2020.10.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300039PMC
February 2021

Altered cortical thickness development in 22q11.2 deletion syndrome and association with psychotic symptoms.

Mol Psychiatry 2021 12 12;26(12):7671-7678. Epub 2021 Jul 12.

Developmental Imaging and Psychopathology Laboratory, Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Schizophrenia has been extensively associated with reduced cortical thickness (CT), and its neurodevelopmental origin is increasingly acknowledged. However, the exact timing and extent of alterations occurring in preclinical phases remain unclear. With a high prevalence of psychosis, 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that represents a unique opportunity to examine brain maturation in high-risk individuals. In this study, we quantified trajectories of CT maturation in 22q11DS and examined the association of CT development with the emergence of psychotic symptoms. Longitudinal structural MRI data with 1-6 time points were collected from 324 participants aged 5-35 years (N = 148 22q11DS, N = 176 controls), resulting in a total of 636 scans (N = 334 22q11DS, N = 302 controls). Mixed model regression analyses were used to compare CT trajectories between participants with 22q11DS and controls. Further, CT trajectories were compared between participants with 22q11DS who developed (N = 61, 146 scans), or remained exempt of (N = 47; 98 scans) positive psychotic symptoms during development. Compared to controls, participants with 22q11DS showed widespread increased CT, focal reductions in the posterior cingulate gyrus and superior temporal gyrus (STG), and accelerated cortical thinning during adolescence, mainly in frontotemporal regions. Within 22q11DS, individuals who developed psychotic symptoms showed exacerbated cortical thinning in the right STG. Together, these findings suggest that genetic predisposition for psychosis is associated with increased CT starting from childhood and altered maturational trajectories of CT during adolescence, affecting predominantly frontotemporal regions. In addition, accelerated thinning in the STG may represent an early biomarker associated with the emergence of psychotic symptoms.
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http://dx.doi.org/10.1038/s41380-021-01209-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873018PMC
December 2021

Chronic Migraine Preventive Treatment by Prefrontal-Occipital Transcranial Direct Current Stimulation (tDCS): A Proof-of-Concept Study on the Effect of Psychiatric Comorbidities.

Front Neurol 2021 13;12:654900. Epub 2021 May 13.

Department of Human Neurosciences, Sapienza-University of Rome, Rome, Italy.

Chronic migraine (CM) is often complicated by medication overuse headache (MOH) and psychiatric comorbidities that may influence the clinical outcome. This study aimed to investigate the relationship between psychiatric comorbidities and the effect of transcranial direct current stimulation (tDCS) in patients with CM with or without MOH. We recruited 16 consecutive CM patients who had an unsatisfactory response to at least three pharmacological preventive therapies. They were treated with anodal right-prefrontal and cathodal occipital tDCS (intensity: 2 mA, time: 20 min) three times per week for 4 weeks. All patients underwent a psychopathological assessment before and after treatment, and five of them were diagnosed with bipolar disorder (BD). After treatment, all the patients showed a significant decrease of severe and overall headache days per month. Despite having a higher migraine burden at baseline, patients with CM and BD showed a significantly greater reduction of severe headaches and psychiatric symptoms. Overall, tDCS seems to be effective in the treatment of CM patients with a poor response to different classes of pharmacological therapies, whereas BD status positively influences the response of migraineurs to tDCS.
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http://dx.doi.org/10.3389/fneur.2021.654900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166222PMC
May 2021

Long-term effects of early treatment with SSRIs on cognition and brain development in individuals with 22q11.2 deletion syndrome.

Transl Psychiatry 2021 05 29;11(1):336. Epub 2021 May 29.

Developmental Imaging and Psychopathology Laboratory, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland.

Cognitive deficits in individuals at risk of psychosis represent a significant challenge for research, as current strategies for symptomatic treatment are often ineffective. Recent studies showed that atypical cognitive development predicts the occurrence of psychotic symptoms. Additionally, abnormal brain development is known to predate clinical manifestations of psychosis. Therefore, critical developmental stages may be the best period for early interventions expected to prevent cognitive decline and protect brain maturation. However, it is challenging to identify and treat individuals at risk of psychosis in the general population before the onset of the first psychotic symptoms. 22q11.2 deletion syndrome (22q11DS), the neurogenetic disorder with the highest genetic risk for schizophrenia, provides the opportunity to prospectively study the development of subjects at risk for psychosis. In this retrospective cohort study, we aimed to establish if early treatment with SSRIs in children and adolescents with 22q11DS was associated with long-term effects on cognition and brain development. We included 98 participants with a confirmed diagnosis of 22q11DS followed up 2-4 times (age range: 10-32). Thirty subjects without psychiatric disorders never received psychotropic medications, thirty had psychotic symptoms but were not treated with SSRIs, and 38 received SSRIs treatment. An increase in IQ scores characterized the developmental trajectories of participants receiving treatment with SSRIs, even those with psychotic symptoms. The thickness of frontal regions and hippocampal volume were also relatively increased. The magnitude of the outcomes was inversely correlated to the age at the onset of the treatment. We provide preliminary evidence that early long-term treatment with SSRIs may attenuate the cognitive decline associated with psychosis in 22q11DS and developmental brain abnormalities.
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http://dx.doi.org/10.1038/s41398-021-01456-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164636PMC
May 2021

Dysmaturation Observed as Altered Hippocampal Functional Connectivity at Rest Is Associated With the Emergence of Positive Psychotic Symptoms in Patients With 22q11 Deletion Syndrome.

Biol Psychiatry 2021 07 18;90(1):58-68. Epub 2021 Jan 18.

Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland.

Background: Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia.

Methods: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups.

Results: Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms.

Conclusions: Our findings suggest a critical period of prefrontal cortex-hippocampal-striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.033DOI Listing
July 2021

Reply: Small aortic annulus: Can we dispel all the Hamletic doubts?

J Thorac Cardiovasc Surg 2021 02;161(2):e160

Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Cardiology, "Pierangeli" Hospital, Pescara, Italy.

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http://dx.doi.org/10.1016/j.jtcvs.2020.10.141DOI Listing
February 2021

Prevalence and characteristics of Alice in Wonderland Syndrome in adult migraineurs: Perspectives from a tertiary referral headache unit.

Cephalalgia 2021 04 9;41(5):515-524. Epub 2020 Nov 9.

Department of Human Neurosciences, Sapienza - University of Rome, Rome, Italy.

Background: Migraine affects how the brain processes sensory information at multiple levels. The aberrant integration of visual and somatosensory stimuli is thought to underlie Alice in Wonderland Syndrome, a disorder often reported as being associated with migraine. However, there is still a lack of knowledge about the epidemiology of this syndrome in migraineurs and the association between Alice in Wonderland Syndrome episodes and migraine attacks. Therefore, we conducted a prospective cohort study to systematically evaluate the prevalence and the clinical features of Alice in Wonderland Syndrome in a large sample of patients with migraine.

Methods: All the patients attending for the first time a tertiary-level headache clinic were consecutively screened for Alice in Wonderland Syndrome symptoms by means of an ad hoc questionnaire and detailed clinical interview, over a period of 1.5 years. Patients experiencing Alice in Wonderland Syndrome symptoms were contacted for a follow-up after 8-12 months.

Results: Two hundred and ten patients were recruited: 40 patients (19%) reported lifetime occurrence of Alice in Wonderland Syndrome, 90% of whom (38/40) had migraine with aura. Thirty-one patients experienced episodes of Alice in Wonderland Syndrome within 1 h from the start of migraine headache. Patients reported either visual or visual and somatosensory symptoms (i.e. somatosensory symptoms never presented alone). We collected the follow-up details of 30 patients with Alice in Wonderland Syndrome, 18 of whom had been prescribed a preventive treatment for migraine. After 8-12 months, 5 of the treated patients reported a decrease, while 13 reported no episodes of Alice in Wonderland Syndrome.

Conclusion: Alice in Wonderland Syndrome prevalence in migraineurs was found to be higher than expected. Alice in Wonderland Syndrome was mostly associated with migraine with aura and tended to occur close to the migraine attack, suggesting the existence of a common pathophysiological mechanism. Patients treated with migraine preventive treatments had a higher chance of decreasing or even resolving Alice in Wonderland Syndrome episodes.
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http://dx.doi.org/10.1177/0333102420968245DOI Listing
April 2021

Validation of the "fitness criteria" for the treatment of older patients with acute myeloid leukemia: A multicenter study on a series of 699 patients by the Network Rete Ematologica Lombarda (REL).

J Geriatr Oncol 2021 05 20;12(4):550-556. Epub 2020 Oct 20.

Department of Hematology, ASST Spedali Civili of Brescia, Brescia, Italy.

Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the "fitness criteria" proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL).

Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded.

Results: "Fitness criteria" were easily applicable in 98.1% of patients. Overall concordance between "fitness criteria" and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS <2, and receiving any treatment other than BSC had a favorable effect on survival (p < 0.001).

Conclusion: These simple "fitness criteria" applied at the time of diagnosis could facilitate, together with AML biologic risk evaluation, the choice of the most appropriate treatment intensity in older AML patients.
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http://dx.doi.org/10.1016/j.jgo.2020.10.004DOI Listing
May 2021

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19.

Cancer 2020 12 10;126(23):5069-5076. Epub 2020 Sep 10.

Hematology Department, ASST Spedali Civili, Brescia, Italy.

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients.

Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19.

Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P = .02) and uninfected hematologic controls (3%; P < .001). The severity of the respiratory syndrome at presentation and active hematologic treatment were independently associated with a worse prognosis. Neither diagnosis nor disease status affected the prognosis. The worst prognosis was demonstrated among patients on active hematologic treatment and those with more severe respiratory syndrome at COVID-19 presentation.

Conclusions: During the COVID-19 pandemic, patients should be advised to seek medical attention at the earliest signs of dyspnea and/or respiratory infection. Physicians should perform a risk-benefit analysis to determine the impact of temporarily deferring nonlifesaving treatments versus the risk of adverse outcomes associated with COVID-19.

Lay Summary: Coronavirus disease 2019 (COVID-19) infection occurs across all different types of hematologic disease; however, the risk of acquiring it is lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive treatment. The 30-day mortality rate is 39.2%, which is far higher than the rates for both uninfected hematologic controls (3%; P < .001) and nonhematologic patients with COVID-19 (23.5%; P = .02) despite matching for age, sex, comorbidities, and severity of disease. Variables independently associated with a worse prognosis are the severity of the respiratory syndrome at presentation and any type of active hematologic treatment. Neither diagnosis nor disease status influence the prognosis.
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http://dx.doi.org/10.1002/cncr.33160DOI Listing
December 2020

Quantification of 1,3-β-d-glucan by Wako β-glucan assay for rapid exclusion of invasive fungal infections in critical patients: A diagnostic test accuracy study.

Mycoses 2020 Dec 17;63(12):1299-1310. Epub 2020 Sep 17.

Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.

Objectives: Rapid and reliable exclusion of invasive fungal infections (IFI) by markers able to avoid unnecessary empirical antifungal treatment is still a critical unmet clinical need. We investigated the diagnostic performance of a newly available β-d-Glucan (BDG) quantification assay, focusing on the optimisation of the BDG cut-off values for IFI exclusion.

Methods: BDG results by Wako β-glucan assay (lower limit of detection [LLOD] = 2.16 pg/mL, positivity ≥ 11 pg/mL) on two consecutive serum samples were retrospectively analysed in 170 patients, admitted to haematological wards (N = 42), intensive care units (ICUs; N = 80), or other wards (N = 48), exhibiting clinical signs and/or symptoms suspected for IFI. Only patients with proven IFI (EORTC/MSG criteria) were considered as true positives in the assessment of BDG sensitivity, specificity and predictive values.

Results: Patients were diagnosed with no IFI (69.4%), proven IFI (25.3%) or probable IFI (5.3%). Two consecutive BDG values < LLOD performed within a median of 1 (interquartile range: 1-3) day were able to exclude a proven IFI with 100% sensitivity and negative predictive value (primary study goal). Test's specificity improved by using two distinct positivity and negativity cut-offs (7.7 pg/mL and LLOD, respectively), but remained suboptimal in ICU patients (50%), as compared to haematological or other patients (93% and 90%, respectively).

Conclusions: The classification of Wako's results as negative when < LLOD, and positive when > 7.7 pg/mL, could be a promising diagnostic approach to confidently rule out an IFI in both ICU and non-ICU patients. The poor specificity in the ICU setting remains a concern, due to the difficulty to interpret positive results in this fragile population.
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http://dx.doi.org/10.1111/myc.13170DOI Listing
December 2020

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study.

Am J Hematol 2020 12 31;95(12):1466-1472. Epub 2020 Aug 31.

Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, "Sapienza" Università di Roma, Rome, Italy.

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.
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http://dx.doi.org/10.1002/ajh.25957DOI Listing
December 2020

Abnormal Auditory Processing and Underlying Structural Changes in 22q11.2 Deletion Syndrome.

Schizophr Bull 2021 01;47(1):189-196

Functional Brain Mapping Laboratory, Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland.

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H-) reveals no change in MMN response in 22q11.2DS (H+ and H-) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH- and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms.
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http://dx.doi.org/10.1093/schbul/sbaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825015PMC
January 2021

Birth Weight and the Development of Functional Gastrointestinal Disorders in Infants.

Pediatr Gastroenterol Hepatol Nutr 2020 Jul 3;23(4):366-376. Epub 2020 Jul 3.

Department of Biomedical Science and Human Oncology, Aldo Moro University of Bari, Bari, Italy.

Purpose: To assess the association between birth weight and the development of functional gastrointestinal disorders (FGIDs) in the first year of life.

Methods: This is a secondary analysis of a prospective cohort multicenter study including neonates, consecutively enrolled at birth, and followed up for one year. At birth all infants were classified by birth weight as extremely low (ELBW), very low, or low when <1,000, <1,500, and <2,500 g, respectively, and by birth weight for gestational age as appropriate (AGA, weight in the 10-90th percentile), small (SGA, weight <10th percentile), and large (LGA, weight >90th percentile) for gestational age. FGIDs were classified according to the Rome III criteria and assessed at 1, 3, 6, and 12 months of life.

Results: Among 1,152 newborns enrolled, 934 (81.1%) completed the study: 302 (32.3%) were preterm, 35 (3.7%) were ELBW, 104 (11.1%) were SGA, 782 (83.7%) were AGA, and 48 (5.1%) were LGA infants. Overall, throughout the first year of life, 718 (76.9%) reported at least one FGID. The proportion of infants presenting with at least one FGID was significantly higher in ELBW (97%) compared to LBW (74%) (=0.01) and in LGA (85.4%) and SGA (85.6%) compared to AGA (75.2%) (=0.0001). On multivariate analysis, SGA was significantly associated with infantile colic.

Conclusion: We observed an increased risk of FGIDs in ELBW, SGA, and LGA neonates. Our results suggest that prenatal factors determining birth weight may influence the development of FGIDs in infants. Understanding the role of all potential risk factors may provide new insights and targeted approaches for FGIDs.
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http://dx.doi.org/10.5223/pghn.2020.23.4.366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354866PMC
July 2020

Abnormal Development and Dysconnectivity of Distinct Thalamic Nuclei in Patients With 22q11.2 Deletion Syndrome Experiencing Auditory Hallucinations.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 09 8;5(9):875-890. Epub 2020 May 8.

Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland.

Background: Several studies in patients with schizophrenia have demonstrated an abnormal thalamic volume and thalamocortical connectivity. Specifically, hyperconnectivity with somatosensory areas has been related to the presence of auditory hallucinations (AHs). The 22q11.2 deletion syndrome is a neurogenetic disorder conferring proneness to develop schizophrenia, and deletion carriers (22qdel carriers) experience hallucinations to a greater extent than the general population.

Methods: We acquired 442 consecutive magnetic resonance imaging scans from 120 22qdel carriers and 110 control subjects every 3 years (age range: 8-35 years). The volume of thalamic nuclei was obtained with FreeSurfer and was compared between 22qdel carriers and control subjects and between 22qdel carriers with and without AHs. In a subgroup of 76 22qdel carriers, we evaluated the functional connectivity between thalamic nuclei affected in patients experiencing AHs and cortical regions.

Results: As compared with control subjects, 22qdel carriers had lower and higher volumes of nuclei involved in sensory processing and cognitive functions, respectively. 22qdel carriers with AHs had a smaller volume of the medial geniculate nucleus, with deviant trajectories showing a steeper volume decrease from childhood with respect to those without AHs. Moreover, we showed an aberrant development of nuclei intercalated between the prefrontal cortex and hippocampus (the anteroventral and medioventral reuniens nuclei) and hyperconnectivity of the medial geniculate nucleus and anteroventral nucleus with the auditory cortex and Wernicke's area.

Conclusions: The increased connectivity of the medial geniculate nucleus and anteroventral nucleus to the auditory cortex might be interpreted as a lack of maturation of thalamocortical connectivity. Overall, our findings point toward an aberrant development of thalamic nuclei and an immature pattern of connectivity with temporal regions in relation to AHs.
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http://dx.doi.org/10.1016/j.bpsc.2020.04.015DOI Listing
September 2020

Is it Useful to Do a Taxonomy of Complex Visual Symptoms in Migraine? A Comment on Coining the Pablo Picasso Syndrome.

Headache 2020 06;60(6):1200-1201

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1111/head.13813DOI Listing
June 2020

Adding pieces to the Alice in wonderland syndrome puzzle: a comment to the paper by Brooks and colleagues.

Arq Neuropsiquiatr 2020 04;78(4):242-243

Sapienza Università di Roma, Dipartimento di Neuroscienze Umane, Roma, Italia.

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http://dx.doi.org/10.1590/0004-282X20190194DOI Listing
April 2020

Isavuconazole in Hematological Patients: Results of a Real-Life Multicentre Observational Seifem Study.

Hemasphere 2019 Dec 4;3(6):e320. Epub 2019 Nov 4.

Fondazione Policlinico Universitario A. Gemelli-IRCCS Roma, Italy.

Invasive fungal diseases (IFDs) remain a major clinical issue in patients with hematological malignancies (HMs). To confirm the efficacy and safety of the new azole isavuconazole (ISV) in a clinical care setting, we planned a multicenter retrospective study; we collected data on all possible/probable/proven IFDs in patients with HMs treated with ISV in 17 centers. Between July 2016 and November 2018, 128 patients were enrolled, and 122 were fully evaluable. ISV was employed as the 1 line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%) patients. The response rate was 82/122 patients (67.2%); it was similar when using ISV as a 1st or 2nd line treatment (60.5% vs 70.9%, respectively; p = 0.24). In multivariate analysis, both female sex (OR: 2.992; CI: 1.22-7.34) and induction phase of treatment (OR: 3.953; CI: 1.085-14.403) were predictive of a favorable response. At a median follow-up of 5 months, 43 (35.2%) patients were dead; the 1-year overall survival (OS) was 49.9%. In multivariate analysis, the response to ISV (OR: 0.103; CI: 0.041-0.262) and IFD refractoriness to previous antifungals (OR: 3.413; CI: 1.318-8.838) were statistically significant for OS. Adverse events (AEs) were reported in 15/122 patients (12.3%); grade 3-4 AEs were reported in 5 (4%) and led to ISV discontinuation. Our study confirms the safety and tolerability of ISV, also in diseases other than acute leukemia. Phase of hematological disease, gender and refractoriness to previous antifungals are the main predictive factors for the aforementioned response and outcome.
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http://dx.doi.org/10.1097/HS9.0000000000000320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924559PMC
December 2019
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