An unusual arylsulfatase A pseudodeficiency allele carrying a splice site mutation in a metachromatic leukodystrophy patient

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Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation

Alexander disease is a leukodystrophy caused by heterozygous mutations of GFAP gene. Recurrence in siblings from healthy parents provides a confirmation to the transmission of variants through germinal mosaicism. With the use of DNA isolated from peripheral blood, next-generation sequencing (NGS) of GFAP locus was performed with deep coverage (>= 500x) in 11 probands and their parents (trios) with probands heterozygous for apparently de novo GFAP mutations. Indeed, one parent had somatic mosaicism, estimated in the range of 8.9%-16%, for the mutant allele transmitted to the affected sibling. Parental germline mosaicism deserves attention, as it is critical in assessing the risk of recurrence in families with Alexander disease

Blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells as major adverse effects in CAR-T-related deaths: a literature review

Background CAR-T-related deaths observed worldwide are rare. The underlying pathogenetic mechanisms are the subject of study, as are the findings that enable diagnosis. A systematic literature search of the PubMed database and a critical review of the collected studies were conducted from the inception of this database until January 2023. The aim of the study is to determine when death is related to CAR-T cell therapy and to develop a shareable diagnostic algorithm.Methods The database was searched by combining and meshing the terms ("CAR-t" OR "CART") AND ("Pathology" OR "Histology" OR "Histological" OR "Autopsy") AND ("Heart" OR "Cardiac" OR "Nervous System" OR "Kidney" OR "Liver") with 34 results and also the terms: [(Lethal effect) OR (Death)] AND (CAR-T therapy) with 52 results in titles, abstracts, and keywords [all fields]. One hundred scientific articles were examined, 14 of which were additional records identified through other sources. Fifteen records were included in the review.Results Neuronal death, neuronal edema, perivascular edema, perivascular and intraparenchymal hemorrhagic extravasation, as well as perivascular plasmatodendrosis, have been observed in cases with fatal cerebral edema. A cross-reactivity of CAR-T cells in cases of fatal encephalopathy can be hypothesized when, in addition to the increased vascular permeability, there is also a perivascular lymphocyte infiltrate, which appears to be a common factor among most authors.Conclusion Most CAR-T-related deaths are associated with blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells. Further autopsies and microscopic investigations would shed more light on the lethal toxicity related to CAR-T cells. A differential diagnosis of CAR-T-related death is crucial to identifying adverse events. In this article, we propose an algorithm that could facilitate the comparison of findings through a systematic approach. Despite toxicity cases, CAR-T therapy continues to stand out as the most innovative treatment within the field of oncology, and emerging strategies hold the promise of delivering safer therapies in future

Severity of respiratory failure and outcome of patients needing a ventilatory support in the Emergency Department during Italian novel coronavirus SARS-CoV2 outbreak: Preliminary data on the role of Helmet CPAP and Non-Invasive Positive Pressure Ventilation

Background: Novel Coronavirus SARS-CoV-2 pandemic is spreading around the world. At the end of February, the outburst of the pandemic has hit hard on northern Italian's hospitals. As of today, no data have been published regarding the severity of respiratory failure of patients presenting to the Emergency Departments. Moreover, the outcome the patients forced to undergo Continuous Positive Airway Pressure (CPAP) or Non-Invasive Positive Pressure Ventilation (NIPPV) due to lack of Intensive Care resources is unknown. “Papa Giovanni XXIII” hospital (HPG23) of Bergamo is one of the largest hospitals in the Country, with an Emergency Department (ED) managing over 100,000 patients per year. Methods: This is a retrospective observational study based on chart review of patients presenting to the Emergency Department of HPG23 from 29/02/2020 to 10/03/2020 with a clinical condition highly suspicious for COVID-19 infection. Registration of admission rates, severity of respiratory failure (ARDS classification), need of respiratory support, SARS-CoV-2 PCR test and outcome of patients treated with a ventilatory support were registered on 10th of May 2020. Findings: From 29/02 to 10/03 611 patients with a suspected diagnosis of COVID-19 infection were evaluated in our ED; 320 (52%) met the criteria for hospital admission and 99 (31%) needed to be immediately started on ventilatory support (81% CPAP, 7% NIPPV, 12% Invasive Mechanical Ventilation). Eighty-five (86%) of the 99 patients needing a ventilatory support eventually had SARS-CoV-2 infection confirmed by PCR test on nasal-pharyngeal swab. Their median PO2/FiO2 ratio was 128 (IQR 85–168), with 23 patients (29.5%) classified as severe ARDS. Mortality rate as of 10th of May was 76.5%, ranging from 44.4% within patients <60 years old to 85% within those older than 60 years (p = 0.001). NIPPV/CPAP failure occurred in 91.5% of patients. Interpretation: The population of patients suspected for COVID-19 infection presenting at our ED showed a very high rate of severe respiratory failure, with urgent need of a large amount of intensive care resources. Mortality rates of critically ill patients with confirmed COVID-19 (76.5%) are similar to previously reported studies with similar population. CPAP/NIPPV could be a valid strategy to treat severely hypoxic patients that cannot be intubated in the ED due to lack of intensive care resources. Funding: No funds were received for this research project

Long-acting combination of cabotegravir plus rilpivirine: A picture of potential eligible and ineligible HIV-positive individuals from the Italian ARCA cohort

Objectives: We aimed to evaluate the prevalence and characteristics of people living with HIV (PLWH) eligible for the long-acting injectable (LAI) regimen with cabotegravir (CAB) and rilpivirine (RPV), in comparison with ineligible individuals. Methods: This was an observational, cross-sectional study from the ARCA cohort, including virologically suppressed PLWH with at least one genotypic resistance testing (GRT) for reverse transcriptase and integrase from plasma and/or PBMCs. Eligibility criteria for LAI CAB+RPV were: negative HBsAg, absence of previous virological failures and/or resistance-associated mutations for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and/or integrase strand transfer inhibitors. Potential differences between eligible and ineligible individuals were investigated by univariable and multivariable analyses. Results: A total of 514 individuals were included: 377 (73.3%) were male, median age was 51 (IQR: 43–58), on ART for 9 years (IQR: 4–17), virologically suppressed for 63 months (IQR: 35–105). Eligible individuals for CAB+RPV were 229 (44.5%, 95%CI: 40.8–48.8); compared with ineligible individuals, they received a lower number of previous regimens (aOR 0.76, 95% CI 0.71–0.83, P < 0.001) and were on current NNRTIs (aOR 2.16, 95% CI 1.38–3.37, P = 0.001). Conclusions: Less than half of virologically suppressed PLWH in the ARCA cohort were potentially eligible for CAB+RPV. They seem to be “less complicated” with shorter exposure to ART and preferably already on NNRTIs

Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene

Introduction:Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female new-born of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (< 8 g/L) and severe clinical symptoms. Materials and methods: The albumin gene of the index case was screened by single-strand conformation polymorphism, heteroduplex analysis, and direct DNA sequencing. The effect of the splicing mutation was evaluated by examining the cDNA obtained by reverse transcriptase - polymerase chain reaction (RT-PCR) from the albumin mRNA extracted from proband’s leukocytes. Results: DNA sequencing revealed that the proband is homozygous, and both parents are heterozygous, for a novel G>A transition at position c.1652+1, the first base of intron 12, which inactivates the strongly conserved GT dinucleotide at the 5’ splice site consensus sequence of this intron. The splicing defect results in the complete skipping of the preceding exon (exon 12) and in a frame-shift within exon 13 with a premature stop codon after the translation of three mutant amino acid residues. Conclusions: Our results confirm the clinical diagnosis of congenital analbuminemia in the proband and the inheritance of the trait and contribute to shed light on the molecular genetics of analbuminemia

Vaccinations in children of non-European origin: The Vax4globe survey

Background: An equitable immunization coverage to “leave no one behind” is one of the World Health Organization Sustainable Development Goals. However, disparities in vaccination coverage exist. The present study aims to investigate vaccine attitude of non-European parents living in Italy and those factors affecting vaccine uptake and equity. Methods: A cross sectional survey, named Vax4globe, on knowledge and immunization compliance in childhood and pregnancy of non-European (non-EU) parents was carried out among general pediatrician and Vaccine Centers located in Lazio Region, between February and July 2023. Logistic regression models were used in univariate and multivariate analyses to examine the socio-demographic parameters mainly associated with the vaccination status. Results: A total of 310 parent/child pair were included in the study. Most children were born in Italy (262/310; 86.5 %), while while 40/310 (13.2 %) migrated from country of origin and 1/310 (0.3 %) was adopted. Mandatory vaccines were perfomed by 270/306 (88 %) children, however flu, papillomavirus and meningococcal group B were vaccines most commonly refused by 208/289 (72 %), 11/36 (31 %) and 9/36 (25 %) parents, respectively. A lower educational degree of parents (p = 0.040) and the migration status of children (p &lt; 0.001) were associated to incomplete or missed immunization. As to maternal immunization 164/310 (53 %) non-EU women decided not to vaccinate and received less information (155/297;52 %) compared to childhood immunization (268/305; 88 %) (p &lt; 0.0001). The educational degree (p = 0.017), the origin from non-EU European countries (p = 0.008) and the age 25–40 years (p = 0.036) and &gt; 40 years (p = 0.007) were associated to lack of immunization during pregnancy. Finally, while 279/310 (90 %) parents were vaccinated against Sars-CoV-2, only 60/199 (30 %) children had been immunized with this vaccine mainly due to the non-mandatory vaccine request at pediatric age and to the doubts about its value according to 39/127 (31 %) and 29/127 (23 %) parents, respectively. Conclusion: Our study highlights the need for targeted strategies to improve vaccine uptake both in childhood and in pregnancy among non-EU individuals living in Italy. Further, to achieve vaccination equity the role of institutions and healthcare personnel is pivotal to overcome vaccine hesitancy

Modelling the Time Varying Determinants of Portfolio Flows to Emerging Markets

This paper studies how the drivers of portfolio flows change across periods with a model where regression coefficients endogenously change over time in a continuous fashion. The empirical analysis of daily equity portfolio flows to emerging markets shows that the regression coefficients display substantial time variation. Major changes in the importance of the drivers of the flows coincide with important market events/shocks. Overall, investors pay more attention to regional developments in emerging markets in periods when market tensions are elevated. However, extreme tensions generate panics, i.e. periods when changes in uncertainty and risk aversion drive flows, while regional developments play only a marginal role