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The field of inflammatory disease of the heart or cardio-immunology is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

Abstract Background Spinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre–mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery. Methods By RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0). Results We observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into “homogeneous” and “heterogeneous” according to their gene expression pattern. The “heterogeneous” group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern. Conclusions This study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.

Objectives: To compare the long-term cumulative risk of SARS-CoV-2 infection associated with natural and vaccine-induced immunity. Methods: Retrospective population-based cohort study based on registry of COVID-19 vaccinations and SARS-CoV-2 infections among 9.1 million citizens of Lombardy, Italy, eligible for vaccination on 27th December 2020. Those who developed SARS-CoV-2 infection from 24th May to 14th September 2021, provided they did not yet receive the COVID-19 vaccine when infection was confirmed, and those who received the second mRNA vaccine dose, provided they had not yet developed the infection, were selected to be 1:1 matched for sex, age and index date. The latter corresponded to 90 days after confirmed infection or 14 days after vaccine administration. A control cohort including citizens who, on the index date, had neither developed infection nor received vaccination was also selected. Kaplan–Meier curves were used for comparing the cumulative incidence of new SARS-CoV-2 infection from the index date until 22nd June 2022. Results: Overall, 19,418 1:1:1 risk-sets were included. After 9 months of follow-up, the cumulative risk of new SARS-CoV-2 infection was 21.8%, 22.0%, and 25.9%, respectively, among exposed to natural immunity, vaccine-induced immunity and unexposed. Conclusions: Equivalent potential for protecting against new SARS-CoV-2 infection was observed.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Comparing deaths averted by vaccination campaigns is a crucial public health endeavour. Excess all-cause deaths better reflect the impact of the pandemic than COVID-19 deaths. We used a seasonal autoregressive integrated moving average with exogenous factors model to regress daily all-cause deaths on annual trend, seasonality, and environmental temperature in three Italian regions (Lombardy, Marche and Sicily) from 2015 to 2019. The model was used to forecast excess deaths during the vaccinal period (December 2020–October 2022). We used the prevented fraction to estimate excess deaths observed during the vaccinal campaigns, those which would have occurred without vaccination, and those averted by the campaigns. At the end of the vaccinal period, the Lombardy region proceeded with a more intensive COVID-19 vaccination campaign than other regions (on average, 1.82 doses per resident, versus 1.67 and 1.56 in Marche and Sicily, respectively). A higher prevented fraction of all-cause deaths was consistently found in Lombardy (65% avoided deaths, as opposed to 60% and 58% in Marche and Sicily). Nevertheless, because of a lower excess mortality rate found in Lombardy compared to Marche and Sicily (12, 24 and 23 per 10,000 person-years, respectively), a lower rate of averted deaths was observed (22 avoided deaths per 10,000 person-years, versus 36 and 32 in Marche and Sicily). In Lombardy, early and full implementation of adult COVID-19 vaccination was associated with the largest reduction in all-cause deaths compared to Marche and Sicily.

Background and Purpose This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD). Methods This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015–2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0–2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching. Results Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10–19] vs. 4 [2–7], P

Different starch properties may cause alterations in the foodstuff’s external appearance. However, modification processes in starches are usually secretive. The use of chemically modified starches is regulated by international standards, which makes it important to identify its presence and type. Mid-infrared spectroscopy (MIR)-modified starches’ identification can be hindered by the presence of excess glucose. This research investigates types of modification in commercial starches and in approaches that circumvent MIR’s limitations with exploratory analysis. It also considers that enzymatic hydrolysis (α-amylase and amyloglucosidase) can highlight the points of modification in the structure, which can be detected with infrared assays. To determine if sour cassava starch (FCS) is modified and check its type, six samples were selected: a native one, three of the most common cassava modified starches (etherified, esterified, and FCS), and two laboratory processed samples (Acid, Oxidized). The results showed that the sour cassava starch showed similarities with a commercial ester and an oxidized cassava starch, which may be due to the formation of a graft, corresponding to what the literature has already reported for corn starch treated with lactic acid and gamma radiation.

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Objective: To report the case of a newborn with a pre-pyloric mucosal diaphragm with repercussions on weight gain and food acceptance. This is a rare congenital gastrointestinal malformation and corresponds to approximately 1% of all etiologies of gastrointestinal obstruction in newborns. Description: Female NB, started post-feeding vomiting at 4 hours of life. Multiple attempts of oral feeding reintroduction were performed, episodes of post-feeding vomiting and inadequate weight gain were maintained. Imaging exams did not show intestinal obstruction, an upper digestive endoscopy (UDE) was performed on the 19th day of life, which identified and corrected a pre-pyloric mucous diaphragm with transposition of the membrane by the device. Formula was reintroduced, with a gradual increase in supply and satisfactory weight gain. He was discharged at 24 days of life, with total acceptance of the diet and complete remission of the condition. Comments: This study shows that it is important to consider the performance of UDE in cases of prolonged neonatal vomiting, after excluding more prevalent causes, such as APLV and GERD, as it is capable of diagnosing and treating some causes of obstruction of the gastrointestinal tract, such as the diaphragm pre-pyloric mucosa.

Purpose: To describe a clinical case of lumen obstruction a few days after implantation of the PreserFlo® Microshunt which has been resolved by anterior vitrectomy. Observation: A 76-year-old patient with advanced and progressing primary open-angle glaucoma (POAG) presented ten days after PreserFlo® Microshunt implantation in his left eye with an intraocular pressure (IOP) of 24 mmHg because of vitreous obstruction. Anterior vitrectomy with 25 Gauge vitrector was performed to remove the vitreous using a bimanual technique with two corneal accesses. The surgery was successful in lowering uncontrolled IOP without device repositioning. A free lumen and a IOP in the low range of tens was observed during follow-up. Conclusions and importance: PreserFlo ® MicroShunt obstruction by vitreous in pseudophakic patient is a possible complication. Anterior vitrectomy without the need of tube repositioning was successful in lowering uncontrolled IOP.

Introdução: A viremia por citomegalovírus (CMV) após transplante alogênico de células-tronco hematopoiéticas (TCTH) está associada ao risco aumentado de mortalidade geral, aumento do número de infecções, doença do enxerto vs hospedeiro (DECH), e aumento do tempo de hospitalização. O uso de terapia preemptiva diminui a mortalidade mas não impede a viremia por CMV. Este é um estudo descritivo que avalia o impacto da viremia por CMV nos receptores de TCTH. Objetivos: Primário: Descrever a proporção de óbitos relacionados à viremia por CMV em até 6 meses após o TCTH alogênico em adultos soropositivos para CMV. Secundário: Proporção de viremia por CMV associada a outras infecções e DECH. Métodos: Estudo observacional, transversal, centro único (Hospital Amaral Carvalho, em Jaú/SP). A data em que os transplantes foram realizados variou de Jan 2014 a Jul 2021, e os dados foram coletados retrospectivamente de Ago 2021 a Fev 2022. Critérios de inclusão: ≥18 anos, CMV R+ submetidos ao TCTH alogênico. As variáveis foram resumidas por meio de estatística descritiva. Como análise secundária, foram separados os pacientes com CMV-viremia e os sem CMV-viremia, e foi realizada uma análise descritiva. O método utilizado para detecção de CMV-viremia foi o teste de antigenemia pp65. O resultado do teste de antigenemia ≥ 1 célula foi considerado positivo. Resultados: O tamanho total da amostra final foi de 340 pacientes. A viremia por CMV ocorreu em 271 pacientes (79,7%), enquanto em 69 não houve CMV-viremia (20,2%). Um total de 51 pacientes (15%) morreram nos primeiros 6 meses pós TCTH. Nesta série, CMV-viremia não afetou a sobrevida global dos pacientes. Com relação ao tempo de internação, a média foi maior no grupo com CMV-viremia em comparação com o grupo sem CMV-viremia, p = 0,019. Falha/rejeição do enxerto foi observada em 12 pacientes (4,4%) com CMV-viremia e em três pacientes (4,3%) sem CMV-viremia. DECH foi observada em 178 pacientes com CMV-viremia (65,7%) e em 29 (42%) sem CMV-viremia (p < 0,001). Conclusão: Considerando as limitações do desenho do estudo (centro único, tamanho amostral pequeno), não encontramos diferenças na mortalidade entre o grupo que teve viremia por CMV e aqueles que não tiveram. Porém, este estudo evidenciou aumento do tempo de internação e maior incidência de DECH em pacientes com viremia por CMV. Isso pode sugerir um potencial benefício do uso de antivirais para a profilaxia impedindo a viremia ou reativação do CMV.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Abstract The trisomy 18 syndrome, also known as Edwards syndrome, is a common chromosomal disorder due to the presence of an extra chromosome 18, either full, mosaic trisomy, or partial trisomy 18q. The condition is the second most common autosomal trisomy syndrome after trisomy 21. The live born prevalence is estimated as 1/6,000-1/8,000, but the overall prevalence is higher (1/2500-1/2600) due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis. The prevalence of trisomy 18 rises with the increasing maternal age. The recurrence risk for a family with a child with full trisomy 18 is about 1%. Currently most cases of trisomy 18 are prenatally diagnosed, based on screening by maternal age, maternal serum marker screening, or detection of sonographic abnormalities (e.g., increased nuchal translucency thickness, growth retardation, choroid plexus cyst, overlapping of fingers, and congenital heart defects ). The recognizable syndrome pattern consists of major and minor anomalies, prenatal and postnatal growth deficiency, an increased risk of neonatal and infant mortality, and marked psychomotor and cognitive disability. Typical minor anomalies include characteristic craniofacial features, clenched fist with overriding fingers, small fingernails, underdeveloped thumbs, and short sternum. The presence of major malformations is common, and the most frequent are heart and kidney anomalies. Feeding problems occur consistently and may require enteral nutrition. Despite the well known infant mortality, approximately 50% of babies with trisomy 18 live longer than 1 week and about 5-10% of children beyond the first year. The major causes of death include central apnea, cardiac failure due to cardiac malformations, respiratory insufficiency due to hypoventilation, aspiration, or upper airway obstruction and, likely, the combination of these and other factors (including decisions regarding aggressive care). Upper airway obstruction is likely more common than previously realized and should be investigated when full care is opted by the family and medical team. The complexity and the severity of the clinical presentation at birth and the high neonatal and infant mortality make the perinatal and neonatal management of babies with trisomy 18 particularly challenging, controversial, and unique among multiple congenital anomaly syndromes. Health supervision should be diligent, especially in the first 12 months of life, and can require multiple pediatric and specialist evaluations.

Abstract Background Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. Methods 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. Results We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines. Conclusions Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis.

Abstract Eosinophilic gastrointestinal disorders (EGIDs) are chronic/remittent inflammatory diseases associated with a substantial diagnostic delay, often attributable to misdiagnosis and variable clinical presentation in adults. In the pediatric population, few studies have been conducted worldwide reporting EGID diagnostic delay and its consequences on patients. This study aims to analyze and identify potential clinical factors and complications associated with a longer diagnostic time. We performed a retrospective analysis of pediatric patients with EGIDs followed at the Center for Pediatric EGIDs in Pavia, Italy. A total of 60 patients with EGIDs were enrolled. Thirty-nine (65%) patients had EoE, and 21 (35%) non-esophageal EGIDs. EGID diagnosis was achieved about 2 years after the symptom onset, and the median diagnostic time was 12 months (IQR 12–24 months). Diagnostic time was 12 months (IQR 12–69) in non-esophageal EGIDs and 12 months (IQR 4–24 months) in EoE patients. EoE patients presenting with FTT and feeding issues experienced a longer diagnostic time (p = 0.02 and p = 0.05, respectively) than children without growth and feeding impairments. In this study, symptoms appeared about 2 years before the definitive EGID diagnosis was reached, and this diagnostic time was shorter than the delay observed in other published studies. Especially in EoE children, the diagnostic time is significantly associated with impaired child growth, highlighting the importance of an early diagnosis to prevent esophageal stenosis and failure to thrive.

Behavioural phenotype and autism-related traits of 38 patients affected by Cornelia de Lange syndrome (CdLS) were assessed using a specific neuropsychiatric protocol. Subsequently,we search for possible genotype-phenotype correlations comparing individuals with NIPBL variants and patients with negative molecular results. Firstly results showed a higher percentage of subjects with normal intellectual quotient (IQ) and borderline IQ; adaptive skills were lower than expected for age in all participants. 39.5% of the sample presented with autism spectrum disorder (ASD), NIPBL mutated individuals demonstrated a worse trend in comparison with the clinical diagnosis group. non-truncating individuals displayed no ASD and better communication abilities than truncating individuals. Findings increase our awareness of the strengths and weaknesses points in CdLS individuals., Author(s): Paola Francesca Ajmone [sup.1] , Beatrice Allegri [sup.1] , Anna Cereda [sup.2] , Giovanni Michelini [sup.3] , Francesca Dall'Ara [sup.1] , Milena Mariani [sup.4] , Claudia Rigamonti [sup.1] , [...]

After the first reports of autochthonous cases of monkeypox (MPX) in Europe at the beginning of May, the World Health Organization (WHO) and the European Centre for Disease Prevention and [...]