Plasma pNfH levels differentiate SBMA from ALS

Spinal and bulbar muscular atrophy (SBMA), known as Kennedy disease (KD), is a slowly progressive adult-onset X-linked neuromuscular disorder with no effective treatment. It is characterised by progressive limb and bulbar muscle weakness, associated with metabolic and endocrine alterations.1 2 SBMA is caused by the expansion of a CAG repeat in exon 1 of the androgen receptor (AR) gene; more than 37 repeats are pathogenic.1 While the genetic test is diagnostic, biomarkers would aid the initial differential diagnosis, and furthermore, there is a strong need for disease activity and progression markers to inform effective clinical trials design. Neurofilaments (Nfs), both light and heavy chains, are now becoming a widely accepted marker of neuronal damage and a prognostic biomarker for amyotrophic lateral sclerosis (ALS) and other neurodegenerative disease.3–7 Recently, plasma neurofilament light chain (NfL) levels were unexpectedly found not to be raised in patients with SBMA.8 This finding supports other lines of evidence, including an increase in plasma muscle damage markers, myopathic changes in biopsies and a series of genetic experiments in mouse models, that point to a primary myopathic involvement in SBMA.2 9 10 We here used the highly sensitive single molecule array (SIMOA) platform to investigate plasma levels of phosphorylated neurofilament heavy chain (pNfH), another well-established marker of neuronal damage, in patients with SBMA and in a rodent model of disease

Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations

Adverse Events Associated with BNT162b2 and AZD1222 Vaccines in the Real World: Surveillance Report in a Single Italian Vaccine Center

Aim: Despite huge efforts in developing specific drugs, vaccination represents the only effective strategy against COVID-19. Efficacy and safety of the COVID-19 vaccines were established during clinical trials. Nonetheless, it is very important to perform continuous surveillance. This observational study aimed to report potential Adverse Events Following Immunization (AEFI) following the first dose of two different COVID-19 vaccines, BNT162b2 and AZD1222. Methods and Results: Subjects who underwent vaccination at the vaccine center of the University Hospital of Salerno, Italy, were interviewed using an ad hoc questionnaire. AZD-vac group (n = 175) who received AZD1222 had a higher number of AEFI than the BNT-vac group (n = 1613) who received BNT162b2 (83% vs. 42%). The most frequent AEFI associated with AZD1222 and BNT162b2 were fever and pain at the injection site, respectively. The AZD-vac group used drugs to contrast AEFI more frequently than the BNT-vac group. In the BNT-vac group, there was a higher incidence of AEFI in women than in men (26.2% vs. 15.8%, p = 0.01), while no gender-related difference was observed in the AZD-vac group. Conclusions: AZD1222 and BNT162b2 vaccines show a good safety profile. Based on our results and literature data, there are no reasons to justify the reluctance that persists towards immunization

Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population

Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (N = 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in GTF2H2 (5q13; alternative T allele: OR [CI] = 8.16[1.08; 61.52], FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- [\u3b2(SE) = -0.039(0.013); FDR = 0.039] and caudate-PRS [0.043(0.013); 0.028] with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R2 = 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (~20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features

Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients

The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved in vivo and in vitro cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients

I-Support: A robotic platform of an assistive bathing robot for the elderly population

In this paper we present a prototype integrated robotic system, the I-Support bathing robot, that aims at supporting new aspects of assisted daily-living activities on a real-life scenario. The paper focuses on describing and evaluating key novel technological features of the system, with the emphasis on cognitive human–robot interaction modules and their evaluation through a series of clinical validation studies. The I-Support project on its whole has envisioned the development of an innovative, modular, ICT-supported service robotic system that assists frail seniors to safely and independently complete an entire sequence of physically and cognitively demanding bathing tasks, such as properly washing their back and their lower limbs. A variety of innovative technologies have been researched and a set of advanced modules of sensing, cognition, actuation and control have been developed and seamlessly integrated to enable the system to adapt to the target population abilities. These technologies include: human activity monitoring and recognition, adaptation of a motorized chair for safe transfer of the elderly in and out the bathing cabin, a context awareness system that provides full environmental awareness, as well as a prototype soft robotic arm and a set of user-adaptive robot motion planning and control algorithms. This paper focuses in particular on the multimodal action recognition system, developed to monitor, analyze and predict user actions with a high level of accuracy and detail in real-time, which are then interpreted as robotic tasks. In the same framework, the analysis of human actions that have become available through the project’s multimodal audio–gestural dataset, has led to the successful modeling of Human–Robot Communication, achieving an effective and natural interaction between users and the assistive robotic platform. In order to evaluate the I-Support system, two multinational validation studies were conducted under realistic operating conditions in two clinical pilot sites. Some of the findings of these studies are presented and analyzed in the paper, showing good results in terms of: (i) high acceptability regarding the system usability by this particularly challenging target group, the elderly end-users, and (ii) overall task effectiveness of the system in different operating modes