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Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Abstract Tumor dissemination to the central nervous system (CNS) is almost a rule in the treatment journey of advanced HER2+ breast cancer (BC). Recent results demonstrated high intracranial efficacy with Trastuzumab Deruxtecan (T-DXd). However, a real-world evidence is lacking in literature. We conducted a multicenter, observational, retrospective real-world analysis on 39 cases collected at 12 Italian Oncological Units. Patients with brain metastases (BMs) from HER2 + BC treated with T-DXd in various treatment lines were enrolled. Primary endpoint was the intracranial overall response rate (iORR). Secondary endpoints were intra- and global progression free survival (iPFS - gPFS); other secondary objectives were the intracranial disease control rate (iDCR), duration of response (iDoR), clinical benefit rate at 6 and 12 months (iCBr), overall survival, and safety. iORR was 59%, iPFS was 15.6 months, gPFS was 11.8 months. iDCR was 94.9%, iDoR was 11.9 months, and iCBr at 6 and 12 months were 69.2% and 59%, respectively. OS was not reached, with an overall rate of 77.9% of patients alive at 12 months. This study confirmed the high intracranial efficacy and manageable safety profile of T-DXd in this first-ever real world analysis.

Abstract Background We previously reported the safety and immunogenicity data from a randomized trial comparing the booster responses of vaccinees who received monovalent (MV) recombinant protein Beta-variant (MVB.1.351) and MV ancestral protein (MVD614) vaccines with AS03 adjuvant (Sanofi/GSK) to booster response of vaccinees who received mRNA MV ancestral strain BNT162b2 vaccine (Pfizer-BioNTech). Methods First booster of the vaccines was administered in adult participants previously primed with 2 doses of MV ancestral strain BNT162b2. A subset of these participants with available blood samples collected at Day 0 (D0), at 28 days (D28), and 3 months (M3) post-booster were contacted for additional testing (195/208 participants). The persistence of cross-neutralizing antibodies, including against Omicron BA.1 and BA.4/5, up to 3 months after boosting was evaluated using a validated pseudovirus neutralization assay. Results Across the whole population, MVB.1.351 vaccine induces highest NAbs titers against Omicron BA.1 and BA.4/5 variants at D28 and M3 post-booster. In participants with SARS-CoV-2 infection between D28 and M3, both MVB.1.351 and BNT162b2 vaccine groups show an increase in GMTs against Omicron BA.1 and Omicron BA.4/5 following infection. Among uninfected participants, the ratio of M3 to D28 GMTs was higher for the MVB.1.351 group than the BNT162b2 group against Omicron BA.1 (0.64 [0.53;0.77] versus 0.43 [0.35;0.53]), Omicron BA.4/5 (0.61 [0.50; 0.75] versus 0.44 [0.34; 0.56]), and D614 (0.68 [0.58,0.81] versus 0.46 [0.39,0.55]). Conclusions The MVB.1.351 vaccine induces higher and durable cross-neutralizing antibodies against Omicron subvariants up to 3 months after boosting compared to an MV ancestral and mRNA BNT162b2 booster vaccine.

To maintain the carbon dioxide concentration below the no-return threshold for climate change, we must consider the reduction in anthropic emissions coupled to carbon capture methods applied in synergy. In our recent papers, we proposed a green and reliable method for carbon mineralization using ascorbic acid aqueous solution as the reducing agent for carbon (IV) to carbon (III), thus obtaining oxalic acid exploiting green reagents. Oxalic acid is made to mineralize as calcium (as the model cation) oxalate. Oxalates are solid-state reservoirs suitable for long-term carbon storage or carbon feedstock for manufacturing applications. The carbon mineralization reaction is a double-step process (carbon reduction and oxalate precipitation), and the carbon capture efficiency is invariably represented by a double-slope curve we formerly explained as a decrease in the reducing effectiveness of ascorbic acid during reaction. In the present paper, we demonstrated that the reaction proceeds via a “pure CO2-capture” stage in which ascorbic acid oxidizes into dehydroascorbic acid and carbon (IV) reduces to carbon (III) and a “mixed” stage in which the redox reaction competes with the degradation of ascorbic acid in producing oxalic acid. Despite the irreversibility of the reduction reaction, that was demonstrated in abiotic conditions, the analysis of costs according to the market price of the reagents endorses the application of the method.

In this paper the possible use of end-of-life tire rubber as a substitute for aggregate in cement mortars was explored. The aim of this paper was to investigate the effect of rubber surface modification by acidic treatment on the final properties of mortars. In fact, through treatment with sulfuric acid at moderate concentrations, a significant improvement in rubber wettability and interaction with cement has been observed. The compressive strength of mortars containing 15%w treated rubber as a replacement of natural aggregate is comparable to those of standard mortars. This suggests that surface modification of rubber plays a very important role in the possible integration of end-of-life tire rubber in mortar and concrete. The results presented in this paper confirm that recycling in mortar and concrete is a promising way for improving rubber waste management and sustainable innovation in the construction industry.

The time-evolution of dynamics as well as microstructure and mechanical response of phosphate-based geopolymers was probed using x-ray photon correlation spectroscopy and rheological tests. The analyzed relaxation processes in the freshly prepared geopolymer mixes evidenced a q-independent mode of the autocorrelation function, ascribed to density fluctuations of the already established molecular network, undergoing reconfiguration without significant mass transport. Upon curing, the detected motions are localized and depict a system evolving toward structural arrest dominated by slower hyperdiffusive dynamics, characterized by a compressed exponential regime, pointing to a structural relaxation process subjected to internal stresses, in a context of marked dynamical and structural heterogeneity. The system ages through a "densification" process producing declining small angle scattered intensity, as two finely intermixed gel-like reaction products, namely, one hydrated aluminophosphate and one hydrated silica, form a percolated network possessing surface fractal scaling of progressively shorter average correlation length. In this scenario, the nominal Al/P molar ratio of the mix, being an index of network-forming ability, is positively correlated with the dynamic viscosity and the overall kinetics, whereas the contrary occurs for the fraction of water. [ABSTRACT FROM AUTHOR]

Objetivos: Apresentar os impactos no processo de trabalho do método não invasivo de determinação de bioparâmetros na triagem de doadores de sangue, nos serviços de hemoterapia da rede HEMEPAR- Paraná. Material e métodos: A triagem clínica consiste na anamnese e avaliação das condições clínicas, a saber: estado de saúde, hábitos de vida e situação epidemiológica. A Portaria de Consolidação nº5/2017 anexo IV que aponta a necessidade de proteger os doadores com a determinação da concentração de hemoglobina (Hb) ou hematócrito (Ht) obtida por punção digital, por venopunção ou por método validado que possa vir a substituí-los. Na perspectiva de otimizar o processo de trabalho na triagem, tanto para profissionais que a executam quanto para os candidatos a doação, a rede HEMEPAR no ano de 2021 realizou contratualização para aquisição do Medidor de Biosinais que apresenta metodologia não invasiva de determinação de bioparâmetros com resultados quase que imediatos de pressão arterial, saturação de oxigênio, taxa de pulso periférico, hemoglobina, hematócrito, eritrócitos, eliminando riscos biológicos de contaminação, pois a medição é realizada no tecido capilar, apenas com as extremidades distais dos quatro quirodáctilos de ambas as mãos. Resultados: Para a implantação da metodologia não invasiva foi realizado processo de validação clínica com comparação entre 3 outras metodologias, sendo que o dispositivo apresentou uma acuracidade de aproximadamente 96,21% em relação ao padrão ouro. O dispositivo não invasiso, além de sua precisão, otimizou o processo em 23 unidades da rede HEMEPAR que fazem uso do método com 45 dispositivos, que tem apresentado benefícios como um profissional executando a triagem clínica e hematológica, maior agilidade, eliminação do erro de transcrição de resultados, bem como, a satisfação e conforto do doador. Discussão: Para a efetivação da doação de sangue é obrigatório a mensuração dos bioparâmetros, que devem estar em níveis determinados com o sexo do doador. No Paraná a aquisição de dispositivo não invasivo, além de proporcionar alívio aos candidatos, também impacta positivamente no processo de trabalho das Unidades, considerando que a possibilita a garantia de determinação dos valores aceitavéis de hemoglobina ou hematócrito, sustentabilidade relacionada a redução de insumos que se transformam em resíduos de substâncias infectantes, adequação de recursos humanos para unificação de triagem clínica e hematológica. O método não invasivo mantém a garantia dos resultados, uma vez que não foram observadas perdas ou desvios na qualidade do produto final. Conclusão: O monitoramento de bio-parâmetros com dispositivo não invasivo em tempo real otimizou o processo de trabalho em relação a variável tempo, permitiu avaliação segura da triagem hematológica considerando a ampla validação que o dispositivo fora submetido, preveniu infeção relacionada ao procedimento dantes invasivo e promoveu economicidade de recursos financeiros, percebeu-se a potencialização em todo o ciclo do sangue, ou seja, possibilitou maior resolutividade, agilidade, segurança e qualidade do trabalho, reduzindo erros e perdas de bolsas de hemocomponentes, além de ser preciso e de fácil utilização, com tecnologia capaz de medir de forma não invasiva seis marcadores hemodinâmicos e hematológicos em um único dispositivo.

Background: Meropenem–vaborbactam (MEM-VAB) is a novel carbapenem-beta-lactamase-inhibitor combination that demonstrates activity against carbapenem-resistant (CR) Gram-negative bacteria, and more specifically KPC-producers, since vaborbactam is an effective inhibitor of KPC enzymes in vitro. This study aimed to describe the initial uses and efficacy of MEM-VAB for compassionate treatment during the first 21 months following its early access in France. Method: A national multicenter retrospective study was conducted, including all patients who received at least one dose of MEM-VAB between 20 July 2020, and 5 April 2022. Clinical characteristics and outcomes were collected using a standardized questionnaire. The minimum inhibitory concentration (MIC) of antimicrobials, and complete genome sequencing of bacteria were performed when bacterial isolates were available. Results: Ultimately, 21 patients from 15 French hospitals were included in the study. The main indication for MEM-VAB treatment was respiratory tract infections (n = 9). The targeted bacteria included Pseudomonas aeruginosa (n = 12), Klebsiella pneumoniae (n = 3), Enterobacter spp (n = 3), Citrobacter freundii (n = 1), Escherichia coli (n = 1), and Burkholderia multivorans (n = 1). Overall, no significant advantage of vaborbactam over meropenem alone was observed across all strains of P. aeruginosa in terms of in vitro susceptibility. However, MEM-VAB demonstrated a notable impact, compared to carbapenem alone, on the MIC for the two KPC-3-producing K. pneumoniae and B. multivorans. Conclusions: MEM-VAB seems effective as a salvage treatment in compassionate use, but vaborbactam was shown to lack benefits compared to meropenem in treating P. aeruginosa-related infections. Therefore, it is crucial to compare meropenem to MEM-VAB MICs, particularly for P. aeruginosa, before prescribing MEM-VAB.

In this study, a new and straightforward process for the preparation of budesonide 21-phosphate (Bud-21P) and its disodium salt (Bud-21P-Na2) is described. The method results in a yield comparable to those obtained by diphosphoryl chloride, but it is more manageable, less expensive, and safer. The new compounds are characterized by better water solubility compared to the parent compound. Moreover, they have been evaluated for their anti-inflammatory activity and the obtained results clearly evidence that Bud-21P and Bud-21P-Na2 retained anti-inflammatory activity like the parent compound budesonide (Bud) in mice with cutaneous induced edema.

Background: Human metapneumovirus (hMPV) is one of the leading respiratory viruses. This prospective observational study aimed to describe the clinical features and the outcomes of hMPV-associated lower respiratory tract infections in adult inpatients. Methods: Consecutive adult patients admitted to one of the 31 participating centers with an acute lower respiratory tract infection and a respiratory multiplex PCR positive for hMPV were included. A primary composite end point of complicated course (hospital death and/or the need for invasive mechanical ventilation) was used. Results: Between March 2018 and May 2019, 208 patients were included. The median age was 74 [62–84] years. Ninety-seven (47 %) patients were men, 187 (90 %) had at least one coexisting illness, and 67 (31 %) were immunocompromised. Median time between first symptoms and hospital admission was 3 [2–7] days. The two most frequent symptoms were dyspnea (86 %) and cough (85 %). The three most frequent clinical diagnoses were pneumonia (42 %), acute bronchitis (20 %) and acute exacerbation of chronic obstructive pulmonary disease (16 %). Among the 52 (25 %) patients who had a lung CT-scan, the most frequent abnormality was ground glass opacity (41 %). While over four-fifths of patients (81 %) received empirical antibiotic therapy, a bacterial coinfection was diagnosed in 61 (29 %) patients. Mixed flora (16 %) and enterobacteria (5 %) were the predominant documentations. The composite criterion of complicated course was assessable in 202 (97 %) patients, and present in 37 (18 %) of them. In the subpopulation of pneumonia patients (42 %), we observed a more complicated course in those with a bacterial coinfection (8/24, 33 %) as compared to those without (5/60, 8 %) (p = 0.02). Sixty (29 %) patients were admitted to the intensive care unit. Among them, 23 (38 %) patients required invasive mechanical ventilation. In multivariable analysis, tachycardia and alteration of consciousness were identified as risk factors for complicated course. Conclusion: hMPV-associated lower respiratory tract infections in adult inpatients mostly involved elderly people with pre-existing conditions. Bacterial coinfection was present in nearly 30 % of the patients. The need for mechanical ventilation and/or the hospital death were observed in almost 20 % of the patients.