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Abstract Background Artemisinin-based combination therapy (ACT) is currently recommended for treatment of uncomplicated malaria. However, the emergence and spread of partial artemisinin resistance threatens their effectiveness for malaria treatment in sub-Saharan Africa where the burden of malaria is highest. Early detection and reporting of validated molecular markers (pfk13 mutations) in Plasmodium falciparum is useful for tracking the emergence and spread of partial artemisinin resistance to inform containment efforts. Methods Genomic surveillance was conducted at 50 surveillance sites across four regions of Uganda in Karamoja, Lango, Acholi and West Nile from June 2021 to August 2023. Symptomatic malaria suspected patients were recruited and screened for presence of parasites. In addition, dried blood spots (DBS) were collected for parasite genomic analysis with PCR and sequencing. Out of 563 available dried blood spots (DBS), a random subset of 240 P. falciparum mono-infections, confirmed by a multiplex PCR were selected and used for detecting the pfk13 mutations by Sanger sequencing using Big Dye Terminator method. Regional variations in the proportions of pfk13 mutations were assessed using the chi square or Fisher’s exact tests while Kruskal–Wallis test was used to compare absolute parasite DNA levels between wild type and mutant parasites. Results Overall, 238/240 samples (99.2%) contained sufficient DNA and were successfully sequenced. Three mutations were identified within the sequenced samples; pfk13 C469Y in 32/238 (13.5%) samples, pfk13 A675V in 14/238 (5.9%) and pfk13 S522C in (1/238 (0.42%) samples across the four surveyed regions. The prevalence of pfk13 C469Y mutation was significantly higher in Karamoja region (23.3%) compared to other regions, P = 0.007. The majority of parasite isolates circulating in West Nile are of wild type (98.3), P = 0.002. Relative parasite DNA quantity did not differ in samples carrying the wild type, C469Y and A675V alleles (Kruskal–Wallis test, P = 0.6373). Conclusion Detection of validated molecular markers of artemisinin partial resistance in multiple geographical locations in this setting provides additional evidence of emerging threat of artemisinin partial resistance in Uganda. In view of these findings, periodic genomic surveillance is recommended to detect and monitor levels of pfk13 mutations in other regions in parallel with TES to assess potential implication on delayed parasite clearance and associated treatment failure in this setting. Future studies should consider identification of potential drivers of artemisinin partial resistance in the different malaria transmission settings in Uganda.

We report a case of Burkholderia mallei causing glanders in a 73-year-old patient from the Northeast Region of Brazil. The patient was hospitalized with severe pneumonia. PCR and genomic sequencing confirmed B. mallei in pleural drainage. Genotyping revealed a novel genotype, emphasizing the need for genetic surveillance in zoonotic infections.

Abstract In this work our aim was to identify early biomarkers in plasma samples associated with mortality in children with perinatal HIV treated early in life, to potentially inform early intervention targeting this vulnerable group. 20/215 children (9.3%) with perinatal HIV, enrolled within 3 months of age died prematurely within the first year of the study, despite early ART initiation. Using a propensity score, we selected 40 alive study participants having similar clinical and virological records compared to the deceased group. 13 HIV unexposed (HU) healthy children were additionally used as controls. Baseline plasma samples were analyzed using a targeted proteomic approach, and to assess pathogen-associated and damage-associated molecular patterns (PAMPs, DAMPs) levels. Data from deceased participants were compared to both control groups, with multivariate logistic regression models used to evaluate the association between mortality and plasma proteins. We developed a machine learning model to predict mortality risk, finding that IL-6 and CXCL11 not only were higher in deceased children than Matched-children with HIV (p

Abstract The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex uses its rhomboid pseudo-protease subunit, Dsc2, to assess the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex likely interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be extracted by Cdc48 for endosome and Golgi associated proteasomal degradation (EGAD), while others will undergo ESCRT dependent vacuolar degradation. Some substrates are degraded by both, EGAD- or ESCRT pathways. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thereby preserves cellular membrane protein and lipid composition.

Abstract Background Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation- relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs. Results Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-α /IFN-γ stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism. Conclusion This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphometric approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.

Phylogenetic analyses showed that the virus responsible for a May 2024 Oropouche fever outbreak in Cuba was closely related to viruses from Brazil in 2023. Pools of Ceratopogonidae spp. biting midges and Culex quinquefasciatus mosquitoes were positive for Oropouche viral RNA. No cases were severe. Virus extension to new areas may increase case numbers and severity.

Abstract Introduction Despite an improved understanding of its pathogenesis, dry eye disease (DED) remains relatively underestimated and its treatment challenging. A better alignment between the clinical evaluation and the patient self-assessment also requires capturing the whole patient experience of DED. This project aimed to unveil this experience through narrative medicine (NM). Methods The project involved 38 expert centres in Italy and one in San Marino, targeting adult patients with DED, their informal caregivers and their treating ophthalmologists. Written narratives and sociodemographic and quality of life (QoL)-related data were anonymously collected through the project’s webpage. Narratives were analysed through MAXQDA (VERBI Software, Berlin, Germany), NM classifications and content analysis. Results A total of 171 patients with DED, 37 informal caregivers and 81 ophthalmologists participated in the research. DED was defined as a disabling condition by 19% of patients and 35% of caregivers; 70% of patients reported that a therapeutic alliance is an integral part of DED treatment and 32% hope for more effective therapies. Forty-four per cent of patients assessed their own QoL as good; however, DED emerged as importantly impacting work performance and social events. DED physical, emotional and economic burden and the cruciality of a trusting care relationship represent the main themes that emerged across all narratives, while empathy and effective treatment are among the factors favouring coping with DED. Conclusion This project marked a pioneering initiative investigating the lived experience of patients with DED through NM, simultaneously involving all viewpoints involved in the care pathway. NM enabled the unveiling of factors favouring the ability to cope with DED and its associated QoL implications and provided valuable insights to improve the therapeutic alliance.

Background. The emotional state, the length of screen time and the level of educational motivation of schoolchildren are often a matter of concern for many parents. The study examines the relationship between educational motivation, the level of anger, and parenting styles from the adolescents’ point of view. Objectives. Identification and description of the specific interrelations between various aspects of parenting and the teenagers' motivation and anger in the context of global digitalization. Study Participants. The study involved 265 people (54% — female). The average age of the respondents was 13.8 years (M = 13.8, Me = 14, SD = 1.62). Methods. To study parenting styles, teenagers filled out the ad hoc questionnaire “Adolescents about parents”. The motivational and emotional components of the adolescents’ personality were examined by means of Andreeva & Prikhozhan’ questionnaire “Motivation of learning and emotional attitude to learning”. The level of digital engagement of adolescents was assessed on the basis of daily statistics of the average time spent using a mobile phone. Statistical analysis was performed using the general linear model (GLM) method in the Jamovi 2.3.16.0 program. Results. According to the results of the GLM model, the adolescents’ achievement motivation is negatively related to their average screen time. The level of educational motivation of adolescents is positively associated with the positive interest and autonomy provided by their parents. The teenagers’ level of anger is positively associated with directiveness, hostility and inconsistency of parents. According to the Wilcoxon test results, parenting styles such as directiveness, hostility and autonomy are more pronounced in fathers than in mothers. Conclusions. The most favorable parenting style for achieving high academic motivation and reducing the level of anger in adolescents is a pronounced positive interest and autonomy provided by parents along with a low level of directiveness, hostility and inconsistency. Achievement motivation has a negative relationship with the length of teenagers' screen time.

Abstract CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLCγ1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE.

Resumen: Antecedentes y objetivo: La hiperpotasemia (HK) es una alteración electrolítica en la concentración de iones potasio (K+), cuyo riesgo aumenta en pacientes con enfermedad renal crónica (ERC) o insuficiencia cardiaca (IC) y/o en pacientes en tratamiento con inhibidores del sistema renina-angiotensina-aldosterona (iSRAA). Los nuevos quelantes orales de K+ ofrecen un tratamiento seguro y eficaz para mantener la normopotasemia en estos pacientes. El objetivo del análisis es estimar el coste-efectividad del ciclosilicato de sodio y zirconio (CSZ) para el tratamiento de la HK crónica en pacientes con ERC o IC vs. tratamiento estándar (poliestireno sulfonato cálcico y modificaciones del estilo de vida) desde la perspectiva del Sistema Nacional de Salud (SNS) español. Materiales y métodos: Se utilizaron dos modelos de microsimulación que reflejan la historia natural de la ERC y de la IC. En ambos modelos se realizó una simulación de forma individual de los niveles de K+. Con base en la eficacia (reducción de los niveles de K+), la calidad de vida de los pacientes (utilidades según estado de salud, y disutilidades de los eventos derivados de cada patología y los eventos adversos [EA] del tratamiento) y a los costes contemplados (coste del tratamiento para la HK, del tratamiento con iSRAA y su modificación, de los estados de salud, del manejo de los eventos derivados de cada patología, de los episodios de HK, y de los EA del tratamiento) (€, 2022), se obtuvieron resultados de beneficio clínico (años de vida ajustados por calidad [AVAC]) y costes. Se empleó un horizonte temporal de toda la vida del paciente y se aplicó una tasa de descuento del 3% para costes y resultados. Resultados: El CSZ resulta una opción más efectiva en ambas patologías, con una diferencia de AVAC de 0,476 en ERC, y de 0,978 en IC vs. tratamiento estándar, y supone un coste incremental de 3.616 € y 14.749 €, respectivamente, obteniéndose un ratio coste-utilidad incremental (RCUI) de 7.605 €/AVAC en ERC y 15.078 €/AVAC en IC. Conclusiones: El CSZ es una alternativa con una buena relación coste-efectividad para el tratamiento de la HK en pacientes con ERC o IC, teniendo en cuenta los valores de eficiencia de referencia empleados habitualmente en España. Abstract: Background and objective: Hyperkalemia (HK) is an electrolyte disturbance in the concentration of potassium ions (K+), whose risk increases in patients with chronic kidney disease (CKD) or heart failure (HF) and/or in patients being treated with renin-angiotensin-aldosterone system inhibitors (RAASi). The new oral K+ chelators offer a safe and effective treatment to maintain normokalemia in these patients. The objective of the analysis is to estimate the cost-effectiveness of sodium zirconium cyclosilicate (SZC) for the treatment of chronic HK in patients with CKD or HF versus standard treatment (calcium polystyrene sulfonate and lifestyle modifications) from the perspective of the Spanish National Health System. Materials and methods: Two microsimulation models reflecting the natural history of CKD and HF were used. In both models, K+ levels were simulated individually. Based on efficacy (reduction of K+ levels), quality of life of patients (utilities according to health states, and disutilities of events derived from each pathology and adverse events [AEs] of treatment) and costs considered (cost of treatment for HK, of RAASi treatment and its modification, health states, management of events derived from each pathology, HK episodes, and AEs treatment) (€, 2022), clinical benefit (quality-adjusted life years [QALYs]) and cost results were obtained. A time horizon of the patient's lifetime was used and a discount rate of 3% was applied for costs and outcomes. Results: SZC is a more effective option in both pathologies, with a difference in QALYs of 0.476 in CKD and 0.978 in HF compared to standard treatment, and it represents an incremental cost of € 3,616 and € 14,749, respectively, obtaining an incremental cost-utility ratio of € 7,605 /QALY in CKD and € 15,078 /QALY in HF. Conclusions: SZC is a cost-effective alternative for the treatment of HK in patients with CKD or HF, taking into account the reference efficiency values commonly used in Spain.

Background: Despite extraordinary improvements in the management of psoriasis in recent times, some areas of the body, such as the pretibial area, still show an unsatisfactory response and a more significant impact on patient quality of life. This multicentre study focuses on psoriasis affecting sensitive areas (particularly the pretibial area), its impact on quality of life and the therapeutic response to risankizumab. Methods: This multicentre prospective observational study recruited patients with moderate-to-severe psoriasis with pretibial area involvement. All patients underwent treatment with risankizumab (150 mg every 3 weeks), and efficacy was assessed after 24 weeks. Results: The study included 128 patients with a mean age of 51 years, suffering from moderate-to-severe psoriasis with involvement of the pretibial area with median total Psoriasis Area Severity Index score of 17.05 and Dermatology Life Quality Index of 16.27. The group was further divided into two sub-groups: the ‘mother patch’ group, in whom the very first psoriatic plaque appeared in the pretibial region (45 patients), and the ‘non-mother patch’ group, in whom the psoriatic lesion in the pretibial region was present but not as the first manifestation (83 patients). In order to better assess the involvement of psoriasis in the pretibial area, the pretibial plaque lesion severity index was also calculated at baseline in all patients: extent 2.75, erythema 2.64, infiltration 2.45 and desquamation 2.38. All participants in this study showed a good therapeutic response, with a reduction in all scores. Conclusions: The pretibial area is becoming an object of therapeutic interest due to some resistance to clearance and the consequent impairment of patient quality of life. This study showed that risankizumab can give favourable therapeutic results not only in patients with moderate-to-severe psoriasis with involvement of the difficult-to-treat areas but particularly in patients with recalcitrant plaques in the pretibial area.

Artikkelen undersøker hvordan Nav-veilederes blikk på brukerne og deres problemer formes av de institusjonelle og organisatoriske rammene de jobber under. Datamaterialet består av seks fokusgruppeintervjuer med to ulike grupper Nav-veiledere. Begge gruppene jobber med innvandrede brukere med sammensatte utfordringer i møte med arbeidslivet, men under svært ulike arbeidsbetingelser. Mens den første gruppen jobber med mange brukere, høyt tidspress og tydelig arbeidsretting av tjenestene, har den andre gruppen færre brukere, mer tid til oppfølging og et bredere mandat. Analysene viser hvordan den første gruppen veiledere i liten grad har tid til å utforske årsakene til brukeres manglende oppmøte, samarbeid eller norskferdigheter. De ser ofte brukerne som umotiverte eller motvillige: Brukerne er problemet, og de må endre seg før de kan dra nytte av Navs tjenestetilbud. Den andre gruppen veiledere kan i større grad ta tak i de aktuelle problemstillingene brukerne opplever, og utforske hvordan omstendigheter og livssituasjon gir brukerne problemer. Disse er mer tilbøyelige til å beskrive brukernes problemer som noe de har – og dermed noe Nav kan hjelpe dem med å løse. Analysene illustrerer hvordan arbeidsbetingelsene innad i Nav påvirker ikke bare hvordan veiledere avdekker, fortolker og håndterer innvandrede brukeres utfordringer og problemer, men også hvordan dette får konsekvenser for tjenestetilbudet.

This paper considers the current problems of knowledge and information systems management, which are solved with the help of digital institutes for the purpose of the development of high-tech production in the conditions of Industry 4.0. The paper identifies the role of knowledge in the innovative development of industrial production, characterises the specifics of the influence of digital technologies on the technological development of companies and production processes, and focuses on the sensitivity of high-tech production to the level of intellectual support of production processes. Emphasis is made on the necessity of using comprehensive digital institutes, which can expand the boundaries of production companies and use the potential of digital platforms and systems in full. The research methodology combines traditional and new scientific directions and institutional theories in disciplines that study the research problem in the context of an increase in the intellectualisation of labour in the conditions of Industry 4.0. The research methodology covers general scientific methods of synthesis, analysis, the monographic method, observation, generalisation, and comparison. The paper contains important thoughts regarding the features of digital institutes from the position of their formation and influence on knowledge management in high-tech companies. It considers the structure and functions of the digital institutes of knowledge and information systems management in the conditions of Industry 4.0 and characterises selected institutes in the context of their influence on the digital transformation of the economy and the improvement of the state of knowledge management.

Rationale: Electrocardiography (ECG) is an objective and widely available method for the diagnosis of cardiovascular disorders recommended for identification of abnormalities, including those in patients with malignancies. A few studies have been published on the assessment of changes in ECG over time in patients with hemoblastoses under high-dose chemotherapy (HDCT) with subsequent transplantation of autologous hematopoietic stem cells (autoHSCT). Aim: To study ECG abnormalities before HDCT with autoHSCT and after treatment and their association with cardiac dysfunction in patients with hematological malignancies. Materials and methods: This prospective cohort observational study included 71 patients with confirmed hemoblastoses. Before HDCT with autoHSCT and at the average of 20 weeks thereafter, a 12-lead standard ECG, echocardiography, and measurement of cardiac biomarkers (troponin T [TnT] and N-terminal pro-peptide of brain natriuretic peptide (NT-proBNP) were performed. We assessed P wave abnormalities, PQ duration, QRS, ST segment, and T wave. The following cut-off values were considered abnormal: duration of P wave above 110 ms, of PQ interval above 210 ms, of QRS above 110 ms. The QTc intervals were calculated according to Bazett and Fridericia. QTc above 450 ms in men and above 460 in women was considered as prolonged. Results: After HDCT with autoHSCT, increased left ventricular myocardial mass index (LVMMI) was more commonly found in the patients with prolonged P wave ( 110 ms) at baseline (χ2 = 7.214; odds ratio (OR) 4.179; 95% confidence interval [CI] 1.425–12.250; p = 0.015), and increased left atrial volume index (LAVI) was more common for those with initially two-humped P wave (χ2 = 11.169; OR 19.231; 95% CI 2.064–179.212; p = 0.004). Before HDCT with autoHSCT, flattened T wave was present in 14 (19.7%) of the study patients. After the treatment, 8 (11.3%) of the patients demonstrated a new T wave abnormalities, associated with more frequent new TnT increase ( 14 pg/mL) (χ2 = 7.945; p = 0.025), as well as with increased LAVI (p = 0.018) and LVMMI (p = 0.018). Before HDCT with autoHSCT, 10 (14.1%) of the study patients had a prolonged QTc interval, which correlated to the increased NT-proBNP level ( 125 pg/mL) (r = 0.247; p = 0.038). The assessment of the QTc length after HDCT with autoHSCT showed, that the increase of NT-proBNP levels by 1 pg/mL was associated with an increase of the QTc duration by 0.003 mc (p = 0.027). Conclusion: In patients with hematological malignancies, baseline P wave abnormalities are the risk factor for increased LVMMI and LAVI after HDCT with autoHSCT. New T wave abnormalities and QTc prolongation after HDCT with autoHSCT are associated with the signs of myocadial injury and dysfunction.

Abstract Introduction Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service.

Abstract The emerging world of 3D food printing is reviewed. Its role in food manufacturing, including benefits and impacts, underemphasized gastrophysical aspects, and limitations are discussed. Foods can be digitally designed and physically prepared using the layer-by-layer deposition of food components, unleashing opportunities to deliver nutritionally personalized food and new food-human interactions. Existing bottlenecks, under-researched gastropsychophysical aspects, and the lack of harmonized standards hindering its use for mass production are mentioned.

Varicose vein disease of the lower extremities is an inflammatory disorder with abnormal structure and functional activity of the venous valves, venous walls and cells, as well as with abnormal activity of the infiltrating leukocytes. The abnormally changed varicose vein are characterized by increased venous pressure, blood accumulation and congestion, ischemia, and metabolic and energy turnover derangement, which result in clinical manifestations of complications, such as pain, edema and formation of trophic ulcers. For many years, flavonoids have been used to treat varicose veins. The most effective flavonoids used in varicose vein disease and its complications, are hesperidin and diosmin, as well as their combinations. The review sets forth the state-of-the-art knowledge on the universal inflammatory processes playing a leading role in the pathophysiology of many cardiovascular disorders, including venous ones. In the recent years, it has been found that one of the main causes of inflammation is the formation of intracellular protein complexes (inflammasomes), which both produce a set of proinflammatory cytokines and are responsible for their excretion from the cells. In addition, inflammasomes control the development of regulated necrosis (pyroptosis) that takes part in the process of ulceration. The inflammasome activity can be modified by various mechanisms, of which the gene independent synthesis of the inflammasomal proteins has been recognized as the leading one. It has been shown that flavonoids inhibit the activation of a key factor NF-kappa B and suppress the synthesis of proteins, including NOD-like receptor protein 3 (NLRP3) inflammasome components, decrease the expression of NLRP3 receptor, protein ASC and caspase 1, as well as diminish interleukin 1 beta, interleukin 6 and tumor necrosis factor-alpha expression. Thus, this is the explanation of positive effects observed with the use of hesperidin, diosmin and their combination in clinical practice.

Abstract Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no enhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.

Abstract Scrapie is a transmissible spongiform encephalopathy affecting sheep and goats. The prion protein-encoding gene (PRNP) plays a crucial role in determining susceptibility and resistance to scrapie. At the European level, surveillance of scrapie is essential to prevent the spread of the disease to livestock. According to the Regulation EU 2020/772 polymorphisms K222, D/S146 could function as resistance alleles in the genetic management of disease prevention. In Italy, a breeding plan for scrapie eradication has not been implemented for goats. However, surveillance plans based on the PRNP genotype have been developed as a preventive measure for scrapie. This research aimed to describe the polymorphisms at 7 positions within the PRNP gene in 956 goats of the Alpine, Saanen and mixed populations farmed in the Lombardy Region in Italy. PRNP polymorphisms were detected using single nucleotide polymorphism markers included in the Neogen GGP Goat 70 k chip. The K222 allele occurred in all populations, with frequencies ranging from 2.1 to 12.7%. No animals carried the S/D146 resistance allele. However, it has been demonstrated that polymorphisms in the other positions analysed could influence resistance or susceptibility to scrapie outbreaks in different ways. Ten potentially distinct haplotypes were found, and the most prevalent of the three populations was H2, which differed from the wild type (H1) in terms of mutation (S vs P) at codon 240. This study provided additional information on the genetic variability of the PRNP gene in these populations in the Lombardy region of Italy, contributing to the development of genetic control measures for disease prevention.

The title compound, bis[dithiobis(formamidinium)] hexabromidoruthenium dibromide trihydrate, [(NH2)2CSSC(NH2)2]2[RuBr6]Br2·3H2O, crystallizes in the orthorhombic system, space group Cmcm, Z = 4. The [RuBr6]2− anionic complex has an octahedral structure. The Ru—Br distances fall in the range 2.4779 (4)–2.4890 (4) Å. The S—S and C—S distances are 2.0282 (12) and 1.783 (2) Å, respectively. The H2O molecules, Br− ions, and NH2 groups of the cation are linked by hydrogen bonds. The conformation of the cation is consolidated by intramolecular O—H...Br, O—H...O, N—H...Br and N—H...O hydrogen bonds. The [(NH2)2CSSC(NH2)2]2+ cations form a hydrogen-bonded system involving the Br − ions and the water molecules. Two Br − anions form four hydrogen bonds, each with the NH2 groups of two cations, thus linking the cations into a ring. The rings are connected by water molecules, forming N—H...O—H...Br hydrogen bonds.

Abstract Background The associations of vegetarian diets with risks for site-specific cancers have not been estimated reliably due to the low number of vegetarians in previous studies. Therefore, the Cancer Risk in Vegetarians Consortium was established. The aim is to describe and compare the baseline characteristics between non-vegetarian and vegetarian diet groups and between the collaborating studies. Methods We harmonised individual-level data from 11 prospective cohort studies from Western Europe, North America, South Asia and East Asia. Comparisons of food intakes, sociodemographic and lifestyle factors were made between diet groups and between cohorts using descriptive statistics. Results 2.3 million participants were included; 66% women and 34% men, with mean ages at recruitment of 57 (SD: 7.8) and 57 (8.6) years, respectively. There were 2.1 million meat eaters, 60,903 poultry eaters, 44,780 pescatarians, 81,165 vegetarians, and 14,167 vegans. Food intake differences between the diet groups varied across the cohorts; for example, fruit and vegetable intakes were generally higher in vegetarians than in meat eaters in all the cohorts except in China. BMI was generally lower in vegetarians, particularly vegans, except for the cohorts in India and China. In general, but with some exceptions, vegetarians were also more likely to be highly educated and physically active and less likely to smoke. In the available resurveys, stability of diet groups was high in all the cohorts except in China. Conclusions Food intakes and lifestyle factors of both non-vegetarians and vegetarians varied markedly across the individual cohorts, which may be due to differences in both culture and socioeconomic status, as well as differences in questionnaire design. Therefore, care is needed in the interpretation of the impacts of vegetarian diets on cancer risk.

Plasmablasts are a population of short-lived B cells that appear in the circulation shortly after vaccination and during acute infection. Plasmablasts are formed from resting B lymphocytes, from which they differ in their ability to secrete antibodies, making them similar to plasma cells. Plasmablasts are terminally differentiated cells that can form at various nodes and branches of the B cell response. The plasmablast response is an indicator of the success of vaccination and also helps in predicting antibody levels after recovery or vaccination. However, the definition and classification of plasmablasts faces great experimental and theoretical difficulties. The aim of the work was to determine the characteristics of the plasmablast response during acute SARS-CoV-2 infection. The study included patients (n = 28) with a severe form of COVID-19. Blood sampling was carried out once on the 10–18th day from the moment of hospitalization. B cells were isolated by immunomagnetic separation. Cells were phenotyped using flow cytometry. Secretion of IgM and IgG was determined by ELISpot method. B cell subsets were isolated using a cell sorter. Patients with COVID-19 had an approximately fourfold increase in total plasmablast levels compared to healthy donors. An even more pronounced excess over the negative control was observed for RBD-specific plasmablasts. In terms of their composition, plasmablasts were one third IgM⁺ cells. This distribution between B-cell BCR receptor isotypes was consistent with the primary nature of the immune response in COVID-19. Approximately a third of plasmablasts carried the CD138 antigen. CD138 marker is characteristic of the late stage of plasmablast maturation and is also found on plasma cells. The CD27+CD38⁺ population was divided according to the expression of the CD138 antigen. Using the ELISpot method, we have shown that a significant portion of circulating plasmablasts are antibody-secreting cells. Among circulating plasmablasts, both early and late plasmablasts can be distinguished, which are characterized by the absence of a surface BCR, but which carry the CD138 antigen. Determining how plasmablasts relate to other B cell populations is of paramount importance for the development of new treatments for COVID-19 and for the creation of promising vaccines against SARS-CoV-2 infection.

Abstract Background SMA is a hereditary neuromuscular disease that causes progressive muscle weakness and atrophy. Several studies have shown that the burden of SMA is very high at many levels. Functional assessment tools currently used do not completely address the impact of the disease in patients’ life. The objective of this qualitative study was to identify aspects of SMA that are relevant to patients and to design items useful for assessment purposes. Results Five focus group sessions were run during an annual SMA families meeting in Madrid, Spain. Focus groups were composed by parents of SMA type I children, sitter children type II-III, parents of sitter children type II-III, adult patients, and parents of walker children. Two trained facilitators conducted the focus groups using a semi-structured guideline to cover previously agreed topics based on the input of a Scientific and Patient Advisory Committee. The guideline was adapted for the different groups. According to what was communicated by participants, SMA entails a high burden of disease for both patients and their parents. Burden was perceived in physical, psychological, and social areas. Patient’s physical domain was the most relevant for participants, especially for parents of non-ambulant children, followed by limitations of motor scales to capture all changes, parents psychological burden, treatment expectations and patient’s psychological burden. Ten domains were the main areas identified as impacted by the disease: mobility and independence, fatigue and fatigability, infections and hospital consultations, scoliosis and contractures, vulnerability, pain, feeding, time spent in care, breathing, and sleep and rest. Conclusions This study confirms the necessity of evaluating other aspects of the disease that are not assessed in the functional motor scale. Measures of other aspects of the disease, such as pain, fatigue, feeding, should be also considered. A patient-reported outcomes instrument measuring such aspects in a valid and reliable way would be very useful. This study generated a list of new items relevant to be systematically measured in the assessment of the impact of SMA on the patients’ everyday life.

ZnO–TiO2 thin films containing 0.5 mol%, 1.0 mol%, and 5.0 mol% ZnO were synthesized by oxidative solid-phase pyrolysis. The materials contained anatase and rutile phases with particle size of 6–13 nm, as confirmed using X-ray phase analysis and scanning electron microscopy. When a certain number of ZnO crystallites appeared in the TiO2 film structure in the temperature range of room temperature to 220 °C, a two-level response of the film resistance was observed, differing by approximately 10%, as obtained by electrophysical measurements. The two-level response correlates with the formation of two donor energy levels of 0.28 and 0.33 eV in the band structure of the ZnO–TiO2 films. The donor level with a higher activation energy corresponded to the Ti vacancy (V−Ti), and that with a lower activation energy corresponded to the Zn vacancy (V−Zn). Two levels of gas-sensitive properties were noted for 0.5ZnO–TiO2, 1ZnO–TiO2, and 5ZnO–TiO2 under the influence of 50 ppm NO2 at 250 °C. Such two-level responses can be ascribed to the pinning of the Fermi level on ZnO and TiO2 nanocrystallites. The mechanism of the beak-shaped and two-level responses of sensors based on composite nanomaterials when exposed to various gases was elucidated.

Abstract Background Recent studies revealed an elevated likelihood of unintended pregnancies among women with psychiatric disorders compared to their counterparts without such vulnerability. Despite the importance of understanding family planning decision-making in this group, qualitative inquiries are lacking. This study explored family planning decisions among women with psychiatric disorders. Methods Utilizing a qualitative approach, three focus group discussions were conducted with purposive sampling: women with a history of unintended pregnancies (N = 3), women without children (N = 5), and women with a history of intended pregnancies (N = 9), all of whom had self-reported psychiatric disorders. Using thematic framework analysis, we investigated the themes “Shadow of the past,” reflecting past experiences, and “Shadow of the future,” reflecting future imaginaries, building upon the existing “Narrative Framework.” Results The Narrative Framework formed the foundation for understanding family planning among women with psychiatric disorders. The retrospective dimension of focus group discussions provided opportunities for reflective narratives on sensitive topics, revealing emotions of regret, grief and relief. Childhood trauma, adverse events, and inadequate parenting enriched the "Shadow of the past". The “Shadow of the present” was identified as a novel theme, addressing awareness of psychiatric disorders and emotions toward psychiatric stability. Social influences, stigma, and concerns about transmitting psychiatric disorders shaped future imaginaries in the shadow of the future. Conclusions This study enlightens how family planning decision-making in women with psychiatric disorders might be complex, as marked by the enduring impact of past experiences and societal influences in this sample. These nuanced insights underscore the necessity for tailored support for women with psychiatric disorders.

Abstract Purpose In this study, we present DeepVirusClassifier, a tool capable of accurately classifying Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral sequences among other subtypes of the coronaviridae family. This classification is achieved through a deep neural network model that relies on convolutional neural networks (CNNs). Since viruses within the same family share similar genetic and structural characteristics, the classification process becomes more challenging, necessitating more robust models. With the rapid evolution of viral genomes and the increasing need for timely classification, we aimed to provide a robust and efficient tool that could increase the accuracy of viral identification and classification processes. Contribute to advancing research in viral genomics and assist in surveilling emerging viral strains. Methods Based on a one-dimensional deep CNN, the proposed tool is capable of training and testing on the Coronaviridae family, including SARS-CoV-2. Our model’s performance was assessed using various metrics, including F1-score and AUROC. Additionally, artificial mutation tests were conducted to evaluate the model’s generalization ability across sequence variations. We also used the BLAST algorithm and conducted comprehensive processing time analyses for comparison. Results DeepVirusClassifier demonstrated exceptional performance across several evaluation metrics in the training and testing phases. Indicating its robust learning capacity. Notably, during testing on more than 10,000 viral sequences, the model exhibited a more than 99% sensitivity for sequences with fewer than 2000 mutations. The tool achieves superior accuracy and significantly reduced processing times compared to the Basic Local Alignment Search Tool algorithm. Furthermore, the results appear more reliable than the work discussed in the text, indicating that the tool has great potential to revolutionize viral genomic research. Conclusion DeepVirusClassifier is a powerful tool for accurately classifying viral sequences, specifically focusing on SARS-CoV-2 and other subtypes within the Coronaviridae family. The superiority of our model becomes evident through rigorous evaluation and comparison with existing methods. Introducing artificial mutations into the sequences demonstrates the tool’s ability to identify variations and significantly contributes to viral classification and genomic research. As viral surveillance becomes increasingly critical, our model holds promise in aiding rapid and accurate identification of emerging viral strains.

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include ‘priming’ MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.

Abstract The widespread adoption of Connected and Automated Vehicles (CAVs) is being propelled, not only in the realm of private vehicles but also within transit systems. This development serves to enhance urban transport activities, rendering transportation more appealing to passengers. The present study aims to identify and examine the safety effects of testing different operational speed shuttle bus services in various future mobility conditions. To investigate impacts of autonomous shuttle bus services and to further examine their operational speed, the microscopic simulation method was performed. Specifically, four sets of simulation scenarios were comprised: a baseline scenario representing the current conditions and three operational speed scenarios (15 km/h, 30 km/h and 45 km/h) for an autonomous shuttle service. Each one of these sets included eleven CAV market penetration rates (MPRs) of CAVs of the general traffic (ranging from 0 to 100% in 10% increments). By analyzing the trajectory data extracted from microsimulation, traffic conflicts were identified and further analyzed by developing Mixed-Effects Multinomial Logit Regression models (ME-MLMs) in order to associate conflict type taking into account network characteristics as well as traffic conditions. Several aspects were determined as statistical significant parameters influencing type of conflict. The analysis yielded several significant findings that provide quantitative measurements and assessments of the effects observed, enabling a better understanding of the safety implications associated with the widespread adoption of automated services.

Abstract Background Past findings demonstrate that arthropods can egest midgut microbiota into the host skin leading to dual colonization of the vertebrate host with pathogens and saliva microbiome. A knowledge gap exists on how the saliva microbiome interacts with the pathogen in the saliva. To fill this gap, we need to first define the microbial composition of mosquito saliva. Methods The current study aimed at analyzing and comparing the microbial profile of Aedes albopictus saliva and midgut as well as assessing the impact of Zika virus (ZIKV) infection on the midgut and saliva microbial composition. Colony-reared Ae. albopictus strains were either exposed to ZIKV infectious or noninfectious bloodmeal. At 14 ays postinfection, the 16S V3–V4 hypervariable rRNA region was amplified from midgut and saliva samples and sequenced on an Illumina MiSeq platform. The relative abundance and diversity of midgut and saliva microbial taxa were assessed. Results We observed a richer microbial community in the saliva compared with the midgut, yet some of the microbial taxa were common in the midgut and saliva. ZIKV infection did not impact the microbial diversity of midgut or saliva. Further, we identified Elizabethkingia spp. in the Ae. albopictus saliva. Conclusions This study provides insights into the microbial community of the Ae. albopictus saliva as well as the influence of ZIKV infection on the microbial composition of its midgut and saliva. The identification of Elizabethkingia spp., an emerging pathogen of global health significance, in Ae. albopictus saliva is of medical importance. Future studies to assess the interactions between Ae. albopictus saliva microbiome and ZIKV could lead to novel strategies for developing transmission barrier tools. Graphical Abstract

Background: Contradictory findings link trait conscientiousness in mid- and late life to increased healthspan and lifespan, as well as to death by suicide. It remains unclear whether conscientiousness is associated with higher odds of attempting suicide or with more severe suicidal behavior among attempters, and whether its relationship to suicide risk varies with aging-related stressors, such as declining health. Methods: In this cross-sectional study comprising 313 depressed adults aged ≥40 years and participating in the Longitudinal Research Program in Late-Life Suicide (Pittsburgh, USA), we employed logistic and linear regression to test whether conscientiousness was associated with the presence of recent suicidal behavior (≤2 years) and with intent severity in recent attempters (n = 84). We further tested whether the above relationships varied based on mental, cognitive, and physical health status, measured as depression severity, cognitive functioning, and the presence/absence of severe physical illness. Results: Participants were 62.1 years old on average (SD = 7.6), 85% White, and 53% female. Recent attempters had a mean age of 61.8 years at their most recent attempt (SD = 8.5), had lower cognitive functioning and were more likely severely physically ill than comparisons. Conscientiousness was positively associated with a higher likelihood of recent suicidal behavior overall (adjusted OR = 1.44, 95% CI = 1.09, 1.90, p = .010), but not in case of co-occurring severe physical illness (interaction OR = 0.54, 95% CI = 0.30, 0.97, p = .039). Conscientiousness was also positively associated with suicidal intent at the most recent attempt (adjusted β = 1.60, SE = 0.62, p = .012), explaining 7% of its variance, although this association lost significance after adjusting for other personality dimensions. Conclusions: Highly conscientious middle-aged and older adults may be at increased risk of resolute suicidal behavior, although conscientiousness may not confer additional suicide risk among those severely physically ill.

Kearns-Sayre Syndrome (KSS) is a variant of mitochondrial disorder caused by a Mitochondrial Deoxyribonucleic Acid (mtDNA) deletion. Clinical manifestations of KSS can include different organ and system involvement. Different organ malfunctions, more often cardiac dysfunction, can lead to death. No effective treatment of this condition exists to date. Here, we report two patients with KSS. Female patient with a large-scale deletion of 7,020 base pairs (bp) suffered from hypogonadism, diabetes mellitus with fluctuating glucose levels, and had poor general health. A male patient with a common 4,977 bp deletion did not have diabetes mellitus but had impaired glucose tolerance. He also had a higher level of general health than our female patient. Both patients had reduced Bone Mineral Density (BMD). In female patients, calcium and vitamin D supplementation combined with metabolic therapy and nutritional drink supplements helped increase BMD (up to 32% in L1-L4). Comparing these two patients suggests that the larger the mtDNA deletion is, the more severe the course of the disease is. Not only does the size of the mtDNA deletion probably determine the severity of the disease, but also such factors as mtDNA heteroplasmy level, presence of mtDNA duplications, and pleioplasmy. Moreover, continuous nonconsecutive metabolic therapy and nutritional supplements are helpful in the prevention of deterioration of symptoms and general health.

BackgroundPost-Traumatic Stress Disorder (PTSD) is a severe and pervasive mental disorder, and patients experience numerous distressing symptoms and impairments that significantly impact their lives. In addition to being a mental disorder, PTSD is strongly associated with a wide range of metabolic abnormalities that affect the entire body. Existing treatment options of psychotherapy and medications are often ineffective. Exploring other potential treatments is necessitated. The ketogenic diet has shown potential as a metabolic therapy in certain neurological and mental disorders and is a promising intervention in the treatment of PTSD.AimThis study aimed to examine if a 4-week ketogenic diet intervention supplemented with exogenous ketones (KD-KS) was feasible in adult patients with PTSD, to what extent it was possible to recruit patients, attain and maintain ketosis (plasma concentration of β-hydroxybutyrate (BHB) ≥ 0.5 mmol/L), the occurrence of serious adverse reactions and adverse reactions to KD-KS, and acceptance of treatment. Our exploratory aims were changes in PTSD symptoms and health-related quality of life (QoL) from baseline to 4 weeks.MethodsPatients 18 ≤ 65 years old, diagnosed with PTSD, and receiving outpatient treatment for PTSD at Southern Oslo District Psychiatric Centre (DPC), Oslo University Hospital, Oslo, Norway, were included. The intervention consisted of a ketogenic diet supplemented with β-hydroxybutyrate salt to obtain ketosis. PTSD symptoms were measured with the PTSD Checklist for DSM-5 (PCL-5) and QoL was measured with the RAND 36-Item Health Survey 1.0.ResultsDuring a 21-week inclusion period, three of four eligible patients (75% [95% CI: 30 to 95%]) were included. Two patients (67% [95% CI: 21 to 94%]) completed the 4-week intervention and one patient (33% [95% CI: 6 to 79%]) completed 2 weeks of intervention before discontinuing. Ketosis was achieved on day 1 in one patient, and on day 2 in two patients, and was maintained in 87% of the intervention. There were no serious adverse reactions. Adverse reactions were reported in a total of 70% of intervention days, the most frequent being headache followed by fatigue. The participant-perceived degree of adverse reactions was low to moderate. The treatment was accepted by patients on all intervention days. PCL-5 decreased by 20 points (70 to 50) in patient 1 and by 10 points (50 to 40) in patient 2, from baseline to 4 weeks, which is a reliable and clinically meaningful improvement. QoL improved in six of eight RAND-36 subscales in patient 1 and three of eight in patient 2. Patient 3 did not complete assessments after week 2.ConclusionTo the best of our knowledge, this feasibility study is the first study examining a ketogenic diet intervention in patients with PTSD. Three of four predefined feasibility criteria were achieved. Ketosis was attained fast and maintained, patients were compliant and there were clinically meaningful improvements in PTSD symptoms and QoL. Despite the small sample size, the knowledge obtained in this study is important for the planning of future studies with ketogenic diet interventions in this patient group. It is a first step for potential dietary and metabolic therapies in PTSD. Further feasibility and pilot studies with larger sample sizes are needed to determine feasibility and safety before planning future randomised controlled trials investigating an effect.Clinical trial registrationhttps://ClinicalTrials.gov, identifier NCT05415982.

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis on patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow-up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence (CI) of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%, p=0.18) due to a lower CI of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower CI of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%, p=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and 2 inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR-T cells.

The serine/threonine-specific protein kinases (STKs) are important for cell survival, proliferation, differentiation, and apoptosis. In B cells, these kinases play indispensable roles in regulating important cellular functions. Multiple studies on human and other animal cells have shown that multiple STKs are involved in different stages of B cell development and antibody production. However, how STKs affect B cell development and function is still not completely understood. Considering that B cells are clinically important in immunity and diseases, our understanding of STKs’ roles in B cells is in great need of investigation with current technologies. Investigating serine/threonine kinases will not only deepen our insight into B cell-related disorders but also facilitate the identification of more effective drug targets for conditions like lymphoma and systemic lupus erythematosus.

The history of turkey (Meleagris gallopavo) domestication can be traced back to the period between 700 and 200 BC in Mexico. This process involved multiple contributors and resulted in the development of modern local turkey breeds. This research investigates the complete mitochondrial diversity across a diverse range of local turkeys. Seventy-three turkeys were sampled from various populations, including autochthonous Italian breeds, an American breed (Narragansett), as well as wild turkeys from the USA and Mexico. The mitochondrial DNA (mtDNA) was employed as a powerful tool for biodiversity and breed phylogeny investigation. An analysis of the entire mtDNA was conducted to identify breed-specific unique traits, mitochondrial-specific characteristics, and the phylogenetic relationship among turkey populations. A total of 44 polymorphic sites were identified. Brianzolo and Narragansett birds were characterized as genetically homogeneous populations. Thirty-two different haplotypes were identified when our samples were compared with mtDNA D-loop of 96 online available turkeys from various geographical countries. H1 and H2, differing for one mutation, were the most abundant, comprising 132 of the 185 sequences. H1 included samples coming from every region, while H2 was predominantly characterized by Italian samples. USA and Mexican samples appear to be more variable in their mtDNA than the other populations.

Summary: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: −22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case–control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: −17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: −17.9% to 89.6%), and further increased to 80.9% (95% CI: −17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

Summary: Background: Surgical care holds significant importance in healthcare, especially in low and middle-income countries, as at least 50% of the 4.2 million deaths within the initial 30 days following surgery take place in these countries. The Lancet Commission on Global Surgery proposed six indicators to enhance surgical care. In Colombia, studies have been made using secondary data. However, strategies to reduce perioperative mortality have not been implemented. This study aims to describe the fourth indicator, perioperative mortality rate (POMR), with primary data in Colombia. Methods: A multicentre prospective cohort study was conducted across 54 centres (hospitals) in Colombia. Each centre selected a 7-day recruitment period between 05/2022 and 01/2023. Inclusion criteria involved patients over 18 years of age undergoing surgical procedures in operating rooms. Data quality was ensured through a verification guideline and statistical analysis using mixed-effects multilevel modelling with a case mix analysis of mortality by procedure-related, patient-related, and hospital-related conditions. Findings: 3807 patients were included with a median age of 48 (IQR 32–64), 80.3% were classified as ASA I or II, and 27% of the procedures had a low-surgical complexity. Leading procedures were Orthopedics (19.2%) and Gynaecology/Obstetrics (17.7%). According to the Clavien–Dindo scale, postoperative complications were distributed in major complications (11.7%, 10.68–12.76) and any complication (31.6%, 30.09–33.07). POMR stood at 1.9% (1.48–2.37), with elective and emergency surgery mortalities at 0.7% (0.40–1.23) and 3% (2.3–3.89) respectively. Interpretation: The POMR was higher than the ratio reported in previous national studies, even when patients had a low–risk profile and low-complexity procedures. The present research represents significant public health progress with valuable insights for national decision-makers to improve the quality of surgical care. Funding: This work was supported by Universidad del Rosario and Fundación Cardioinfantil-Instituto de Cardiología grant number CTO-057-2021, project-ID IV-FGV017.

Objective To estimate real-life European Alliance of Associations for Rheumatology (EULAR)/European Renal Association (ERA)-European Dialysis and Transplantation Association (EDTA) response rates and predictors for no response in patients with lupus nephritis (LN) managed with conventional immunosuppressive therapies.Methods Ambidirectional cohort study of patients with new-onset LN (period 2014–to date). Response rates in the first year were calculated, and all treatment modifications were recorded. Univariate and multivariate regression analyses were performed to assess determinants of failure to respond at 12 months.Results 140 patients were included (81.4% women, median (IQR) age at LN diagnosis 38 (22) years). Among them, 32.1% presented with nephrotic range proteinuria, 28.6% with glomerular filtration rate

Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, – highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma.

Abstract Background Current definition of chronic kidney disease (CKD) identifies only advanced stages, but effective management demands early detection. Urinary albumin‐to‐creatinine ratio (ACR) 30 mg/g is a cut‐off point for CKD clinical diagnosis. Patients with lower values (normoalbuminuria) and eGFR > 60 mL/min/1.73 m2 are considered at no increased cardiorenal risk. However, higher incidence of renal function decline and cardiovascular events have been shown within the normoalbuminuria range. Novel subclinical indicators may help to identify higher‐risk patients. Urinary extracellular vesicles (uEVs) are sentinels of renal function non‐invasively. Here we aimed to approach the early assessment of cardiorenal risk by investigating the protein cargo of uEVs. Methods Hypertensive patients were classified in control group (C) with ACR 6200 uEVs proteins identified, 43 define a panel significantly altered in HN patients without variation in urine, mostly annotated in the tubule (39 out of 43). The tubular transporter long‐chain fatty acid transport protein 2 (SLC27A2) and the apical membrane protein amnionless (AMN) confirmed their alteration in HN patients evidencing impaired tubular reabsorption. SLC27A2 showed tubular expression and significantly reduced levels in patients with diagnostic criteria for CKD. Conclusions Alterations in the EV‐mediated molecular profile are evident before pathological ACR levels are reached. Direct quantitation of SLC27A2 and AMN in uEVs helps identifying normoalbuminuric subjects with higher cardiorenal risk in early monitoring of CKD.

Abstract The lattice geometry of natural materials and the structural geometry of artificial materials are crucial factors determining their physical properties. Most materials have predetermined geometries that lead to fixed physical characteristics. Here, the demonstration of a carbon nanotube network serves as an example of a system with controllable orientation achieving on‐demand optical properties. Such a network allows programming their optical response depending on the orientation of the constituent carbon nanotubes and leads to the switching of its dielectric tensor from isotropic to anisotropic. Furthermore, it also allows for the achievement of wavelength‐dispersion for their principal optical axes – a recently discovered phenomenon in van der Waals triclinic crystals. The results originate from two unique carbon nanotubes features: uniaxial anisotropy from the well‐defined cylindrical geometry and the intersection interaction among individual carbon nanotubes. The findings demonstrate that shaping the relative orientations of carbon nanotubes or other quasi‐one‐dimensional materials of cylindrical symmetry within a network paves the way to a universal method for the creation of systems with desired optical properties.

Objectives Cardiovascular disease is a leading cause of mortality in systemic lupus erythematosus (SLE). Frailty has been associated with an increased cardiovascular disease risk (CVR) in the general population. We aimed to examine the association between frailty and subclinical cardiovascular disease in patients with SLE.Methods In this cross-sectional study, we included all patients with SLE who underwent carotid/femoral artery ultrasound in our unit between 2016 and 2018. Clinical and laboratory data were collected at the time of ultrasound testing. Frailty was measured using the Systemic Lupus International Collaborating Clinics-Frailty Index (SLICC-FI). CVR (low, moderate, high, very high) was evaluated by the Systematic COronary Risk Evaluation (SCORE) model. Determinants of atherosclerotic plaque presence were assessed by logistic regression analyses, adjusting for potential confounders.Results 202 patients were included in the study. Atherosclerotic plaques (20.8% carotid, 17.3% femoral) were observed in 52/202 (25.7%) patients (89.1% women, mean (±SD) age 46.7±12.6). Median (IQR) SLICC-FI was 0.08 (0.04–0.10). 39 (19.3%) patients were classified as robust, 91 (45%) as relatively less fit, 59 (29.2%) as least fit and 13 (6.4%) as frail. In univariate analysis, plaque presence was significantly associated with age, disease duration, smoking, hypertension, systolic blood pressure, dyslipidaemia, SCORE, CVR class and SLICC-FI. CVR class (OR 5.16, p=0.000) and SLICC-FI (OR 1.34, p=0.03 per 0.05 point increase) remained significant in multivariate analysis after adjustment for traditional and disease-related CVR factors.Conclusions SLICC-FI is independently associated with plaque presence. Further studies are warranted to determine whether frailty-specific interventions can reduce CVR in patients with SLE.

Abstract Background Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS). Methods The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations. Results Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features. Conclusions The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.

Abstract Objective In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. Methods In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy‐seven ALSpts performed 3T MRI scans to measure cortical thickness. Between‐group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. Results Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P

Crimean-Congo hemorrhagic fever (CCHF), caused by CCHF virus, is a tickborne disease that can cause a range of illness outcomes, from asymptomatic infection to fatal viral hemorrhagic fever; the disease has been described in >30 countries. We conducted a literature review to provide an overview of the virology, pathogenesis, and pathology of CCHF for clinicians. The virus life cycle and molecular interactions are complex and not fully described. Although pathogenesis and immunobiology are not yet fully understood, it is clear that multiple processes contribute to viral entry, replication, and pathological damage. Limited autopsy reports describe multiorgan involvement with extravasation and hemorrhages. Advanced understanding of CCHF virus pathogenesis and immunology will improve patient care and accelerate the development of medical countermeasures for CCHF.

Crimean-Congo hemorrhagic fever (CCHF) is a tickborne infection that can range from asymptomatic to fatal and has been described in >30 countries. Early identification and isolation of patients with suspected or confirmed CCHF and the use of appropriate prevention and control measures are essential for preventing human-to-human transmission. Here, we provide an overview of the epidemiology, clinical features, and prevention and control of CCHF. CCHF poses a continued public health threat given its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, and potential for severe and fatal illness, in addition to the limited medical countermeasures for prophylaxis and treatment. A high index of suspicion, comprehensive travel and epidemiologic history, and clinical evaluation are essential for prompt diagnosis. Infection control measures can be effective in reducing the risk for transmission but require correct and consistent application.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread tickborne viral infection worldwide and has a fatality rate of up to 62%. Despite its widespread range and high fatality rate, no vaccines or treatments are currently approved by regulatory agencies in the United States or Europe. Supportive treatment remains the standard of care, but the use of antiviral medications developed for other viral infections have been considered. We reviewed published literature to summarize the main aspects of CCHFV infection in humans. We provide an overview of diagnostic testing and management and medical countermeasures, including investigational vaccines and limited therapeutics. CCHFV continues to pose a public health threat because of its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, potential for severe and fatal illness, and limited medical countermeasures for prophylaxis and treatment. Clinicians should become familiar with available diagnostic and management tools for CCHFV infections in humans.

Abstract Several studies have documented the significant impact of methodological choices in microbiome analyses. The myriad of methodological options available complicate the replication of results and generally limit the comparability of findings between independent studies that use differing techniques and measurement pipelines. Here we describe the Mosaic Standards Challenge (MSC), an international interlaboratory study designed to assess the impact of methodological variables on the results. The MSC did not prescribe methods but rather asked participating labs to analyze 7 shared reference samples (5 × human stool samples and 2 × mock communities) using their standard laboratory methods. To capture the array of methodological variables, each participating lab completed a metadata reporting sheet that included 100 different questions regarding the details of their protocol. The goal of this study was to survey the methodological landscape for microbiome metagenomic sequencing (MGS) analyses and the impact of methodological decisions on metagenomic sequencing results. A total of 44 labs participated in the MSC by submitting results (16S or WGS) along with accompanying metadata; thirty 16S rRNA gene amplicon datasets and 14 WGS datasets were collected. The inclusion of two types of reference materials (human stool and mock communities) enabled analysis of both MGS measurement variability between different protocols using the biologically-relevant stool samples, and MGS bias with respect to ground truth values using the DNA mixtures. Owing to the compositional nature of MGS measurements, analyses were conducted on the ratio of Firmicutes: Bacteroidetes allowing us to directly apply common statistical methods. The resulting analysis demonstrated that protocol choices have significant effects, including both bias of the MGS measurement associated with a particular methodological choices, as well as effects on measurement robustness as observed through the spread of results between labs making similar methodological choices. In the analysis of the DNA mock communities, MGS measurement bias was observed even when there was general consensus among the participating laboratories. This study was the result of a collaborative effort that included academic, commercial, and government labs. In addition to highlighting the impact of different methodological decisions on MGS result comparability, this work also provides insights for consideration in future microbiome measurement study design.