3D Printed Lenses for Vertical Beam Collimation of Optical Phased Arrays.

This article presents the design, fabrication, and characterization of edge-coupled 1D optical phased arrays (OPAs) combined with collimating lenses. Our concept was tested with two OPAs having different collimation ranges. Both OPA designs have 3-µm waveguide spacing and the maximum beam steering range is about 30° based on wavelength tuning around 1550 nm. The first generation had 37 channels with 108 µm of waveguide array width and the second generation had 512 channels with 1.5 mm array width. As the array outputs are edge coupled, suitable lenses are required to collimate the beam vertically. We report the comparison between a commercially available straight cylindrical lens and custom 3D printed curved cylindrical lenses. In the experiments, we demonstrate 1D beam steering of the light outcoupled from the waveguide facets and collimated by these lenses and analyzed parameters such as Rayleigh range and beam divergence. These parameters are estimated to be 9.9 mm and 7.0 mrad (0.4°), respectively, for the commercial lens, whereas 40.1 mm and 3.5 mrad (0.2°) for the dedicated 3D printed lens, showing a clear improvement.

Classification and risk stratification in T-lineage acute lymphoblastic leukemia.

Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part due to risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. While risk stratification is well-developed for patients with B lineage ALL (B-ALL), it remains challenging for those with T lineage ALL (T-ALL). Prognostic factors validated across clinical trials and real-world data in T-ALL include age, central nervous system (CNS) involvement, and minimal residual disease (MRD) response. Immunophenotype, including early T-cell precursor (ETP) ALL is widely used to classify T-ALL, but is not consistently associated with outcome in multivariable risk models. Historically, few genetic alterations have been consistently associated with outcome, but recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with outcome independent of MRD. This review highlights ongoing efforts to identify reliable prognostic biomarkers and underscores the potential of genomics-based classification to guide future T-ALL treatment strategies.

Feature sequence-based genome mining uncovers the hidden diversity of bacterial siderophore pathways.

Microbial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequence-to-function mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here, we developed a knowledge-guided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes of Pseudomonas bacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of iron-loaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data.

A novel high-level phenyllactic acid fungal producer, Kodamaea ohmeri w5 screened from fermented broad bean-chili-paste.

Phenyllactic acid (PLA) is a broad-spectrum and efficient antimicrobial phenolic acid with potential applications in the food industry. Previous studies have demonstrated that fungi may be ideal producers of PLA. In this study, 15 fungi screened from Doubanjiang with the ability to produce PLA were first reported, including Wickerhamomyces anomalus, Candida etchellsii, Candida parasitosis, Pichia kudriavzevii, Pichia membranifaciens and Kodamaea ohmeri. Among them, K. ohmeri w5 had the highest PLA yield, producing up to 7160 mg/L PLA in shake flask fermentation with phenylalanine as substrate, which was more than ten times higher than the PLA produced by wild-type LAB under the similar conditions. In addition, K. ohmeri w5 was able to grow under extreme hypertonic conditions of 20 % NaCl (w/v) and 50 % glucose (w/v) as well as produce 57.12 ± 0.42 and 1609.22 ± 36.26 mg/L of PLA, respectively. Furthermore, the fermentation supernatant of K. ohmeri w5 demonstrated direct inhibitory effects against foodborne pathogenic microorganisms, Aspergillus flavus and Bacillus cereus. However, the inhibitory effect was weaker than that of the PLA standard at the same concentration. Further, 12,497,932 bp of w5 genome-wide information was obtained by sequencing and assembling. And its gene model was predicted based on transcriptomic evidence, which showed that a total of 7 genes related to PLA synthesis were identified in the w5 genome. Based on qRT-PCR, structure prediction, and molecular docking, a potentially key genetic resource from K. ohmeri w5 for PLA production was uncovered. The results will provide novel producers of PLA and its potential genetic resources.

Mammalian Esterase Activity: Implications for Peptide Prodrugs.

As a traceless, bioreversible modification, the esterification of carboxyl groups in peptides and proteins has the potential to increase their clinical utility. An impediment is the lack of strategies to quantify esterase-catalyzed hydrolysis rates for esters in esterified biologics. We have developed a continuous Förster resonance energy transfer (FRET) assay for esterase activity based on a peptidic substrate and a protease, Glu-C, that cleaves a glutamyl peptide bond only if the glutamyl side chain is a free acid. Using pig liver esterase (PLE) and human carboxylesterases, we validated the assay with substrates containing simple esters (e.g., ethyl) and esters designed to be released by self-immolation upon quinone methide elimination. We found that simple esters were not cleaved by esterases, likely for steric reasons. To account for the relatively low rate of quinone methide elimination, we extended the mathematics of the traditional Michaelis-Menten model to conclude with a first-order intermediate decay step. By exploring two regimes of our substrate → intermediate → product (SIP) model, we evaluated the rate constants for the PLE-catalyzed cleavage of an ester on a glutamyl side chain (kcat/KM = 1.63 × 103 M-1 s-1) and subsequent spontaneous quinone methide elimination to regenerate the unmodified peptide (kI = 0.00325 s-1; t1/2 = 3.55 min). The detection of esterase activity was also feasible in the human intestinal S9 fraction. Our assay and SIP model increase the understanding of the release kinetics of esterified biologics and facilitate the rational design of efficacious peptide prodrugs.

Citrus wastewater as a source of value-added products: Quali-quantitative analysis and in vitro screening on breast cancer cell lines.

Citrus wastewater from industries is a source of bioactive compounds whose recovery could be a useful approach to convert processing waste into potential resources to be exploited in food, pharmaceutical, and chemical companies. Citrus wastewater, obtained from the industrial processing of Citrus sinensis, was freeze-dried and qualitative/quantitative evaluated using HPLC/MS Q-TOF analysis. Antiproliferative activity was investigated on MDA-MB-231 (triple-negative breast cancer cell line), MCF-7 (breast cancer cell line), and its multidrug-resistant variant MCF-7R. Fraction 8 emerged for its cytotoxicity toward MCF-7R cells. Its main component, the polymethoxylated flavone nobiletin (80%), is likely involved in increasing the number of G1-phase MCF-7R cells without inducing cell death. Notably, fraction 8 sensitizes MCF7-R cells to the antiproliferative effects of doxorubicin, thus contributing to overcoming MCF7-R multidrug resistance. Our studies highlighted the possibility of applying a sustainable strategy for citrus wastewater recycling to recover functional compounds as useful adjuvants for the prevention and treatment of malignancies.

Vaccines and vaccination in prison settings: availability and model of service delivery in 20 European countries.

Prisons, due to various risk factors, are environments that are conducive to infectious disease transmission, with significantly higher prevalence of infectious diseases within prisons compared to the general population. This underscores the importance of preventive measures, particularly vaccination. As part of the international project "Reaching the hard-to-reach: Increasing access and vaccine uptake among the prison population in Europe" (RISE-Vac), this study aimed to map the availability and delivery framework of vaccination services in prisons across Europe and beyond. A questionnaire designed to collect data on the availability and delivery model of vaccination services in prisons was validated and uploaded in SurveyMonkey in July 2023. Then, it was submitted to potential participants, with at least one representative from each European country. Potential participants emailed an invitation letter by the RISE-Vac partners and by the European Organization of Prison and Correctional Services (EUROPRIS). Twenty European countries responded. Vaccines are available in European countries, although their availability differs by country and type of vaccine. The first dose is offered to people living in prisons (PLP), mostly within one month, COVID-19 is the most widely offered vaccine. In all countries, vaccines are actively offered by healthcare workers; in most countries, there is no evaluation of vaccination status among people who work in prison. The survey shows variance in vaccine availability for PLP and staff across countries and vaccine types. Quality healthcare in prisons is not only a matter of the right to health but also a critical public health investment: enhancing vaccine uptake consistently among PLP and staff should be prioritized.

Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.

Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.

The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease.

Treatment of renal artery aneurysm by ex-situ repair and autotransplantation: a nationwide cohort study.

Introduction Renal artery aneurysm (RAA) is a rare vascular disease with a mortality rate of up to 80% upon rupture. This study aims to investigate the safety and efficacy of ex-situ repair and autotransplantation for endovascularly untreatable RAA. Methods A retrospective nationwide cohort study was conducted in RAA patients undergoing ex-situ repair and autotransplantation in the Netherlands. Surgical techniques, postoperative complications, and graft outcomes were assessed. Results Ex-situ repair was performed in 9 patients with 11 RAAs. Eight RAAs were located at the first bifurcation, one on the main trunk, one on the first branch, and one on the second branch. Nephrectomy was performed via laparoscopy (n=7), robotic-assisted laparoscopy (n=1) and laparotomy (n=1). Postoperative complications were recorded in four patients, including bowel obstruction, delirium, pneumonia and hydronephrosis due to double-J dislocation. Median estimated glomerular filtration rate (eGFR) was 83 ml/min/1.73m2 pretransplant and 88 ml/min/1.73m2 posttransplant. By an average follow-up of 3 years, two patients had died due to lung adenocarcinoma and stroke, while all autotransplanted kidneys had good patency and remained functional. Conclusions Ex-situ repair and autotransplantation are safe and feasible for endovascularly untreatable RAA cases. Larger cohorts with longer follow-up periods are necessary to further evaluate the role of this surgical approach.

Deeper but smaller: Higher-order interactions increase linear stability but shrink basins.

A key challenge of nonlinear dynamics and network science is to understand how higher-order interactions influence collective dynamics. Although many studies have approached this question through linear stability analysis, less is known about how higher-order interactions shape the global organization of different states. Here, we shed light on this issue by analyzing the rich patterns supported by identical Kuramoto oscillators on hypergraphs. We show that higher-order interactions can have opposite effects on linear stability and basin stability: They stabilize twisted states (including full synchrony) by improving their linear stability, but also make them hard to find by markedly reducing their basin size. Our results highlight the importance of understanding higher-order interactions from both local and global perspectives.

Loss of collagen content is localized near cartilage lesions on the day of injurious loading and intensified on day 12.

Joint injury can lead to articular cartilage damage, excessive inflammation, and post-traumatic osteoarthritis (PTOA). Collagen is an essential component for cartilage function, yet current literature has limited understanding of how biochemical and biomechanical factors contribute to collagen loss in injured cartilage. Our aim was to investigate spatially dependent changes in collagen content and collagen integrity of injured cartilage, with an explant model of early-stage PTOA. We subjected calf knee cartilage explants to combinations of injurious loading (INJ), interleukin-1α-challenge (IL) and physiological cyclic loading (CL). Using Fourier transform infrared microspectroscopy, collagen content (Amide I band) and collagen integrity (Amide II/1338 cm-1 ratio) were estimated on days 0 and 12 post-injury. We found that INJ led to lower collagen content near lesions compared to intact regions on day 0 (p < 0.001). On day 12, near-lesion collagen content was lower compared to day 0 (p < 0.05). Additionally, on day 12, INJ, IL, and INJ + IL groups exhibited lower collagen content along most of tissue depth compared to free-swelling control group (p < 0.05). CL groups showed higher collagen content along most of tissue depth compared to corresponding groups without CL (p < 0.05). Immunohistochemical analysis revealed higher MMP-1 and MMP-3 staining intensities localized within cell lacunae in INJ group compared to CTRL group on day 0. Our results suggest that INJ causes rapid loss of collagen content near lesions, which is intensified on day 12. Additionally, CL could mitigate the loss of collagen content at intact regions after 12 days.

Association Between 25(OH) Vitamin D Levels and Adverse Pregnancy Outcomes in Systemic Lupus Erythematosus.

OBJECTIVE: We evaluated the association of 25(OH) vitamin D levels with adverse pregnancy outcomes in systemic lupus erythematosus (SLE). METHODS: The Hopkins Lupus Cohort includes visits of pregnant patients, including assessment of 25(OH) vitamin D at each visit. We examined the relationship between 25(OH) vitamin D levels and adverse pregnancy outcomes (miscarriage, preterm delivery, and small for gestational age). We also used a time-to-event analysis to assess whether time-varying of 25(OH) vitamin D levels were associated with time to miscarriage or preterm delivery. RESULTS: In subgroups of patients defined by the average of 25(OH) vitamin D levels, we observed significantly different risks of miscarriage (p=0.0045), preterm delivery (p=0.0007) and the composite measure of all three adverse pregnancy outcomes (p=0.011). The highest risks were observed among those with lowest or highest levels of vitamin D. Nine out of 10 pregnancies with low vitamin D during the 2nd trimester resulted in a premature delivery. The time-to-event model confirmed the same U-shaped association after adjustment for SLE disease activity, however, the increased risk among those with highest levels of vitamin D was not statistically significant. Body mass index did not appear to be a confounding factor. CONCLUSION: Our study is not able to prove causation, but the results strongly suggest an association of 25(OH) vitamin D at both lower and higher levels with adverse pregnancy outcomes. We recommend monitoring of maternal serum 25(OH) vitamin D levels during SLE pregnancies, aiming for the ideal range of 40-59 ng/mL.

The Use of Survival Dose-Rate Dependencies as Theoretical Discrimination Criteria for In-Silico Dynamic Radiobiological Models.

Introduction: Cell repair dynamics are crucial in optimizing anti-cancer therapies. Various assays (eg, comet assay and γ-H2AX) assess post-radiation repair kinetics, but interpreting such data is challenging and model-based data analyses are required. However, ambiguities in parameter calibration remain an unsolved challenge. To address this, we propose combining survival dose-rate effects with computer simulations to gain knowledge about repair kinetics. Methods: After a literature review, theoretical discriminators based on common fractionation/dose-rate-related effects were defined to discard unrealistic model dynamics. The Multi-Hit Repair (MHR) model was calibrated with canine osteosarcoma Abrams cell line data to study the discriminators' efficacy in scenarios with limited survival data. Additionally, survival dose-rate-dependent data from the human SiHa cervical cancer cell line were used to illustrate the survival behavior at diverse dose-rates and the capability of the MHR to model these data. Results: SiHa data confirmed the validity of the proposed discriminators. The discriminators filtered 99% of parameter sets, improving the calibration of Abrams cells data. Furthermore, results from both cell lines may hint universal aspects of cellular repair. Conclusions: Dose-rate theoretical discrimination criteria are an effective method to understand repair kinetics and improve radiobiological model calibration. Moreover, this methodology may be used to analyze diverse biological data using dynamic models in-silico.

Transcriptome analysis unravels the biocontrol mechanism of Serratia plymuthica A30 against potato soft rot caused by Dickeya solani.

Endophytic bacterium Serratia plymuthica A30 was identified as a superior biocontrol agent due to its effective colonization of potato tuber, tolerance to cold conditions, and strong inhibitory action against various soft rot pathogens, including Dickeya solani. We characterized transcriptome changes in potato tubers inoculated with S. plymuthica A30, D. solani, or both at the early and the late phases of interaction. At the early phase and in the absence of the pathogen, A30 influenced the microbial recognition system to initiate plant priming. In the presence of the pathogen alongside biocontrol strain, defense signaling was highly stimulated, characterized by the induction of genes involved in the detoxification system, reinforcement of cell wall structure, and production of antimicrobial metabolites, highlighting A30's role in enhancing the host resistance against pathogen attack. This A30-induced resistance relied on the early activation of jasmonic acid signaling and its production in tubers, while defense signaling mediated by salicylic acid was suppressed. In the late phase, A30 actively interferes with plant immunity by inhibiting stress- and defense-related genes expression. Simultaneously, the genes involved in cell wall remodeling and indole-3-acetic acid signaling were activated, thereby enhancing cell wall remodeling to establish symbiotic relationship with the host. The endophytic colonization of A30 coincided with the induction of genes involved in the biosynthesis and signaling of ethylene and abscisic acid, while downregulating those related to gibberellic acid and cytokinin. This combination suggested fitness benefits for potato tubers by preserving dormancy, and delaying sprouting, which affects durability of tubers during storage. This study contributes valuable insights into the tripartite interaction among S. plymuthica A30, D. solani, and potato tubers, facilitating the development of biocontrol system for soft rot pathogens under storage conditions.

The impact of macrophage phenotype and heterogeneity on the total internalized gold nanoparticle counts.

Macrophages play a pivotal role in the internalization and processing of administered nanoparticles (NPs). Furthermore, the phagocytic capacity and immunological properties of macrophages can vary depending on their microenvironment, exhibiting a spectrum of polarization states ranging from pro-inflammatory M1 to anti-inflammatory M2. However, previous research investigating this phenotype-dependent interaction with NPs has predominantly relied on semi-quantitative techniques or conventional metrics to assess intracellular NPs. Here, we focus on the interaction of human monocyte-derived macrophage phenotypes (M1-like and M2-like) with gold NPs (AuNPs) by combining population-based metrics and single-cell analysis by focused ion beam-scanning electron microscopy (FIB-SEM). The multimodal analysis revealed phenotype-dependent response and uptake behavior differences, becoming more pronounced after 48 hours. The study also highlighted phenotype-dependent cell-to-cell heterogeneity in AuNPs uptake and variability in particle number at the single-cell level, which was particularly evident in M2-like macrophages, which increases with time, indicating enhanced heteroscedasticity. Future efforts to design NPs targeting macrophages should consider the phenotypic variations and the distribution of NPs concentrations within a population, including the influence of cell-to-cell heterogeneity. This comprehensive understanding will be critical in developing safe and effective NPs to target different macrophage phenotypes.

Effect on post-operative pulmonary complications frequency of high flow nasal oxygen versus standard oxygen therapy in patients undergoing esophagectomy for cancer: study protocol for a randomized controlled trial-OSSIGENA study.

Background: Postoperative pulmonary complications (PPCs) remain a challenge after esophagectomy. Despite improvement in surgical and anesthesiological management, PPCs are reported in as many as 40% of patients. The main aim of this study is to investigate whether early application of high-flow nasal cannula (HFNC) after extubation will provide benefit in terms of reduced PPC frequency compared to standard oxygen therapy. Methods: Patients aged 18-85 years undergoing esophagectomy for cancer treatment with radical intent, excluding those with American Society of Anesthesiologists (ASA) score >3 and severe systemic comorbidity (cardiac, pulmonary, renal or hepatic disease) will be randomized at the end of surgery to receive HFNC or standard oxygen therapy (Venturi mask or nasal goggles) after early extubation (within 12 hours after the end of surgery) for 48 hours. The main postoperative goals are to obtain SpO2 ≥94% and adequate pain control. Oxygen therapy after 48 hours will be stopped unless the physician deems it necessary. In case of respiratory clinical worsening, patients will be supported with the most appropriate tool (noninvasive ventilation or invasive mechanical ventilation). Pulmonary [pneumonia, pleural effusion, pneumothorax, atelectasis, acute respiratory distress syndrome (ARDS), tracheo-bronchial injury, air leak, reintubation, and/or respiratory failure] complications will be recorded as main outcome. Secondary outcomes, including cardiovascular, surgical, renal and infective complications will also be recorded. The primary analysis will be carried out on 320 patients (160 per group) and performed on an intention-to-treat (ITT) basis, including all participants randomized into the treatment groups, regardless of protocol adherence. The primary outcome, the PPC rate, will be compared between the two treatment groups using a chi-square test for categorical data, or Fisher's exact test will be used if the assumptions for the chi-square test are not met. Discussion: Recent evidence demonstrated that early application of HFNC improved the respiratory rate oxygenation index (ROX index) after esophagectomy but did not reduce PPCs. This randomized controlled multicenter trial aims to assess the potential effect of the application of HFNC versus standard oxygen over PPCs in patients undergoing esophagectomy. Trial Registration: This study is registered at clinicaltrial.gov NCT05718284, dated 30 January 2023.

Childhood Physical Fitness as a Predictor of Cognition and Mental Health in Adolescence: The PANIC Study.

BACKGROUND: Cognitive and mental health problems are highly prevalent in adolescence. While higher levels of physical fitness may mitigate these problems, there is a lack of long-term follow-up studies on the associations of physical fitness from childhood with cognition and mental health in adolescence. OBJECTIVE: We investigated the associations of physical fitness from childhood to adolescence over an 8-year follow-up with cognition and mental health in adolescence. METHODS: The participants were 241 adolescents (112 girls), who were 6-9 years at baseline and 15-17 years at 8-year follow-up. Average and change scores for cardiorespiratory fitness (maximal power output [Wmax]; peak oxygen uptake [VO2peak]), motor fitness (10 × 5-m shuttle run), and muscular fitness (standing long jump; hand grip strength) were calculated. Global cognition score was computed from six individual cognitive tasks, and perceived stress and depressive symptoms were assessed at the 8-year follow-up. The data were analysed using linear regression models adjusted for age, sex, and parental education. RESULTS: Average motor fitness was positively associated with global cognition score (standardised regression coefficient [ß] - 0.164, 95% confidence interval [CI] - 0.318 to - 0.010) and inversely with perceived stress (ß = 0.182, 95% CI 0.032-0.333) and depressive symptoms (ß = 0.181, 95% CI 0.028-0.333). Average cardiorespiratory fitness was inversely associated with perceived stress (Wmax: ß = - 0.166, 95% CI - 0.296 to - 0.036; VO2peak: ß = - 0.149, 95% CI - 0.295 to - 0.002) and depressive symptoms (Wmax: ß = - 0.276, 95% CI - 0.405 to - 0.147; VO2peak: ß = - 0.247, 95% CI - 0.393 to - 0.102). A larger increase in cardiorespiratory fitness was associated with lower perceived stress (Wmax: ß = - 0.158, 95% CI - 0.312 to - 0.003; VO2peak: ß = - 0.220, 95% CI - 0.395 to - 0.044) and depressive symptoms (Wmax: ß = - 0.216, 95% CI - 0.371 to - 0.061; VO2peak: ß = - 0.257, 95% CI - 0.433 to - 0.080). CONCLUSIONS: Higher levels of motor fitness in childhood and adolescence were associated with better cognition in adolescence. Higher levels of and larger increases in cardiorespiratory fitness from childhood to adolescence were associated with better mental health in adolescence.

Protective immune response against Rhodococcus equi: An innate immunity-focused review.

Rhodococcus equi causes pyogranulomatous pneumonia in foals and immunocompromised people. Despite decades of research efforts, no vaccine is available against this common cause of disease and death in foals. The purpose of this narrative review is to summarise the current understanding of interactions between R. equi and the host innate immune system, to describe features of the immune response that are associated with resistance or susceptibility to R. equi infection, and help guide strategies for developing novel approaches for preventing R. equi infections. Virulence of R. equi in foals has been attributed to the virulence associated protein A which allows intracellular survival in macrophages by preventing acidification of R. equi-containing vacuole. Additionally, foal susceptibility to R. equi infection is associated with immaturity and naivety of innate and adaptive immune systems, while adult horses with fully functional immune system are resistant to pneumonia. Specific interaction between R. equi and innate immune cells can result in bacterial survival or death; learning how to manipulate these responses to control infection is critical to prevent pneumonia in foals. Administration of live vaccines and stimulation of innate immune responses appears to improve foals' immune response and has the potential to overcome the challenges of foal active vaccination and elicit protection against pneumonia.

SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.

Objective: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment. Methods: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed. Results: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy. Conclusion: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.