Search

OBJECTIVE: To study the phenotype characteristics of the largest to date cohort of patients with pediatric granulomatous arthritis (PGA) and documented mutations in the NOD2 gene. METHODS: We analyzed merged data from 2 prospective cohorts of PGA patients, the International PGA Registry and a Spanish cohort. A systematic review of the medical records of interest was performed to identify phenotype characteristics. RESULTS: Forty-five patients with PGA (23 sporadic cases and 22 from familial pedigrees) and documented NOD2 mutations were identified and formed the basis of the study. Of these 45 patients, 18 had the R334W-encoding mutation, 18 had R334Q, 4 had E383K, 3 had R587C, 1 had C495Y, and 1 had W490L. The majority of patients manifested the typical triad of dermatitis, uveitis, and arthritis. In contrast, in 13 patients, the following 'atypical' manifestations were noted: fever, sialadenitis, lymphadenopathy, erythema nodosum, leukocytoclastic vasculitis, transient neuropathy, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, hypertrophic cardiomyopathy, pericarditis, pulmonary embolism, hepatic granulomatous infiltration, splenic involvement, and chronic renal failure. In addition, 4 individuals who were asymptomatic carriers of a disease-causing mutation were documented. CONCLUSION: NOD2-associated PGA can be a multisystem disorder with significant visceral involvement. Treating physicians should be aware of the systemic nature of this condition, since some of these manifestations may entail long-term morbidity. [ABSTRACT FROM AUTHOR]

Depression is related to increased morbidity and mortality from coronary heart disease (CHD), but the underlying mechanisms are unclear. One possibility is that depressive symptoms influence CHD pathogenesis by fostering endothelial dysfunction. To evaluate this possibility, we studied one hundred and two adolescent women with no known or suspected major health problems. Depressive symptoms were assessed using the Beck Depression Inventory (BDI) and endothelial function with a non-invasive beat-to-beat plethysmographic recording of the finger arterial pulse-wave amplitude (PWA) before and after occlusion of the brachial artery. Regression analysis revealed a significant inverse relationship between depressive symptoms and endothelial function. This persisted after controlling for age, ethnicity, health practices and waist circumference. Depression explained 4-6% of the variance in endothelial function above and beyond the effects of covariates. Most patients in our sample had subclinical depressive symptoms, suggesting that even mild affective difficulties are capable of negatively influencing endothelial function in otherwise healthy youngsters. [ABSTRACT FROM AUTHOR]

Accelerated baccalaureate nursing programs are in great demand in the United States. Currently there are 197 such programs, but little research has been conducted on student characteristics and program outcomes. This quantitative study explores preferences of second-degree students and traditional generic students with regard to teaching methods and relationships with faculty. The results indicate that statistically significant differences exist between the two groups of students. Three areas of significance are ability for self-directed learning, expectations of faculty and classroom structure, and obtaining a grade that really matters. [ABSTRACT FROM AUTHOR]

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 'Blau mutations.' [ABSTRACT FROM AUTHOR]

Pancreatic islet β-cells express the Cpt1a gene, which encodes the enzyme carnitine palmitoyltransferase 1A (CPT1A), an enzyme that facilitates entry of long chain fatty acids into the mitochondria. Because fatty acids are required for glucose-stimulated insulin secretion, we tested the hypothesis that CPT1A is essential to support islet β-cell function and mass. In this study, we describe genetic deletion of Cpt1a in pancreatic tissue (Cpt1a Pdx1-/- ) using C57BL/6J mice. Islet morphology, β-cell transcription factor abundance, islet ATP levels, GLUT2 abundance, and expression of the de-differentiation marker ALDH1A3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance were assessed to investigate the metabolic status of genetic reductions in Cpt1a. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. Pancreatic deletion of Cpt1a reduced glucose tolerance but did not alter insulin sensitivity. Glucose-stimulated insulin secretion was reduced both in vivo and in islets isolated from Cpt1a Pdx1-/- mice relative to control islets. Pancreatic islets from Cpt1a Pdx1-/- mice displayed elevations in ALDH1A3, a marker of de-differentiation, but no reduction in nuclear abundance of the β-cell transcription factors MafA and Nkx6.1 or the GLUT2 glucose transporter. However, intracellular ATP abundance was markedly decreased in islets isolated from Cpt1a Pdx1-/- relative to littermate control mice. We conclude that there is an important physiological role for pancreatic CPT1A to maintain whole-body glucose homeostasis by supporting glucose-stimulated insulin secretion and maintaining intracellular ATP levels in male mice., Competing Interests: Conflict of Interest Statement The authors have nothing to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to assess the interobserver variability of semi-automatic diameter and volumetric measurements versus manual diameter measurements for small lung nodules identified on computed tomography scans., Methods: The radiological patient database was searched for CT thorax examinations with at least one noncalcified solid nodule (∼3-10 mm). Three radiologists with four to six years of experience evaluated each nodule in accordance with the Fleischner Society guidelines using standard diameter measurements, semi-automatic lesion diameter measurements, and volumetric assessments. Spearman's correlation coefficient measured intermeasurement agreement. We used descriptive Bland-Altman plots to visualize agreement in the measured data. Potential discrepancies were analyzed., Results: We studied a total of twenty-six nodules. Spearman's test showed that there was a much stronger relationship ( p < 0.05) between reviewers for the semi-automatic diameter and volume measurements (avg. r = 0.97 ± 0.017 and 0.99 ± 0.005, respectively) than for the manual method (avg. r = 0.91 ± 0.017). In the Bland-Altman test, the semi-automatic diameter measure outperformed the manual method for all comparisons, while the volumetric method had better results in two out of three comparisons. The incidence of reviewers modifying the software's automatic outline varied between 62% and 92%., Conclusions: Semi-automatic techniques significantly reduced interobserver variability for small solid nodules, which has important implications for diagnostic assessments and screening. Both the semi-automatic diameter and semi-automatic volume measurements showed improvements over the manual measurement approach. Training could further diminish observer variability, given the considerable diversity in the number of adjustments among reviewers., Competing Interests: The authors declare no conflicts of interest.

Background: Native knee joint infections, while uncommon, present a serious condition predominantly instigated by bacteria such as Staphylococcus aureus . Without timely intervention, they can result in joint destruction or sepsis, with risk factors encompassing preexisting medical conditions and iatrogenic procedures. The diagnostic process includes a comprehensive patient history, clinical evaluation, laboratory testing, imaging studies, and microbiological investigations. Treatment typically involves joint aspiration and arthroscopy. This study aims to examine and establish correlations between diagnostic criteria and treatment modalities, enhancing the speed and specificity of future therapeutic strategies. Materials and methods: The present study is a retrospective cohort study conducted at a 1200-bed university clinic between 2007 and 2017, with an in-depth examination of patient details, symptoms, treatments, and outcomes. A scoring system was developed to classify the severity of knee joint impairment, categorizing patients on the basis of hospital stay duration, surgeries, and postoperative factors such as recurring symptoms, pain, and range of motion. Results: This study of 116 patients with knee joint infections revealed that clinical symptoms such as pain, swelling, and effusion are common but not definitive for diagnosis. Laboratory analysis revealed no significant differences in CRP or leukocyte counts between cultures positive or negative for pathogens. Hospital stay and disease severity are influenced by factors such as age, sex, presence of polyarthritis, neutrophil count, and type of pathogen, with higher weight and cortisone treatment associated with poorer outcomes. Conclusions: This study highlights the diagnostic challenges in native knee joint infections, revealing the need for comprehensive approaches given the nonspecificity of clinical symptoms and laboratory findings. This underscores the importance of advancing research through standardized methodologies and prospective studies to increase the accuracy of diagnosis and the effectiveness of treatment in this field.

Nonribosomal peptide synthetases (NRPSs) are mega-enzymes responsible for the biosynthesis of many clinically important natural products, from early modern medicines (penicillin, bacitracin) to current blockbuster drugs (Cubicin, vancomycin) and newly-approved therapeutics (rezafungin) 1,2 . The key chemical step in these biosyntheses is amide bond formation between aminoacyl building blocks, catalyzed by the condensation (C) domain 3 . There has been much debate over the mechanism of this reaction 3-12 . NRPS condensation has been difficult to fully characterize because it is one of many successive reactions in the NRPS synthetic cycle and because the canonical substrates are each attached transiently as thioesters to mobile carrier domains, which are often both contained in the same very flexible protein as the C domain. We have produced a dimodular NRPS protein in two parts, modified each with appropriate non-hydrolysable substrate analogs 13,14 assembled the two parts with protein ligation 15 , and solved structures of the substrate- and product-bound states. The structures show precise orientation of the megaenzyme preparing the nucleophilic attack of its key chemical step, and allow biochemical assays and quantum mechanical simulations to precisely interrogate the reaction. These data suggest that NRPSs C domains use a concerted reaction mechanism, where the active site histidine likely serves not a as general base, but as a crucial stabilizing hydrogen bond acceptor for the developing ammonium., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/Objectives : Patients with Gaucher disease have a high risk of bone disease, with osteonecrosis representing the most debilitating complication. The pathogenesis of osteonecrosis has not been fully elucidated yet, and there is an unmet need for predictive biomarkers of bone complications. We aimed to assess the utility of angiogenesis and bone turnover biomarkers as predictors of osteonecrosis in Gaucher disease. Methods : Angiogenesis and bone turnover biomarkers were measured in 146 Gaucher disease patients (70M:76F, median age 49.5 [IQR 36.7 to 61]) with/without osteonecrosis enrolled in the UK-based registry GAUCHERITE [enrolment 2015-2017]. Receiver-operating characteristic curve analysis was used to compare the osteonecrosis predictive value of angiogenesis and bone turnover biomarkers and determine the optimal cut-off values for each biomarker. Results : Sixty-two patients had osteonecrosis before study enrolment, 11 had osteonecrosis during follow-up, and 73 remained osteonecrosis-free. Patients with osteonecrosis showed increased osteopontin and matrix metalloproteinase (MMP)-2 levels and decreased MMP-9 and vascular endothelial growth factor (VEGF)-C compared with those free from osteonecrosis. MMP-9 predicted future osteonecrosis with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC] 0.84 [95% CI 0.84-0.99]; sensitivity/specificity 82%/75%; cutoff value ≤ 72,420 pg/mL) than osteopontin, MMP-2 and VEGF-C when taken alone. The combination of MMP-9 and VEGF-C further increased the discriminating accuracy. Conclusions : The osteopontin-MMPs-VEGF axis is dysregulated in Gaucher disease patients with osteonecrosis. The combination of MMP-9 and VEGF-C circulating levels may serve to identify Gaucher disease patients at risk of osteonecrosis.

Ataxia telangiectasia (AT) is a rare autosomal-recessive disorder characterized by profound neurodegeneration, combined immunodeficiency, and an increased risk for malignant diseases. Treatment options for AT are limited, and the long-term survival prognosis for patients remains grim, primarily due to the emergence of chronic respiratory pathologies, malignancies, and neurological complications. Understanding the dysregulation of the immune system in AT is fundamental for the development of novel treatment strategies. In this context, we performed a retrospective longitudinal immunemonitoring of lymphocyte subset distribution in a cohort of AT patients ( n = 65). Furthermore, we performed FACS analyses of peripheral blood mononuclear cells from a subgroup of 12 AT patients to examine NK and T cells for the expression of activating and functional markers. We observed reduced levels of peripheral blood CD3 + CD8 + cytotoxic T cells, CD3 + CD4 + T helper cells, and CD19 + B cells, whereas the amount of CD3 -- CD56 + NK cells and CD3 + CD56 + NKT-like cells was similar compared with age-matched controls. Notably, there was no association between the age-dependent kinetic of T-, B-, or NK-cell counts and the occurrence of malignancy in AT patients. Additionally, our results indicate an altered NK- and T-cell response to cytokine stimulation in AT with increased levels of TRAIL, FasL, and CD16 expression in NK cells, as well as an elevated activation level of T cells in AT with notably higher expression levels of IFN-γ, CD107a, TRAIL, and FasL. Together, these findings imply function alterations in AT lymphocytes, specifically in T and NK cells, shedding light on potential pathways for innovative therapies., Competing Interests: EU has no COIs directly related to this manuscript. EU has a sponsored research project with Gilead, BMS, and CRIION. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Graafen, Heinze, Albinger, Salzmann-Manrique, Ganß, Hünecke, Cappel, Wölke, Donath, Trischler, Theilen, Heller, Königs, Ehl, Bader, Klingebiel, Klusmann, Zielen, Schubert and Ullrich.)

Viruses can selectively repress the translation of mRNAs involved in the antiviral response. RNA viruses exploit the Grb10-interacting GYF (glycine-tyrosine-phenylalanine) proteins 2 (GIGYF2) and eukaryotic translation initiation factor 4E (eIF4E) homologous protein 4EHP to selectively repress the translation of transcripts such as Ifnb1 , which encodes the antiviral cytokine interferon-β (IFN-β). Herein, we reveal that GIGYF1, a paralog of GIGYF2, robustly represses cellular mRNA translation through a distinct 4EHP-independent mechanism. Upon recruitment to a target mRNA, GIGYF1 binds to subunits of eukaryotic translation initiation factor 3 (eIF3) at the eIF3-eIF4G1 interaction interface. This interaction disrupts the eIF3 binding to eIF4G1, resulting in transcript-specific translational repression. Depletion of GIGYF1 induces a robust immune response by derepressing IFN-β production. Our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism has profound implications for the host response to viral infections.

Background and Purpose: Magnetic Resonance Imaging (MRI)-guided Stereotactic body radiotherapy (SBRT) treatment to prostate bed after radical prostatectomy has garnered growing interests. The aim of this study is to evaluate intra-fractional anatomic and dose/volume metric variations for patients receiving this treatment., Materials and Methods: Nineteen patients who received 30-34 Gy in 5 fractions on a 0.35T MR-Linac were included. Pre- and post-treatment MRIs were acquired for each fraction (total of 75 fractions). The Clinical Target Volume (CTV), bladder, rectum, and rectal wall were contoured on all images. Volumetric changes, Hausdorff distance, Mean Distance to Agreement (MDA), and Dice similarity coefficient (DSC) for each structure were calculated. Median value and Interquartile range (IQR) were recorded. Changes in target coverage and Organ at Risk (OAR) constraints were compared and evaluated using Wilcoxon rank sum tests at a significant level of 0.05., Results: Bladder had the largest volumetric changes, with a median volume increase of 48.9 % (IQR 28.9-76.8 %) and a median MDA of 5.1 mm (IQR 3.4-7.1 mm). Intra-fractional CTV volume remained stable with a median volume change of 1.2 % (0.0-4.8 %). DSC was 0.97 (IQR 0.94-0.99). For the dose/volume metrics, there were no statistically significant changes observed except for an increase in bladder hotspot and a decrease of bladder V 32.5 Gy and mean dose. The CTV V 95% changed from 99.9 % (IQR 98.8-100 %) to 99.6 % (IQR 93.9-100 %)., Conclusion: Despite intra-fractional variations of OARs, CTV coverage remained stable during MRI-guided SBRT treatments for the prostate bed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, ViewRay, and Intelligent Automation; equity in ViewRay; and serving on the Janssen advisory board and Boston Scientific; received research funds from Janssen and Point Biopharma and ViewRay. Dr. Low reports corporate grant with Varian, consulting and presentation travel and fees from ViewRay, SAB for TAE Life Sciences, and founder of Pulmonum LLC. Dr. Ma and Dr. Steinberg reports honorarium from ViewRay. Dr. Cao reports corporate grant with Varian, honorarium and consulting fees from Varian and ViewRay. All other authors do not have any potential conflicts of interest to disclose. Funding support for the SCIMITAR trial was partially provided by ViewRay, Inc., but ViewRay, Inc. has no role in the conduct of this analysis., (© 2024 The Authors.)

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in TARDBP (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR-Cas9, we engineered two homozygous knock-in induced pluripotent stem cell lines carrying mutations in TARDBP encoding TDP-43 A382T and TDP-43 G348C , two common yet understudied ALS TDP-43 variants. Motor neurons (MNs) differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43 A382T and TDP-43 G348C MN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings suggest that MN dysfunction may precede the occurrence of TDP-43 pathology and neurodegeneration in ALS and further implicate synaptic and excitability defects in the pathobiology of this disease., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Spiking neural networks (SNNs) mimic their biological counterparts more closely than their predecessors and are considered the third generation of artificial neural networks. It has been proven that networks of spiking neurons have a higher computational capacity and lower power requirements than sigmoidal neural networks. This article introduces a new type of SNN that draws inspiration and incorporates concepts from neuronal assemblies in the human brain. The proposed network, termed as class-dependent neuronal activation-based SNN (CDNA-SNN), assigns each neuron learnable values known as CDNAs which indicate the neuron's average relative spiking activity in response to samples from different classes. A new learning algorithm that categorizes the neurons into different class assemblies based on their CDNAs is also presented. These neuronal assemblies are trained via a novel training method based on spike-timing-dependent plasticity (STDP) to have high activity for their associated class and low firing rate for other classes. Also, using CDNAs, a new type of STDP that controls the amount of plasticity based on the assemblies of pre-and postsynaptic neurons is proposed. The performance of CDNA-SNN is evaluated on five datasets from the University of California, Irvine (UCI) machine learning repository, as well as Modified National Institute of Standards and Technology (MNIST) and Fashion MNIST, using nested cross-validation (N-CV) for hyperparameter optimization. Our results show that CDNA-SNN significantly outperforms synaptic weight association training (SWAT) ( p 0.0005) and SpikeProp ( p 0.05) on 3/5 and self-regulating evolving spiking neural (SRESN) ( p 0.05) on 2/5 UCI datasets while using the significantly lower number of trainable parameters. Furthermore, compared to other supervised, fully connected SNNs, the proposed SNN reaches the best performance for Fashion MNIST and comparable performance for MNIST and neuromorphic-MNIST (N-MNIST), also utilizing much less (1%-35%) parameters.

In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications., Competing Interests: Competing interests statement:The authors declare no competing interest.

Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.

Objectives: To assess the associations between the single leg hop tests at two premises; baseline and the change after 12 months, and change in patient reported outcome measures and persistent instability after 12 months in patients with recurrent lateral patellar dislocation (RLPD)., Methods: 61 RLPD patients aged 12-30 with a mean (±SD) of 19.2 (±5.3) were assessed at baseline, and at 12 months after treatment with either active rehabilitation alone, or medial patellofemoral ligament reconstruction and active rehabilitation. Single leg hop for distance, triple hop for distance, crossover hop for distance and 6-metre timed hop were performed for both legs, and the Limb Symmetry Index (LSI) was calculated. Persistent patellar instability was self-reported as 'Yes' or 'No' at 12-month follow-up. Knee function in sport and recreational activities and knee-related quality of life were assessed at baseline and 12 months follow-up using the Knee injury and Osteoarthritis Outcome Score (KOOS)., Results: LSI for the baseline single leg hop for distance and the triple hop for distance was significantly associated with persistent patellar instability at 12 months follow-up with an OR of 0.94 (95% CI 0.88 to 0.99) and OR of 0.91 (95% CI 0.84 to 0.99), respectively. No other statistically significant associations were detected., Conclusion: Individuals with higher LSI values for the single leg hop for distance and triple hop for distance conducted at baseline had lower odds for persistent patellar instability at 12 months follow-up. Clinicians can use results from these hop tests to assess the risk of future recurrent patellar instability prior to treatment., Study Design: Retrospective cohort study., Trial Registration Number: NCT02263807., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Novel hormonal therapy (NHT) agents have been shown to prolong overall survival in numerous randomized clinical trials for patients with advanced prostate cancer (PCa). There is a paucity of data regarding the pattern of use of these agents in patients from different racial and ethnic groups., Objective: To assess racial and ethnic disparities in the use of NHT in patients with advanced PCa., Design, Setting, and Participants: This cohort study comprised all men diagnosed with de novo advanced PCa (distant metastatic [M1], regional [N1M0], and high-risk localized [N0M0] per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE] trial criteria) with Medicare Part A, B, and D coverage between January 1, 2011, and December 31, 2017, in a Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database including prescription drug records. Data analysis took place from January through May 2023., Exposures: Race and ethnicity (Black [non-Hispanic], Hispanic, White, or other [Alaska Native, American Indian, Asian, Pacific Islander, or not otherwise specified and unknown]) abstracted from the SEER data fields., Main Outcomes and Measures: The primary outcome was receipt of an NHT agent (abiraterone, enzalutamide, apalutamide, or darolutamide) using a time-to-event approach., Results: The study included 3748 men (median age, 75 years [IQR, 70-81 years]). A total of 312 (8%) were Black; 263 (7%), Hispanic; 2923 (78%), White; and 250 (7%) other race and ethnicity. The majority of patients had M1 disease (2135 [57%]) followed by high-risk N0M0 (1095 [29%]) and N1M0 (518 [14%]) disease. Overall, 1358 patients (36%) received at least 1 administration of NHT. White patients had the highest 2-year NHT utilization rate (27%; 95% CI, 25%-28%) followed by Hispanic patients (25%; 95% CI, 20%-31%) and patients with other race or ethnicity (23%; 95% CI, 18%-29%), with Black patients having the lowest rate (20%; 95% CI, 16%-25%). Black patients had significantly lower use of NHT compared with White patients, which persisted at 5 years (37% [95% CI, 31%-43%] vs 44% [95% CI, 42%-46%]; P = .02) and beyond. However, there was no significant difference between White patients and Hispanic patients or patients with other race or ethnicity in NHT utilization (eg, 5 years: Hispanic patients, 38% [95% CI, 32%-46%]; patients with other race and ethnicity: 41% [95% CI, 35%-49%]). Trends of lower utilization among Black patients persisted in the patients with M1 disease (eg, vs White patients at 5 years: 51% [95% CI, 44%-59%] vs 55% [95% CI, 53%-58%]). After adjusting for patient, disease, and sociodemographic factors in multivariable analysis, Black patients continued to have a significantly lower likelihood of NHT initiation (adjusted subdistribution hazard ratio, 0.76; 95% CI, 0.61-0.94, P = .01)., Conclusions and Relevance: In this cohort study of Medicare beneficiaries with advanced PCa, receipt of NHT agents was not uniform by race, with decreased use observed in Black patients compared with the other racial and ethnic groups, likely due to multifactorial obstacles. Future studies are needed to identify strategies to address the disparities in the use of these survival-prolonging therapies in Black patients.

Background: The ever-increasing availability of high-density genomic markers in the form of single nucleotide polymorphisms (SNPs) enables genomic prediction, i.e. the inference of phenotypes based solely on genomic data, in the field of animal and plant breeding, where it has become an important tool. However, given the limited number of individuals, the abundance of variables (SNPs) can reduce the accuracy of prediction models due to overfitting or irrelevant SNPs. Feature selection can help to reduce the number of irrelevant SNPs and increase the model performance. In this study, we investigated an incremental feature selection approach based on ranking the SNPs according to the results of a genome-wide association study that we combined with random forest as a prediction model, and we applied it on several animal and plant datasets., Results: Applying our approach to different datasets yielded a wide range of outcomes, i.e. from a substantial increase in prediction accuracy in a few cases to minor improvements when only a fraction of the available SNPs were used. Compared with models using all available SNPs, our approach was able to achieve comparable performances with a considerably reduced number of SNPs in several cases. Our approach showcased state-of-the-art efficiency and performance while having a faster computation time., Conclusions: The results of our study suggest that our incremental feature selection approach has the potential to improve prediction accuracy substantially. However, this gain seems to depend on the genomic data used. Even for datasets where the number of markers is smaller than the number of individuals, feature selection may still increase the performance of the genomic prediction. Our approach is implemented in R and is available at https://github.com/FelixHeinrich/GP&#95;with&#95;IFS/ ., (© 2023. The Author(s).)

Lumpfish, Cyclopterus lumpus , have historically been harvested throughout Atlantic Canada and are increasingly in demand as a solution to controlling sea lice in Atlantic salmon farms-a process which involves both the domestication and the transfer of lumpfish between geographic regions. At present, little is known regarding population structure and diversity of wild lumpfish in Atlantic Canada, limiting attempts to assess the potential impacts of escaped lumpfish individuals from salmon pens on currently at-risk wild populations. Here, we characterize the spatial population structure and genomic-environmental associations of wild populations of lumpfish throughout the Northwest Atlantic using both 70K SNP array data and whole-genome re-sequencing data (WGS). At broad spatial scales, our results reveal a large environmentally associated genetic break between the southern populations (Gulf of Maine and Bay of Fundy) and northern populations (Newfoundland and the Gulf of St. Lawrence), linked to variation in ocean temperature and ice cover. At finer spatial scales, evidence of population structure was also evident in a distinct coastal group in Newfoundland and significant isolation by distance across the northern region. Both evidence of consistent environmental associations and elevated genome-wide variation in F ST values among these three regional groups supports their biological relevance. This study represents the first extensive description of population structure of lumpfish in Atlantic Canada, revealing evidence of broad and fine geographic scale environmentally associated genomic diversity. Our results will facilitate the commercial use of lumpfish as a cleaner fish in Atlantic salmon aquaculture, the identification of lumpfish escapees, and the delineation of conservation units of this at-risk species throughout Atlantic Canada., Competing Interests: We declare no conflicts of interest., (© 2023 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

Objective: The aim was to assess the proportion of patients undergoing endovascular therapy for femoropopliteal arterial disease (FP) who would be eligible to take part in seven major randomised controlled trials (RCTs) that investigated the efficacy of some of the currently available paclitaxel based (PTX) devices used in this clinical context. Various RCTs have shown a potential clinical benefit from the use of paclitaxel in FP endovascular therapy. Nonetheless, patients enrolled were highly selected and the generalisability of these findings in pragmatic cohorts is unclear., Methods: Between 1 January and 31 December 2021, all consecutive patients who underwent endovascular procedures for symptomatic FP disease in 16 European centres were retrospectively screened and included in this analysis. The primary outcome measure was individual patient eligibility for inclusion into at least one of the seven RCTs. The reasons for exclusion (clinical and or radiological) as well as in hospital death and morbidity were also reported., Results: A total of 1 567 consecutive patients (959 male, 61%), corresponding to 1 567 lower limbs, were included. Most patients (1 009 patients, 64.39%) were treated for chronic limb threatening ischaemia (CLTI). A total 1 280 patients (81.68%) were not eligible for inclusion in any of the evaluated RCTs. Of them, 741 (47.28%) were excluded for clinical and 1 125 (71.79%) for radiological reasons., Conclusion: The analysed RCTs assessing the efficacy or effectiveness of PTX based endovascular therapies do not seem representative of the patient population with FP disease receiving endovascular therapy in routine clinical practice., (Copyright © 2023 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Pathogenic Xanthomonas bacteria cause disease on more than 400 plant species. These Gram-negative bacteria utilize the type III secretion system to inject type III effector proteins (T3Es) directly into the plant cell cytosol where they can manipulate plant pathways to promote virulence. The host range of a given Xanthomonas species is limited, and T3E repertoires are specialized during interactions with specific plant species. Some effectors, however, are retained across most strains, such as Xanthomonas Outer Protein L (XopL). As an 'ancestral' effector, XopL contributes to the virulence of multiple xanthomonads, infecting diverse plant species. XopL homologs harbor a combination of a leucine-rich-repeat (LRR) domain and an XL-box which has E3 ligase activity. Despite similar domain structure there is evidence to suggest that XopL function has diverged, exemplified by the finding that XopLs expressed in plants often display bacterial species-dependent differences in their sub-cellular localization and plant cell death reactions. We found that XopL from X. euvesicatoria (XopLXe) directly associates with plant microtubules (MTs) and causes strong cell death in agroinfection assays in N. benthamiana. Localization of XopLXe homologs from three additional Xanthomonas species, of diverse infection strategy and plant host, revealed that the distantly related X. campestris pv. campestris harbors a XopL (XopLXcc) that fails to localize to MTs and to cause plant cell death. Comparative sequence analyses of MT-binding XopLs and XopLXcc identified a proline-rich-region (PRR)/α-helical region important for MT localization. Functional analyses of XopLXe truncations and amino acid exchanges within the PRR suggest that MT-localized XopL activity is required for plant cell death reactions. This study exemplifies how the study of a T3E within the context of a genus rather than a single species can shed light on how effector localization is linked to biochemical activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ortmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cyanophycin is a natural polymer composed of a poly-aspartate backbone with arginine attached to each of the aspartate sidechains. Produced by a wide range of bacteria, which mainly use it as a store of fixed nitrogen, it has many promising industrial applications. Cyanophycin can be synthesized from the amino acids Asp and Arg by the widespread cyanophycin synthetase 1 (CphA1), or from the dipeptide β-Asp-Arg by the cyanobacterial enzyme cyanophycin synthetase 2 (CphA2). CphA2 enzymes display a range of oligomeric states, from dimers to dodecamers. Recently, the crystal structure of a CphA2 dimer was solved but could not be obtained in complex with substrate. Here, we report cryo-EM structures of the hexameric CphA2 from Stanieria sp. at ~2.8 Å resolution, both with and without ATP analog and cyanophycin. The structures show a two-fold symmetrical, trimer-of-dimers hexameric architecture, and substrate-binding interactions that are similar to those of CphA1. Mutagenesis experiments demonstrate the importance of several conserved substrate-binding residues. We also find that a Q416A/R528G double mutation prevents hexamer formation and use this double mutant to show that hexamerization augments the rate of cyanophycin synthesis. Together, these results increase our mechanistic understanding of how an interesting green polymer is biosynthesized., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response-adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD-SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next-generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post-AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups., Competing Interests: RWS served as a consultant for Janssen and Sanofi. TMS served as a consultant for Janssen and Sanofi. SB served as a consultant for Adaptive Biotechnologies. BD (MCW) has received honoraria from Bristol Myers Squibb and Karyopharm, served as a consultant for Amgen, GlaxoSmithKline, Janssen, Natera, and Sanofi, and received research funding from GlaxoSmithKline and Sanofi. BD (VU) received research funding from Angiocrine, Poseida, Takeda, Pfizer, Janssen, MEI, Medtemplate, Molecular Templates, and Wugen, served as a consultant for BEAM Therapeutics, Gamida Cell, Jazz, and Arivan, and received honoraria from MJH Biosciences, Taylor and Francis, and Wiley. SC reports research funding from Janssen, Sanofi, and Amgen and received honoraria from GlaxoSmithKline. RFC is currently employed by Abbvie. SG (UAB) received honoraria from CareVive and OncLive and research funding from CareVive and Pack Health. LJC reports consultancy for Janssen, Amgen, Sanofi, BMS, and Adaptive Biotechnologies, honoraria from Janssen, Amgen, Sanofi, BMS, Adaptive Biotechnologies, and Abbvie, and research funding from Janssen, Amgen, BMS, and Abbvie. EB, KG, SG (OHSU), EM, and NSC report no competing interests., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Inhibition of eukaryotic translation initiation through unscheduled RNA clamping of the DEAD-box (DDX) RNA helicases eIF4A1 and eIF4A2 has been documented for pateamine A (PatA) and rocaglates-two structurally different classes of compounds that share overlapping binding sites on eIF4A. Clamping of eIF4A to RNA causes steric blocks that interfere with ribosome binding and scanning, rationalizing the potency of these molecules since not all eIF4A molecules need to be engaged to elicit a biological effect. In addition to targeting translation, PatA and analogs have also been shown to target the eIF4A homolog, eIF4A3-a helicase necessary for exon junction complex (EJC) formation. EJCs are deposited on mRNAs upstream of exon-exon junctions and, when present downstream from premature termination codons (PTCs), participate in nonsense-mediated decay (NMD), a quality control mechanism aimed at preventing the production of dominant-negative or gain-of-function polypeptides from faulty mRNA transcripts. We find that rocaglates can also interact with eIF4A3 to induce RNA clamping. Rocaglates also inhibit EJC-dependent NMD in mammalian cells, but this does not appear to be due to induced eIF4A3-RNA clamping, but rather a secondary consequence of translation inhibition incurred by clamping eIF4A1 and eIF4A2 to mRNA., (© 2023 Naineni et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Cyanophycin is a bacterial biopolymer used for storage of fixed nitrogen. It is composed of a backbone of L-aspartate residues with L-arginines attached to each of their side chains. Cyanophycin is produced by cyanophycin synthetase 1 (CphA1) using Arg, Asp and ATP, and is degraded in two steps. First, cyanophycinase breaks down the backbone peptide bonds, releasing β-Asp-Arg dipeptides. Then, these dipeptides are broken down into free Asp and Arg by enzymes with isoaspartyl dipeptidase activity. Two bacterial enzymes are known to possess promiscuous isoaspartyl dipeptidase activity: isoaspartyl dipeptidase (IadA) and isoaspartyl aminopeptidase (IaaA). We performed a bioinformatic analysis to investigate whether genes for cyanophycin metabolism enzymes cluster together or are spread around the microbial genomes. Many genomes showed incomplete contingents of known cyanophycin metabolizing genes, with different patterns in various bacterial clades. Cyanophycin synthetase and cyanophycinase are usually clustered together when recognizable genes for each are found within a genome. Cyanophycinase and isoaspartyl dipeptidase genes typically cluster within genomes lacking cphA1. About one-third of genomes with genes for CphA1, cyanophycinase and IaaA show these genes clustered together, while the proportion is around one-sixth for CphA1, cyanophycinase and IadA. We used X-ray crystallography and biochemical studies to characterize an IadA and an IaaA from two such clusters, in Leucothrix mucor and Roseivivax halodurans, respectively. The enzymes retained their promiscuous nature, showing that being associated with cyanophycin-related genes did not make them specific for β-Asp-Arg dipeptides derived from cyanophycin degradation., (© 2023. The Author(s).)

It is insightful to report an estimator that describes how certain a model is in a prediction, additionally to the prediction alone. For regression tasks, most approaches implement a variation of the ensemble method, apart from few exceptions. Instead of a single estimator, a group of estimators yields several predictions for an input. The uncertainty can then be quantified by measuring the disagreement between the predictions, for example by the standard deviation. In theory, ensembles should not only provide uncertainties, they also boost the predictive performance by reducing errors arising from variance. Despite the development of novel methods, they are still considered the "golden-standard" to quantify the uncertainty of regression models. Subsampling-based methods to obtain ensembles can be applied to all models, regardless whether they are related to deep learning or traditional machine learning. However, little attention has been given to the question whether the ensemble method is applicable to virtually all scenarios occurring in the field of cheminformatics. In a widespread and diversified attempt, ensembles are evaluated for 32 datasets of different sizes and modeling difficulty, ranging from physicochemical properties to biological activities. For increasing ensemble sizes with up to 200 members, the predictive performance as well as the applicability as uncertainty estimator are shown for all combinations of five modeling techniques and four molecular featurizations. Useful recommendations were derived for practitioners regarding the success and minimum size of ensembles, depending on whether predictive performance or uncertainty quantification is of more importance for the task at hand., (© 2023. The Author(s).)

Background: Climate change and its consequences on our everyday life have also tremendous impacts on public health and the health of each individual. The healthcare sector currently accounts for 4.4% of global greenhouse gas emissions. The share of the emissions in the health care system caused by the transportation sector is 7%. The study analyses the effect of video consultation on the CO 2 emissions during the Covid-19 pandemic in an outpatient clinic of the department of orthopaedics and traumatology surgery at a German university hospital., Methods: The study participants were patients who obtained a video consultation in the period from June to December 2020 and voluntarily completed a questionnaire after the consultation. The type of transport, travel time and waiting time as well as patient satisfaction were recorded by questionnaire., Results: The study comprised 51 consultations. About 70% of respondents would have travelled to the clinic by car. The reduction in greenhouse gas emissions of video consultations compared to a face-to-face presentation was 97% in our model investigation., Conclusion: The video consultation can be a very important part of the reduction of greenhouse gas emissions in the health care system. It also saves time for the doctor and patient and can form an essential part of individual patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Arndt, Jansen, Bojko, Roos, Babasiz, Randau, Welle, Burger and Kabir.)

Genome-wide association studies have uncovered 52 independent common and rare variants across 34 genetic loci, which influence susceptibility to age related macular degeneration (AMD). Of the 5 AMD-associated complement genes, complement factor H (CFH) and CFI exhibit a significant rare variant burden implicating a major contribution of the complement pathway to disease pathology. However, the efforts for developing AMD therapy have been challenging as of yet. Here, we report the identification of ultra-rare variants in complement factors 8A and 8B, two components of the terminal complement membrane attack complex (MAC), by whole exome sequencing of a cohort of AMD families. The identified C8 variants impact local interactions among proteins of C8 triplex in vitro , indicating their effect on MAC stability. Our results suggest that MAC, and not the early steps of the complement pathway, might be a more effective target for designing treatments for AMD., Competing Interests: The authors declare no competing interests.

Cyanophycin is a bacterial polymer mainly used for nitrogen storage. It is composed of a peptide backbone of L-aspartate residues with L-arginines attached to their side chains through isopeptide bonds. Cyanophycin is degraded in two steps: Cyanophycinase cleaves the polymer into β-Asp-Arg dipeptides, which are hydrolyzed into free Asp and Arg by enzymes possessing isoaspartyl dipeptide hydrolase activity. Two unrelated enzymes with this activity, isoaspartyl dipeptidase (IadA) and isoaspartyl aminopeptidase (IaaA) have been shown to degrade β-Asp-Arg dipeptides, but bacteria which encode cyanophycin-metabolizing genes can lack iaaA and iadA genes. In this study, we investigate a previously uncharacterized enzyme whose gene can cluster with cyanophycin-metabolizing genes. This enzyme, which we name cyanophycin dipeptide hydrolase (CphZ), is specific for dipeptides derived from cyanophycin degradation. Accordingly, a co-complex structure of CphZ and β-Asp-Arg shows that CphZ, unlike IadA or IaaA, recognizes all portions of its β-Asp-Arg substrate. Bioinformatic analyses showed that CphZ is found in very many proteobacteria and is homologous to an uncharacterized protein encoded in the "arginine/ornithine transport" (aot) operon of many pseudomonas species, including Pseudomonas aeruginosa . In vitro assays show that AotO is indeed a CphZ, and in cellulo growth experiments show that this enzyme and the aot operon allow P. aeruginosa to take up and use β-Asp-Arg as a sole carbon and nitrogen source. Together the results establish the novel, highly specific enzyme subfamily of CphZs, suggesting that cyanophycin is potentially used by a much wider range of bacteria than previously appreciated.

Background: After enterostomy creation, the distal bowel to the ostomy is excluded from the physiologic passage of stool, nutrient uptake, and growth of this intestinal section. Those infants frequently require long-term parenteral nutrition, continued after enterostomy reversal due to the notable diameter discrepancy of the proximal and distal bowel. Previous studies have shown that mucous fistula refeeding (MFR) results in faster weight gain in infants. The aim of the randomized multicenter open-label controlled MUC ous FI stula RE feeding (" MUC-FIRE ") trial is to demonstrate that MFR between enterostomy creation and reversal reduces the time to full enteral feeds after enterostomy closure compared to controls, resulting in shorter hospital stay and less adverse effects of parenteral nutrition. Methods/Design: A total of 120 infants will be included in the MUC-FIRE trial. Following enterostomy creation, infants will be randomized to either an intervention or a non-intervention group.In the intervention group, perioperative MFR between enterostomy creation and reversal will be performed. The control group receives standard care without MFR.The primary efficacy endpoint of the study is the time to full enteral feeds. Secondary endpoints include first postoperative bowel movement after stoma reversal, postoperative weight gain, and days of postoperative parenteral nutrition. In addition adverse events will be analyzed., Discussion: The MUC-FIRE trial will be the first prospective randomized trial to investigate the benefits and disadvantages of MFR in infants. The results of the trial are expected to provide an evidence-based foundation for guidelines in pediatric surgical centers worldwide., Trial Registration: The trial has been registered at clinicaltrials.gov (number: NCT03469609, date of registration: March 19, 2018; last update: January 20, 2023, https://clinicaltrials.gov/ct2/show/NCT03469609?term=NCT03469609&draw=2&rank=1)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Predictors of genitourinary toxicity after post-prostatectomy radiotherapy remain elusive. A previously defined germline DNA signature (PROSTOX) has shown predictive ability for late grade ≥ 2 GU toxicity after intact prostate stereotactic body radiotherapy. We explore whether PROSTOX would predict toxicity among patients receiving post-prostatectomy SBRT on a phase II clinical trial., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Weidhaas is a co-founder of MiraDx, which holds intellectual property related to germline microRNA mutations as discussed in this manuscript. The other authors have no relevant conflicts of interest., (© 2023 The Authors.)

Enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) are gastrointestinal pathogens responsible for severe diarrheal illness. EHEC and EPEC form "attaching and effacing" lesions during colonization and, upon adherence, inject proteins directly into host intestinal cells via the type III secretion system (T3SS). Injected bacterial proteins have a variety of functions but generally alter host cell biology to favor survival and/or replication of the pathogen. Non-LEE-encoded effector A (NleA) is a T3SS-injected effector of EHEC, EPEC, and the related mouse pathogen Citrobacter rodentium. Studies in mouse models indicate that NleA has an important role in bacterial virulence. However, the mechanism by which NleA contributes to disease remains unknown. We have determined that the following translocation into host cells, a serine and threonine-rich region of NleA is modified by host-mediated mucin-type O-linked glycosylation. Surprisingly, this region was not present in several clinical EHEC isolates. When expressed in C. rodentium, a non-modifiable variant of NleA was indistinguishable from wildtype NleA in an acute mortality model but conferred a modest increase in persistence over the course of infection in mixed infections in C57BL/6J mice. This is the first known example of a bacterial effector being modified by host-mediated O-linked glycosylation. Our data also suggests that this modification may confer a selective disadvantage to the bacteria during in vivo infection., (© 2022 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)