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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.

Introduction: Malaria remains a devastating infectious disease with hundreds of thousands of casualties each year. Antimalarial drug resistance has been a threat to malaria control and elimination for many decades and is still of concern today. Despite the continued effectiveness of current first-line treatments, namely artemisinin-based combination therapies, the emergence of drug-resistant parasites in Southeast Asia and even more alarmingly the occurrence of resistance mutations in Africa is of great concern and requires immediate attention., Areas Covered: A comprehensive overview of the mechanisms underlying the acquisition of drug resistance in Plasmodium falciparum is given. Understanding these processes provides valuable insights that can be harnessed for the development and selection of novel antimalarials with reduced resistance potential. Additionally, strategies to mitigate resistance to antimalarial compounds on the short term by using approved drugs are discussed., Expert Opinion: While employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future. Incorporating resistance propensity assessment during this developmental process will increase the likelihood of effective and enduring malaria treatments.

Electrically percolating nanowire networks are among the most promising candidates for next-generation transparent electrodes. Scientific interest in these materials stems from their intrinsic current distribution heterogeneity, leading to phenomena like percolating pathway rerouting and localized self-heating, which can cause irreversible damage. Without an experimental technique to resolve the current distribution and an underpinning nonlinear percolation model, one relies on empirical rules and safety factors to engineer materials. We introduce Bose-Einstein condensate microscopy to address the longstanding problem of imaging active current flow in 2D materials. We report on performance improvement of this technique whereby observation of dynamic redistribution of current pathways becomes feasible. We show how this, combined with existing thermal imaging methods, eliminates the need for assumptions between electrical and thermal properties. This will enable testing and modeling individual junction behavior and hot-spot formation. Investigating both reversible and irreversible mechanisms will contribute to improved performance and reliability of devices.

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.

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite-regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls., Methods: A longitudinal study was conducted in 134 children with PWS and 157 healthy controls, from the Netherlands, France, and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored., Results: The AG/UAG ratio was lower in the first years of life in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p = 0.114), while the UAG levels decreased from 290 pg/mL in phase 1a to 137 pg/mL in phase 2b (p < 0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p = 0.012)., Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The increasing interest in early identification of people at risk of developing dementia, has led to the development of numerous models aimed at estimating the likelihood of progression from mild cognitive impairment (MCI) to dementia. It is important to study both the need for and possible outcomes related with such prediction models, including the impact of risk predictions on perceived quality of life (QoL)., Objective: This study aimed to quantify the impact that receiving a risk prediction on progression from MCI to dementia has on QoL., Methods: A Discrete Choice Experiment (DCE) and Time Trade Off (TTO) study were performed. Participants completed choice tasks related to dementia prognosis while imagining having MCI. We collected DCE data by an online survey, and TTO data via videoconferencing interviews. DCE data were analyzed using a mixed multinomial logit model and were anchored to a health state utility scale using mean observed TTO valuations., Results: 296 people participated in the DCE and 42 in the TTO. Moderate and high predicted dementia risks were associated with decrements in utility (-0.05 and -0.18 respectively), compared to no prognostic information. Low predicted risk was associated with an increase in utility (0.06), as well as the availability of medication or lifestyle interventions (0.05 and 0.13 respectively)., Conclusions: This study shows a significant impact of dementia risk predictions on QoL and highlights the importance of caution when sharing information about expected MCI disease courses.

Background: MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients., Purpose: (1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra., Methods: Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set., Results: IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance., Conclusion: Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation., (© 2023 American Association of Physicists in Medicine.)

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.)

Background: Since Alexandra Elbanyan founded Sci-Hub in 2011, the website has been used by a growing number of researchers worldwide. Sci-Hub is a so-called shadow library or guerrilla open access format bypassing publishers' paywalls, giving everyone free access to scientific papers. Until today, there have been no publications about usage by orthopaedic and trauma surgeons of Sci-Hub or other "pirate sites" and how it may influence their work., Materials and Methods: Orthopaedic and trauma surgeons of four university hospitals in Germany and Europe were consulted using a standardised questionnaire containing multiple items about the use and evaluation of Sci-Hub. In addition, the Medline and Cochrane databases were screened for all studies related to Sci-Hub. Two reviewers independently reviewed all articles and the references of these articles., Results: Of all orthopaedic surgeons consulted, 69% knew of Sci-Hub and 66.7% used it on a regular basis. Of the younger participants (< 45 years old), 77% knew the webpage, while only 25% of older participants (> 45 years old) knew the webpage. Ninety percent found the quality of their citation and research had been enhanced since using Sci-Hub. On a scale of 1 to 10, user-friendliness was rated with a mean rating of 7.58 (95% CI: 7.262-7.891). Ethical or legal concerns among users seem mixed. On a scale of 1 (no concerns) to 5 (many concerns), the mean score was 2.39 (95% CI: 2.154-2.615). Of doctors using Sci-Hub, 89% would recommend it to other colleagues., Conclusion: The quality and number of articles in Sci-Hub is outstanding, and the rate of young researchers using the website is high. The most important shift in literature research for decades is a phenomenon mostly used by young researchers and is not the subject of current research itself. Sci-Hub may have already changed how orthopaedic research works., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

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.

Purpose: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods., Materials and Methods: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R 2 ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed., Results: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R 2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively., Conclusion: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

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).)

Background: Because 8-10% of children in the emergency room present with acute abdominal pain, a systematic work-up is essential to rule out acute abdomen., Objectives: This article highlights the etiology, symptoms, diagnostic workup, and treatment of acute abdomen in children., Materials and Methods: Review of the current literature., Results: Abdominal inflammation, ischemia, bowel and ureteral obstruction, or abdominal bleeding are causes of acute abdomen. Extra-abdominal diseases such as otitis media in toddlers or testicular torsion in adolescent boys can also lead to symptoms of acute abdomen. Abdominal pain, (bilious) vomiting, abdominal guarding, constipation, blood-tinged stools, abdominal bruise marks, and poor condition of the patient with symptoms such as tachycardia, tachypnea, and hypotonia up to shock are leading symptoms of acute abdomen. In some cases, emergent abdominal surgery is needed to treat the cause of the acute abdomen. However, in patients with pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV‑2 infection (PIMS-TS), a new disease causing an acute abdomen, surgical treatment is rarely needed., Conclusions: Acute abdomen can lead to nonreversible loss of an abdominal organ, such as bowel or ovary, or develop into acute deterioration of the patient's condition up to the state of shock. Therefore, a complete history and thorough physical examination are needed to timely diagnose acute abdomen and initiate specific therapy., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose of Review: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine., Recent Findings: With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes., Summary: The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The planning and implantation of a customized partial pelvis replacement places high demands on both the surgeon and the entire team (engineer, assistants, surgical team). Thanks to careful preoperative planning and meticulous perioperative execution, customized partial pelvic replacement represents a complex but reliable procedure for defect reconstruction even with highly complex acetabular bone defects or after multiple previous surgeries., (© 2023. The Author(s).)

Type 1 diabetes (T1D) develops due to autoimmune targeting of the pancreatic islet β-cells. Clinical symptoms arise from reduced insulin in circulation. The molecular events and interactions between discrete immune cell populations, infiltration of such leukocytes into pancreatic and islet tissue, and selective targeting of the islet β-cells during autoimmunity and graft rejection are not entirely understood. One protein central to antigen presentation, priming of immune cells, trafficking of leukocytes, and vital for leukocyte effector function is the intercellular adhesion molecule-1 (ICAM-1). The gene encoding ICAM-1 is transcriptionally regulated and rapidly responsive (i.e., within hours) to pro-inflammatory cytokines. ICAM-1 is a transmembrane protein that can be glycosylated; its presence on the cell surface provides co-stimulatory functions for immune cell activation and stabilization of cell-cell contacts. ICAM-1 interacts with the β2-integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), which are present on discrete immune cell populations. A whole-body ICAM-1 deletion protects NOD mice from diabetes onset, strongly implicating this protein in autoimmune responses. Since several different cell types express ICAM-1, its biology is fundamentally essential for various physiological and pathological outcomes. Herein, we review the role of ICAM-1 during both autoimmunity and islet graft rejection to understand the mechanism(s) leading to islet β-cell death and dysfunction that results in insufficient circulating quantities of insulin to control glucose homeostasis., Competing Interests: Declaration of Competing Interest Jason Collier reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Covering: 1878 to early 2023Cyanophycin is a biopolymer consisting of a poly-aspartate backbone with arginines linked to each Asp sidechain through isopeptide bonds. Cyanophycin is made by cyanophycin synthetase 1 or 2 through ATP-dependent polymerization of Asp and Arg, or β-Asp-Arg, respectively. It is degraded into dipeptides by exo-cyanophycinases, and these dipeptides are hydrolyzed into free amino acids by general or dedicated isodipeptidase enzymes. When synthesized, chains of cyanophycin coalesce into large, inert, membrane-less granules. Although discovered in cyanobacteria, cyanophycin is made by species throughout the bacterial kingdom, and cyanophycin metabolism provides advantages for toxic bloom forming algae and some human pathogens. Some bacteria have developed dedicated schemes for cyanophycin accumulation and use, which include fine temporal and spatial regulation. Cyanophycin has also been heterologously produced in a variety of host organisms to a remarkable level, over 50% of the host's dry mass, and has potential for a variety of green industrial applications. In this review, we summarize the progression of cyanophycin research, with an emphasis on recent structural studies of enzymes in the cyanophycin biosynthetic pathway. These include several unexpected revelations that show cyanophycin synthetase to be a very cool, multi-functional macromolecular machine.

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.)

It is unclear whether cancer patients enrolled in clinical trials have improved outcomes compared with non-study patients. We compared prostate cancer-specific mortality (PCSM) in patients in a real-world setting (SEER-Medicare database) versus on a trial (NRG/RTOG 0521). The 7-year freedom from PCSM was superior in trial patients (92.4% vs. 88.1%, sHR = 1.77 [95% CI 1.05-2.97], P = 0.03). Black trial patients had significantly superior freedom from PCSM than Black real-world patients (sHR 6.52, 95% CI 1.43-29.72, P = 0.02), which was not seen among non-Black patients. Trial patients may have improved outcomes, and racial disparities are accentuated in the real world., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

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.)

Objective: To assess the efficacy of 177 Lu-PNT2002, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in combination with stereotactic body radiotherapy (SBRT) to all sites of metastasis, vs SBRT alone, in men with oligorecurrent metastatic hormone-sensitive prostate cancer (mHSPC)., Patients and Methods: The 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR) trial is an open-label, randomized, stratified, two-arm, single-centre, Phase 2 trial to compare the efficacy and safety of neoadjuvant 177 Lu-PNT2002 plus SBRT vs SBRT alone in men with oligorecurrent mHSPC. Key eligibility criteria include one to five lesions identified on a PSMA positron emission tomography (PET)/computed tomography (CT) scan centrally reviewed by a board-certified nuclear medicine physician. Key exclusion criteria include castrate-resistant disease, de novo oligometastatic disease and receipt of androgen deprivation therapy (ADT) within 6 months of trial enrolment. The trial aims to enrol 100 patients who will be centrally randomized to one of the two treatment arms, in a 1:1 ratio. Patients in the control arm receive SBRT to all sites of disease. Patients in the experimental arm receive two cycles of neoadjuvant 177 Lu-PNT2002 (6.8 GBq) 6-8 weeks apart, followed by an interval PSMA PET/CT in 4-6 weeks and dose-adapted SBRT to all sites of disease 1-2 weeks later. The primary endpoint is progression-free survival. Secondary endpoints are radiographic and prostate-specific antigen-based progression, acute and late physician-scored toxicity, patient-reported quality of life, ADT-free survival, time to progression, overall survival, locoregional control, and duration of response. Enrolment in the study commenced in September 2022., Results and Conclusions: The addition of 177 Lu-PNT2002 to metastasis-directed therapy alone may potentially further forestall disease progression. The results of this Phase 2 trial will determine, for the first time in a randomized fashion, the added benefit of 177 Lu-PNT2002 to SBRT in patients with oligorecurrent mHSPC., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

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.)

Common molecular phylogenetic characteristics such as long branches and compositional heterogeneity can be problematic for phylogenetic reconstruction when using amino acid data. Recoding alignments to reduced alphabets before phylogenetic analysis has often been used both to explore and potentially decrease the effect of such problems. We tested the effectiveness of this strategy on topological accuracy using simulated data on four-taxon trees. We simulated alignments in phylogenetically challenging ways to test the phylogenetic accuracy of analyses using various recoding strategies together with commonly used homogeneous models. We tested three recoding methods based on amino acid exchangeability, and another recoding method based on lowering the compositional heterogeneity among alignment sequences as measured by the Chi-squared statistic. Our simulation results show that on trees with long branches where sequences approach saturation, accuracy was not greatly affected by exchangeability-based recodings, but Chi-squared-based recoding decreased accuracy. We then simulated sequences with different kinds of compositional heterogeneity over the tree. Recoding often increased accuracy on such alignments. Exchangeability-based recoding was rarely worse than not recoding, and often considerably better. Recoding based on lowering the Chi-squared value improved accuracy in some cases but not in others, suggesting that low compositional heterogeneity by itself is not sufficient to increase accuracy in the analysis of these alignments. We also simulated alignments using site-specific amino acid profiles, making sequences that had compositional heterogeneity over alignment sites. Exchangeability-based recoding coupled with site-homogeneous models had poor accuracy for these data sets but Chi-squared-based recoding on these alignments increased accuracy. We then simulated data sets that were compositionally both site- and tree-heterogeneous, like many real data sets. The effect on the accuracy of recoding such doubly problematic data sets varied widely, depending on the type of compositional tree heterogeneity and on the recoding scheme. Interestingly, analysis of unrecoded compositionally heterogeneous alignments with the NDCH or CAT models was generally more accurate than homogeneous analysis, whether recoded or not. Overall, our results suggest that making trees for recoded amino acid data sets can be useful, but they need to be interpreted cautiously as part of a more comprehensive analysis. The use of better-fitting models like NDCH and CAT, which directly account for the patterns in the data, may offer a more promising long-term solution for analyzing empirical data. [Compositional heterogeneity; models of evolution; phylogenetic methods; recoding amino acid data sets.]., (© The Author(s) 2022. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Treatment of chronic periprosthetic joint infection of the knee requires the removal of the implant and thorough debridement, with reimplantation in a second stage surgery. Intramedullary spacers can be helpful during the interval between explantation and reimplantation and provide a temporary arthrodesis which fixes the knee in extension preserving leg length and administers local antibiotic therapy., Indications: Periprosthetic joint infection of the knee with large bony defects and severe infection of the native joint with advanced destruction/infiltration of the cartilage and bone and/or ligament insufficiency., Contraindications: Suspected antibiotic resistance of the microbiological pathogen to local antibiotic drugs, incompliant patient, and known allergy to bone cement or antibiotic., Surgical Technique: After implant removal, suitable metal rods are coated with antibiotic-loaded bone cement and inserted into the cleaned intramedullary canals of femur and tibia. Rods are joined at the joint line with a connector and joint space is filled with more bone cement to achieve temporary and very stable arthrodesis., Postoperative Management: Partial weight-bearing and no flexion/extension while spacer is in place; second stage reimplantation as soon as infection is controlled., Results: Complications related to the spacer were rare (5.3%). Reimplantation of an implant was possible in 95 of 113 patients (84%), of those, 23 (20%) received an arthrodesis. Of the 95 patients that were reimplanted, 14 showed signs of recurrent infection. Mean time to last follow-up was 15.6 months post reimplantation. Mean knee pain was 2.9/10; overall function was good; 6 patients had an extension lag; mean total range of motion was 88°., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Sliced cooked ham stored in modified atmosphere packaging (MAP) can be spoiled by lactic acid bacteria (LAB) which are dominating under psychrotrophic conditions. Depending on the strains, the colonization can result in a premature spoilage characterized by off-flavors, gas and slime production, discoloration, and acidification. The purpose of this study was the isolation, identification and characterization of potential food culture with protective properties, able to prevent or delay spoilage in cooked-ham. The first step was to identify by means of microbiological analysis, the microbial consortia both in unspoiled and in spoiled lots of sliced cooked ham by the use of media for the detection lactic acid bacteria and total viable count. Counts ranged from values lower than 1 Log CFU/g to 9 Log CFU/g in spoiled and unflawed samples. The interaction between consortia was then studied in order to screen for strains able to inhibit spoilage consortia. Strains showing antimicrobial activity were identified and characterized by molecular methods and tested for their physiological features. Among a total of 140 strains isolated, nine were selected for their ability to inhibit a large number of spoilage consortia, to grow and ferment at 4 °C and to produce bacteriocins. The effectiveness of the fermentation made by food culture was evaluated, through challenge tests in situ, analysing the microbial profiles of artificially inoculated cooked-ham slices during storage by high throughput 16 S rRNA gene sequencing. The native population in situ resulted competitive against the inoculated strains and only one strain was able to significantly reduce the native populations reaching about 46.7% of the relative abundance. The results obtained in this study provide information about the selection of autochthonous LAB on the base of their action against spoilage consortia, in order to select protective potential cultures able to improve the microbial quality of sliced cooked ham., Competing Interests: Declaration of competing interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Periprosthetic joint infection remains a common and serious complication after hip arthroplasty. To improve function and patient comfort after joint removal in two-stage revision, commercially manufactured spacers for the hip joint allow retention of the anatomical joint geometry thereby limiting soft tissue contraction and allow mobilization., Indications: Periprosthetic joint infection of the hip, septic arthritis with severe destruction of the hip cartilage and/or bone requiring arthroplasty., Contraindications: Allergies to polymethylmethacrylate (PMMA) or antibiotics, severe hip dysplasia with insufficient cranial support, incompliant patient, large osseous defect of the acetabulum, insufficient metaphyseal/diaphyseal support of the femoral bone, resistance of the microbiological pathogen to spacer-inert antibiotic medication, inability to perform primary wound closure requiring temporary open-wound therapy., Surgical Technique: Preoperative templating on radiograph; removal of joint prosthesis and thorough debridement with removal of all foreign material; trial spacer selection and insertion and trial reduction of the joint, fixing the spacer with PMMA to the proximal femur, final reduction, radiograph and stability test., Results: Data were analyzed from patients treated between 2016 and 2021. In all, 20 patients were treated with preformed spacers and 16 with custom-made spacers. Pathogens were detected in 23 of the 36 cases (64%). Polymicrobial infections were present in 8 of 36 cases (22%). In patients who received preformed spacers, there were 6 cases of spacer-related complications (30%). Of the 36 patients (83%), 30 were reimplanted with a new implant; 3 patients died due to septic or other complications before reimplantation (8%). Average follow-up was 20.2 months after reimplantation. There were no major differences between the two groups of spacers. Patient comfort was not measured., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: Mobile knee spacers can be utilized in the first stage of a two-stage exchange in periprosthetic joint infection or septic arthritis of the knee to prevent soft tissue contraction, enable local antibiotic elution, and improve patient mobility. Commercially made moulds enable the surgeon to prepare a reproducible spacer design and match the preparation of the arthroplasty, which will be carried out in a second step., Indications: Periprosthetic joint infection of the knee and severe cases of septic arthritis of the knee with advanced destruction/infiltration of the cartilage., Contraindications: Antibiotic resistance of the microbiological pathogen to available antibiotic agents, incompliant patient, large osseous defect preventing proper fixation, known allergy to polymethylmethacrylate (PMMA) or antibiotic, severe soft tissue damage with high ligament instability, especially deterioration of extensor mechanism and insufficient patella/quadricep tendon., Surgical Technique: After thorough debridement and removal of all foreign material, cutting blocks are used to shape femur and tibia to the implant design required. Using a silicone mould, PMMA with suitable antibiotics is moulded into the shape of the future implant. After polymerization, the implants are fixed onto the bone with additional PMMA without pressurize for the sake of easy removal., Postoperative Management: Partial weight bearing with no restriction of flexion/extension while spacer is in place; second stage reimplantation as soon as infection is controlled., Results: In all, 22 cases were treated, mostly with a PMMA spacer containing gentamicin and vancomycin. Pathogens were detected in 13 of 22 cases (59%). We observed two complications (9%). Twenty of 22 patients (86%) were reimplanted with a new arthroplasty; 16 of the 20 patients remained revision-free and infection-free at the last follow-up (average time to follow-up 13 months, range 1-46 months). Average range of motion in flexion and extension at follow-up was 98°., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background and Purpose: We examined the interfractional variations of clinical target volumes (CTVs), planning target volumes (PTVs), and organs-at-risk (OARs) in patients receiving MRI-guided stereotactic body radiotherapy (SBRT) to the prostate bed and evaluated the potential role of adaptive planning., Materials and Methods: 31 patients received 30-34 Gy in five fractions to the prostate bed on a phase II clinical trial. OARs, CTVs, and PTVs were retrospectively contoured on daily pretreatment MRIs (n = 155). Geometric comparisons were made between initial planning contours and daily pretreatment contours. Predicted treatment plans for each fraction were evaluated using the following constraints: CTV V95%>93%, PTV V95%>90%, bladder Dmax < 36.7 Gy, bladder V32.5 Gy < 35%, rectum Dmax < 36.7 Gy, rectum V27.5 Gy < 45%, rectum 32.5 Gy < 30%, and rectal wall V24Gy < 50%. Adaptive planning was simulated for all fractions that failed to meet these criteria. Plans were then re-evaluated., Results: Median change in volume was 0.48% for CTV, -24.5% for bladder, and 6.95% for rectum. Median DSC was 0.89 for CTV, 0.79 for bladder, and 0.76 for rectum. 145/155 fractions (93.5%) met CTV V95%>93%. 75/155 fractions (48.4%) failed at least one OAR dose constraint. Overall, 83/155 fractions (53.5%) met criteria for adapting planning. This affected 24/31 patients (77.4%). Following adaptive planning, all fractions met CTV V95%>93% and PTV V95%>90% and 120/155 fractions (77.4%) met all OAR constraints., Conclusion: Due to significant interfractional variations in anatomy, a majority of fractions failed to meet both target volume and OAR constraints. However, adaptive planning was effective in overcoming these anatomic changes. Adaptive planning should be routinely considered in prostate bed SBRT., Competing Interests: Declaration of Competing Interest 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. Funding support for the SCIMITAR trial was provided by ViewRay, Inc., but ViewRay, Inc. had no role in the conduct of this analysis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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).)

Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (colony stimulating factor 1 receptor [CSF1R] ligands and TGF-β1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia (hMGL). Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of hMGL in culture, with observations that diverge from those previously made in rodent microglia., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

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.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has greater specificity and sensitivity for detection of extraprostatic prostate cancer (PCa) at presentation than conventional imaging. Although the long-term clinical significance of acting on these findings is unknown, it has been shown that the risk of upstaging is prognostic for long-term outcomes in men with high-risk (HR) or very high-risk (VHR) PCa. We evaluated the association between the risk of upstaging on PSMA PET and the Decipher genomic classifier score, a known prognostic biomarker in localized PCa that is being evaluated for its predictive ability to direct systemic therapy intensification. In a cohort of 4625 patients with HR or VHR PCa, the risk of upstaging on PSMA PET was significantly correlated with the Decipher score (p < 0.001). These results should be seen as hypothesis-generating and warrant further studies on the causal pathways linking PSMA findings, Decipher scores, extraprostatic disease, and long-term clinical outcomes. PATIENT SUMMARY: We found significant correlation between the risk of having prostate cancer outside the prostate gland on a sensitive scan (based on prostate-specific membrane antigen [PSMA]) at initial staging and the Decipher genetic score. The results warrant further studies on the causal pathways between PSMA scan findings, Decipher scores, disease outside the prostate, and long-term outcomes., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The need for careful assembly, training, and validation of quantitative structure-activity/property models (QSAR/QSPR) is more significant than ever as data sets become larger and sophisticated machine learning tools become increasingly ubiquitous and accessible to the scientific community. Regulatory agencies such as the United States Environmental Protection Agency must carefully scrutinize each aspect of a resulting QSAR/QSPR model to determine its potential use in environmental exposure and hazard assessment. Herein, we revisit the goals of the Organisation for Economic Cooperation and Development (OECD) in our application and discuss the validation principles for structure-activity models. We apply these principles to a model for predicting water solubility of organic compounds derived using random forest regression, a common machine learning approach in the QSA/PR literature. Using public sources, we carefully assembled and curated a data set consisting of 10,200 unique chemical structures with associated water solubility measurements. This data set was then used as a focal narrative to methodically consider the OECD's QSA/PR principles and how they can be applied to random forests. Despite some expert, mechanistically informed supervision of descriptor selection to enhance model interpretability, we achieved a model of water solubility with comparable performance to previously published models (5-fold cross validated performance 0.81 R 2 and 0.98 RMSE). We hope this work will catalyze a necessary conversation around the importance of cautiously modernizing and explicitly leveraging OECD principles while pursuing state-of-the-art machine learning approaches to derive QSA/PR models suitable for regulatory consideration.

Purpose: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear., Methods and Materials: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression., Results: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38)., Conclusions: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The complex field of femoral defects in revision hip arthroplasty displays a lack of standardized, intuitive pre- and intraoperative assessment. To address this issue, the femoral defect classification (FDC) is introduced to offer a reliable, reproducible and an intuitive classification system with a clear therapeutic guideline., Materials and Methods: The FDC is based on the integrity of the main femoral segments which determine function and structural support. It focuses on the femoral neck, the metaphysis consisting of the greater and lesser trochanter, and the femoral diaphysis. The four main categories determine the location of the defect while subcategories a, b and c are being used to classify the extent of damage in each location. In total, 218 preoperative radiographs were retrospectively graded according to FDC and compared to intraoperatively encountered bone defects. To account for inter-rater and intra-rater agreement, 5 different observers evaluated 80 randomized cases at different points in time., Results: A Cohens kappa of 0.832 ± 0.028 could be evaluated, accounting for excellent agreement between preoperative radiographs and intraoperative findings. To account for inter-rater reliability, 80 patients have been evaluated by 5 different observers. Testing for inter-rater reliability, a Fleiss Kappa of 0.688 could be evaluated falling into the good agreement range. When testing for intra-rater reliability, Cohens Kappa of each of the 5 raters has been analyzed and the mean was evaluated at 0.856 accounting for excellent agreement., Conclusion: The FDC is a reliable and reproducible classification system. It combines intuitive use and structured design and allows for consistent preoperative planning and intraoperative guidance. A therapeutic algorithm has been created according to current literature and expert opinion. Due to the combination of the FDC with the recently introduced Acetabular Defect Classification (ADC) a structured approach to the entire field of hip revision arthroplasty is now available., (© 2021. The Author(s).)

Importance: Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial., Objective: To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance., Design, Setting, and Participants: This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up., Interventions: Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions., Main Outcomes and Measures: The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes., Results: Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month., Conclusions and Relevance: In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist., Trial Registration: ClinicalTrials.gov Identifier: NCT04384770.

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.)