Coronavirus HKU1 infection and development of pediatric acute liver failure with immune dysregulation phenotype.

Pediatric acute liver failure is a rare but serious complication of Coronavirus infections. Our patient is a previously healthy 8-year-old male who presented with acute liver failure in the setting of human coronavirus HKU1 (HCoV-HKU1) infection while asymptomatic from a respiratory perspective. During the hospital course, he developed acute hepatic encephalopathy and was listed for liver transplantation, but fortunately recovered remaining status 7 (inactive) on the transplant list. With a negative diagnostic evaluation other than his viral infection and hyperdense CD8 T-cells on liver immunohistochemical staining, pediatric acute liver failure (PALF) immune dysregulation phenotype was diagnosed.

N-methyl Formamide Electrolyte Additive Enabling Highly Reversible Zn Anodes.

Parasitic side reactions and dendrites formation hinder the application of aqueous zinc ion batteries due to inferior cycling life and low reversibility. Against this background, N-methyl formamide (NMF), a multi-function electrolyte additive is applied to enhance the electrochemical performance. Studied via advanced synchrotron radiation spectroscopy and DFT calculations, the NMF additive simultaneously modifies the Zn2+ solvation structure and ensures uniform zinc deposition, thus suppressing both parasitic side reactions and dendrite formation. More importantly, an ultralong cycling life of 3115 h in the Zn||Zn symmetric cell at a current density of 0.5 mA cm-2 is achieved with the NMF additive. Practically, the Zn||PANI full cell utilizing NMF electrolyte shows better rate and cycling performance compared to the pristine ZnSO4 aqueous electrolyte. This work provides useful insights for the development of high-performance aqueous metal batteries.

Modeling the effect of imported malaria on the elimination programme in KwaZulu-Natal province of South Africa.

Introduction: with imported malaria cases in a given population, the question arises as to what extent the local cases are a consequence of the imports or not. We perform a modeling analysis for a specific area, in a region aspiring for malaria-free status. Methods: data on malaria cases over ten years is subjected to a compartmental model which is assumed to be operating close to the equilibrium state. Two of the parameters of the model are fitted to the decadal data. The other parameters in the model are sourced from the literature. The model is utilized to simulate the malaria prevalence with or without imported cases. Results: in any given year the annual average of 460 imported cases, resulted in an end-of-year season malaria prevalence of 257 local active infectious cases, whereas without the imports the malaria prevalence at the end of the season would have been fewer than 10 active infectious cases. We calculate the numerical value of the basic reproduction number for the model, which reveals the extent to which the disease is being eliminated from the population or not. Conclusion: without the imported cases, over the ten seasons of malaria, 2008-2018, the KwaZulu-Natal province would have been malaria-free over at least the last 7 years of the decade indicated. This simple methodology works well even in situations where data is limited.

Renal macrophages induce hypertension and kidney fibrosis in Angiotensin II salt mice model.

The immune system is involved in hypertension development with different immune cells reported to have either pro or anti-hypertensive effects. In hypertension, immune cells have been thought to infiltrate blood pressure-regulating organs, resulting in either elevation or reduction of blood pressure. There is controversy over whether macrophages play a detrimental or beneficial role in the development of hypertension, and the few existing studies have yielded conflicting results. This study aimed to determine the effects of angiotensin II (Ang II) salt-induced hypertension on renal immune cells and to determine whether renal macrophages are involved in the induction of hypertension. Hypertension was induced by administration of Ang II and saline for two weeks. The effects of hypertension on kidney immune cells were assessed using flow cytometry. Macrophage infiltration in the kidney was assessed by immunohistochemistry and kidney fibrosis was assessed using trichrome stain and kidney real time-qPCR. Liposome encapsulated clodronate was used to deplete macrophages in C57BL/6J mice and investigate the direct role of macrophages in hypertension induction. Ang II saline mice group developed hypertension, had increased renal macrophages, and had increased expression of Acta2 and Col1a1 and kidney fibrotic areas. Macrophage depletion blunted hypertension development and reduced the expression of Acta2 and Col1a1 in the kidney and kidney fibrotic areas in Ang II saline group. The results of this study demonstrate that macrophages infiltrate the kidneys and increase kidney fibrosis in Ang II salt-induced hypertension, and depletion of macrophages suppresses the development of hypertension and decreases kidney fibrosis. This indicates that macrophages play a direct role in hypertension development. Hence macrophages have a potential to be considered as therapeutic target in hypertension management.

Universal Intercalation/Alloying Hybrid Mechanism with -ICOHP Criterion in MAX Toward Steadily Ascending Lithium-Ion Batteries.

Profiting from the unique atomic laminated structure, metallic conductivity, and superior mechanical properties, transition metal carbides and nitrides named MAX phases have shown great potential as anodes in lithium-ion batteries. However, the complexity of MAX configurations poses a challenge. To accelerate such application, a minus integrated crystal orbital Hamilton populations descriptor is innovatively proposed to rapidly evaluate the lithium storage potential of various MAX, along with density functional theory computations. It confirms that surface A-element atoms bound to lithium ions have odds of escaping from MAX. Interestingly, the activated A-element atoms enhance the reversible uptake of lithium ions by MAX anodes through an efficient alloying reaction. As an experimental verification, the charge compensation and SnxLiy phase evolution of designed Zr2SnC MAX with optimized structure is visualized via in situ synchrotron radiation XRD and XAFS technique, which further clarifies the theoretically expected intercalation/alloying hybrid storage mechanism. Notably, Zr2SnC electrodes achieve remarkably 219.8% negative capacity attenuation over 3200 cycles at 1 A g-1. In principle, this work provides a reference for the design and development of advanced MAX electrodes, which is essential to explore diversified applications of the MAX family in specific energy fields.

Anion Additive Integrated Electric Double Layer and Solvation Shell for Aqueous Zinc Ion Battery.

Aqueous zinc ion batteries (AZIBs) show great potential in large-scale energy storage systems. However, the inferior cycling life due to water-induced parasitic reactions and uncontrollable dendrites growth impede their application. Electrolyte optimization via the use of additives is a promising strategy to enhance the stability of AZIBs. Nevertheless, the mechanism of optimal multifunctional additive strategy requires further exploration. Herein, sodium dodecyl benzene sulfonate (SDBS) is proposed as a dual-functional additive in ZnSO4 electrolyte. Benefiting from the additive, both side reactions and zinc dendrites growth are significantly inhibited. Further, a synchrotron radiational spectroscopic study is employed to investigate SDB- adjusted electric double layer (EDL) near the Zn surface and the optimized solvation sheath of Zn2+. First-principles calculations verify the firm adsorption of SDB-, and restriction of random diffusion of Zn2+ on the Zn surface. In particular, the SDBS additive endows Zn||Zn symmetric cells with a 1035 h ultra-stable plating/stripping at 0.2 mA cm-2. This work not only provides a promising design strategy by dual-functional electrolyte additives for high stable AZIBs, but also exhibits the prospect of synchrotron radiation spectroscopy analysis on surface EDL and Zn2+ solvation shell optimization.

The toxicological effect on pak choi of co-exposure to degradable and non-degradable microplastics with oxytetracycline in the soil.

Microplastics and antibiotics are emerging as ubiquitous contaminants in farmland soil, harming crop quality and yield, and thus threatening global food security and human health. However, few studies have examined the individual and joint effects of degradable and/or non-degradable microplastics and antibiotics on crop plants. This study examined the individual and joint effects of polyethylene (PE) and polylactic acid (PLA) microplastics and the antibiotic oxytetracycline (OTC) on pak choi by measuring its growth, photosynthesis, antioxidant enzyme activity, and metabolite levels. Microplastics and/or oxytetracycline adversely affected root weight, photosynthesis, and antioxidant enzyme (superoxide dismutase, catalase, and ascorbate peroxidase) activities. The levels of leaf metabolites were significantly altered, causing physiological changes. Biosynthesis of plant secondary metabolites and amino acids was altered, and plant hormones pathways were disrupted. Separately and together, OTC, PE, and PLA exerted phytotoxic and antagonistic effects on pak choi. Separately and together with OTC, degradable microplastics altered the soil properties, thus causing more severe impacts on plant performance than non-degradable microplastics. This study elucidates the effects on crop plants of toxicity caused by co-exposure to degradable or non-degradable microplastic and antibiotics contamination and suggests mechanisms.

Information and Communication Technology Medicine: Integrative Specialty for the Future of Medicine.

The impact of information and communication technology (ICT) on medicine is unprecedented and ever-increasing. This has made it more and more difficult for doctors to keep pace with ICT developments and to adequately match the input of ICT experts. As a result, medical disciplines may not be able to take full advantage of growing possibilities. In this personal viewpoint paper, I argue for the establishment of a novel medical specialty, ICT medicine. ICT medicine is needed to optimally face the challenges of ICT-based developments, including artificial intelligence (AI), and to ensure their efficient and beneficial use. ICT medicine is rooted in both medicine and ICT, and in contrast to existing medical specialties it is integrative in nature, as long-standing structural collaborations with ICT and other stakeholders cross the boundaries between disciplines. Thus, new concepts and theories may evolve that are better suited to addressing ICT-related issues in medicine. ICT doctors will be instrumental in the conception, development, implementation, and evaluation of digital tools, systems, and services. They provide a bridge between ICT professionals and clinical users and educate doctors in digital applications and services. Notably, ICT doctors may have a pivotal role in the validation, verification, and evaluation of AI models. ICT medicine institutes offer a home to these new professionals, enhancing their independence within health care organizations and in relation to ICT companies. Importantly, in an era of growing technicalization and use of AI algorithms, ICT doctors may safeguard the human factor in medicine. And, from a societal perspective, they may promote digital inclusion and the continuing high quality of digital services and provide leadership in the future digitalization of medicine.

Sexual Motivation in Persons with Multiple Sclerosis: A Controlled Cross-Sectional Study.

Purpose: Sexual motives are major determinants of sexual behaviour. It has been known that sexual motives may vary according to circumstances. Multiple sclerosis (MS) is a chronic disease causing a broad range of symptoms and disabilities, that often interfere with sexual activities. We aimed to investigate the sexual motives in persons with MS. Patients and Methods: Cross-sectional study in 157 persons with MS and 157 controls matched for age, gender, relationship, duration of relationship and educational status via propensity score matching. The Reasons for Having Sex (YSEX) questionnaire assessed the proportion with which a person had engaged in sexual intercourse for each of 140 distinct motives to have sex. Estimated mean differences in scores for four primary factors (Physical, Goal attainment, Emotional, Insecurity) and 13 sub-factors, and sexual satisfaction and importance of sex were calculated as Average Treatment Effect of the Treated using 99% confidence intervals. Results: Persons with MS reported a lower proportion of engaging in sex compared with the controls for the factors Physical (-0.29), Emotional (-0.23) and Insecurity (-0.10); and for the physical sub-factors Pleasure (-0.48), Experience seeking (-0.32), Stress reduction (-0.24), and Physical desirability (-0.16), the emotional sub-factors Love and commitment (-0.27) and Expression (-0.17), and the insecurity sub-factor Self-esteem boost (-0.23). In the control group seven of the top 10 sexual motives were physical versus five in the MS group. The importance of sex was lower in the MS group (-0.68). Conclusion: Findings of this controlled cross-sectional study suggest a reduction in the number of sexual motives in persons with MS, especially of physical motives related to pleasure and experience seeking. Health care professionals may consider assessing sexual motivation when dealing with persons with MS who suffer from decreased sexual desire or another sexual dysfunction.

Impact of polystyrene microplastics with combined contamination of norfloxacin and sulfadiazine on Chrysanthemum coronarium L.

Antibiotics and microplastics including nanoplastics are emerging contaminants which have become global environmental issues. The application of antibiotics along with microplastics in soil and their entrance in food chain may pose a major threat to human health. The single and combined exposure of polystyrene microplastic (MPS), norfloxacin (NF) and sulfadiazine (SFD) on Chrysanthemum coronarium L. a medicinal food crop, were investigated. Accumulation of nutrient element contents (Fe, Mn, Mg, Zn, K) differentially responded to the single or combined treatments compared to the control. Scanning electron microscopy and transmission electron microscopy analysis indicated that MPS, NF and SFD accumulated in roots, shoots, and leaves and affected their ultrastructure. Compared with that of the single contamination, the co-contamination of microplastics and antibiotics had a greater effect on leaf metabolites due to combination of multiple abiotic stresses. MPS, NF and SFD accumulated from roots and transported to shoots and leaves which ultimately impacts plant metabolites and, nutritional value. They subsequently impact agricultural sustainability and food safety of medicinal food plants. This investigation suggests the possible ecological risks of microplastics to medicinal food plants, especially in co-exposure with organic pollutants like antibiotics and help to reveal potential mechanisms of phytotoxicity of different antibiotics with polyethylene microplastic.

Occupational Hazards of Surgical Smoke and Achieving a Smoke Free Operating Room Environment: Asia-Pacific Consensus Statement on Practice Recommendations.

Background: Surgical smoke generated through energy devices may present detrimental effects on individuals present in the operating room (OR). Despite the concerns possibly associated with surgical smoke, there may be no mandatory policies that suggest protective measures and limited firm standards are committed yet to address the same. Aim: The aim of this paper is to present recommendations for surgeons and OR personnel by taking a consensus approach based on available literature and its interpretation by a multi-national panel of experts. Methods: The Asia-Pacific (APAC) group was established with the aims of reviewing literature evidence, discussing key issues regarding surgical smoke and its hazards, and offering a summary of statements in achieving a smoke-free OR environment. Eleven expert surgeons from the international APAC region were gathered with the purpose of coming to a consensus on engineering, best work-practices, and administrative controls in minimizing surgical smoke exposure. A two-phase consensus method was used to obtain opinions from the expert panel of specialists. Statements with an agreement of more than 80% were accepted. Findings: For twenty-one statements, the panel achieved consensus on 17 statements; another 5 were dropped due to lack of consensus. The consensus was obtained on statements that address the need for the implementation of administrative policies, training and awareness, standard procedure for the continued use of engineering controls, stringent work practice controls and preventive controls. Conclusion: The statements presented may guide surgeons and OR personnel in the practical management of surgical smoke safety, mitigating the risks associated with it. The consensus statement also provides a series of recommendations that can be used with other stakeholders, such as policymakers, hospital administrators and professional societies, to highlight and motivate the implementation of meaningful policies.

Phytotoxic effects on chloroplast and UHPLC-HRMS based untargeted metabolomic responses in Allium tuberosum Rottler ex Sprengel (Chinese leek) exposed to antibiotics.

Introduction of antibiotics into agricultural fields poses serious health risks to humans. This study investigated the uptake of antibiotics, their effects on metabolic pathways, and chloroplast structure changes of Allium tuberosum exposed to norfloxacin (NFL), oxytetracycline (OTC), and tetracycline (TC). Among all the antibiotic treatments, the highest accumulation of antibiotics in roots (4.15 mg/kg) and leaves (0.29 mg/kg) was TC, while in bulbs it was NFL (5.94 mg/kg). OTC was with the lowest accumulation in roots: 0.19 mg/kg, bulbs: 0.18 mg/kg, and leaves: 0.11 mg/kg. The number of mitochondira and the number of plastoglobulli increased. The chloroplast structure was disturbed under the stress of NFL, OTC, and TC. Disturbance in the chloroplast ultrastructure leads to altered chlorophyll fluorescence variables. Simultaneously, metabolomic profiling of leaves demonstrated that NFL stress regulated more of metabolic pathways than OTC and TC. Differences in metabolic pathways among the antibiotic treatments showed that each antibiotic has different impact even under the same experimental conditions. TC and NFL have more toxic effects than OTC antibiotic. Metabolic variations induced by antibiotics stress highlighted pools of metabolites that affect the metabolic activities, chlorophyll fluorescence, ultrastructural adjustments, and stimulate defensive impact in A. tubersoum. These findings provide an insight of metabolic destabilization as well as metabolic changes in defensive mechanism and stress response of A. tuberosum to different antibiotics.

Real-Time Sensing with Multiplexed Optomechanical Resonators.

Nanoelectromechanical resonators have been successfully used for a variety of sensing applications. Their extreme resolution comes from their small size, which strongly limits their capture area. This leads to a long analysis time and the requirement for large sample quantity. Moreover, the efficiency of the electrical transductions commonly used for silicon resonators degrades with increasing frequency, limiting the achievable mechanical bandwidth and throughput. Multiplexing a large number of high-frequency resonators appears to be a solution, but this is complex with electrical transductions. We propose here a route to solve these issues, with a multiplexing scheme for very high-frequency optomechanical resonators. We demonstrate the simultaneous frequency measurement of three silicon microdisks fabricated with a 200 mm wafer large-scale process. The readout architecture is simple and does not degrade the sensing resolutions. This paves the way toward the realization of sensors for multiparametric analysis with an extremely low limit of detection and response time.

A Two-Minute Walking Test With a Smartphone App for Persons With Multiple Sclerosis: Validation Study.

BACKGROUND: Walking disturbances are a common dysfunction in persons with multiple sclerosis (MS). The 2-Minute Walking Test (2MWT) is widely used to quantify walking speed. We implemented a smartphone-based 2MWT (s2MWT) in MS sherpa, an app for persons with MS. When performing the s2MWT, users of the app are instructed to walk as fast as safely possible for 2 minutes in the open air, while the app records their movement and calculates the distance walked. OBJECTIVE: The aim of this study is to investigate the concurrent validity and test-retest reliability of the MS sherpa s2MWT. METHODS: We performed a validation study on 25 persons with relapsing-remitting MS and 79 healthy control (HC) participants. In the HC group, 21 participants were matched to the persons with MS based on age, gender, and education and these followed the same assessment schedule as the persons with MS (the HC-matched group), whereas 58 participants had a less intense assessment schedule to determine reference values (the HC-normative group). Intraclass correlation coefficients (ICCs) were determined between the distance measured by the s2MWT and the distance measured using distance markers on the pavement during these s2MWT assessments. ICCs were also determined for test-retest reliability and derived from 10 smartphone tests per study participant, with 3 days in between each test. We interviewed 7 study participants with MS regarding their experiences with the s2MWT. RESULTS: In total, 755 s2MWTs were completed. The adherence rate for the persons with MS and the participants in the HC-matched group was 92.4% (425/460). The calculated distance walked on the s2MWT was, on average, 8.43 m or 5% (SD 18.9 m or 11%) higher than the distance measured using distance markers (n=43). An ICC of 0.817 was found for the concurrent validity of the s2MWT in the combined analysis of persons with MS and HC participants. Average ICCs of 9 test-retest reliability analyses of the s2MWT for persons with MS and the participants in the HC-matched group were 0.648 (SD 0.150) and 0.600 (SD 0.090), respectively, whereas the average ICC of 2 test-retest reliability analyses of the s2MWT for the participants in the HC-normative group was 0.700 (SD 0.029). The interviewed study participants found the s2MWT easy to perform, but they also expressed that the test results can be confronting and that a pressure to reach a certain distance can be experienced. CONCLUSIONS: The high correlation between s2MWT distance and the conventional 2MWT distance indicates a good concurrent validity. Similarly, high correlations underpin a good test-retest reliability of the s2MWT. We conclude that the s2MWT can be used to measure the distance that the persons with MS walk in 2 minutes outdoors near their home, from which both clinical studies and clinical practice can benefit.

Coping With Human-Cat Interactions Beyond the Limits of Domesticity: Moral Pluralism in the Management of Cats and Wildlife.

Although human interactions with cats are often even typically analyzed in the context of domesticity, with a focus on what sorts of interactions might make both people and cats "happy at home," a large number of cats in the world live, for one reason or another, beyond the bounds of domesticity. Human interactions with these more or less free-living cats raise deeply controversial questions about how both the cats and the people they interact with should be sensibly managed, and about the moral imperatives that ought to guide the management of their interactions through the laws and public policies regulating both human interactions with pets and with wildlife. We review the geography of human interactions with cats living beyond the bounds of domesticity. We acknowledge the contributions made to ideas about how to manage cats by the animal protection movement. We review the tensions that have emerged over time between advocates for the eradication of free-living cats, because of the impacts they have on native wildlife species, and those who have imagined alternatives to eradication, most notably one or another variant of trap-neuter-return (TNR). The conflict over how best to deal with cats living beyond the bounds of domesticity and their wildlife impacts raises the prospect of stalemate, and we canvass and critique possibilities for moving beyond that stalemate.

Highly Efficient Semi-Continuous Extraction and In-Line Purification of High ß-O-4 Butanosolv Lignin.

Innovative biomass fractionation is of major importance for economically competitive biorefineries. Lignin is currently severely underutilized due to the use of high severity fractionation methodologies that yield complex condensed lignin that limits high-value applicability. Mild lignin fractionation conditions can lead to lignin with a more regular C-O bonded structure that has increased potential for higher value applications. Nevertheless, such extraction methodologies typically suffer from inadequate lignin extraction efficiencies and yield. (Semi)-continuous flow extractions are a promising method to achieve improved extraction efficiency of such C-O linked lignin. Here we show that optimized organosolv extraction in a flow-through setup resulted in 93-96% delignification of 40 g walnut shells (40 wt% lignin content) by applying mild organosolv extraction conditions with a 2 g/min flowrate of a 9:1 n-butanol/water mixture with 0.18 M H2SO4 at 120°C in 2.5 h. 85 wt% of the lignin (corrected for alcohol incorporation, moisture content and carbohydrate impurities) was isolated as a powder with a high retention of the ß-aryl ether (ß-O-4) content of 63 linking motifs per 100 C9 units. Close examination of the isolated lignin showed that the main carbohydrate contamination in the recovered lignin was butyl-xyloside and other butoxylate carbohydrates. The work-up and purification procedure were investigated and improved by the implementation of a caustic soda treatment step and phase separation with a continuous integrated mixer/separator (CINC). This led to a combined 75 wt% yield of the lignin in 3 separate fractions with 3% carbohydrate impurities and a very high ß-O-4 content of 67 linking motifs per 100 C9 units. Analysis of all the mass flows showed that 98% of the carbohydrate content was removed with the inline purification step, which is a significant improvement to the 88% carbohydrate removal for the traditional lignin precipitation work-up procedure. Overall we show a convenient method for inline extraction and purification to obtain high ß-O-4 butanosolv lignin in excellent yields.

Effects of antibiotics stress on growth variables, ultrastructure, and metabolite pattern of Brassica rapa ssp. chinensis.

Antibiotics frequently contaminate agricultural fields and through plant uptake enter into the food chain. This study aimed to explore the effects of antibiotics; tetracycline (TC), oxytetracycline (OTC) and norfloxacin (NF) on the growth, cell ultrastructure, and metabolite pattern of Brassica rapa ssp. chinensis. Oxytetracycline accumulated more than other antibiotics followed by TC and NF. Plant growth, chlorophyll fluorescence, and antioxidant activities were negatively affected under all antibiotic treatments. Ultrastructural investigation of mesophyll of leaves performed by transmission electron microscopy indicated that antibiotic stress caused the changes in thylakoid orientation, number of plastoglobuli, and starch grains. Identification of functional groups through Fourier transform infrared analysis indicated that carboxyl group, carbonate and ammonium ions are involved in the adsorption of antibiotics. The metabolic profiling of B. rapa leaves demonstrated that all of the antibiotics treatments distorted phenylalanine, tyrosine and tryptophan biosynthesis, d-glutamine and d-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism and TCA cycle. Metabolic alterations as a result of antibiotics stress provide insights of metabolites that affect the physiological changes attributed to antibiotic stress. These results will improve the understanding of antibiotic contamination effects on plants.

Development of highly potent neutralising nanobodies against multiple SARS-CoV-2 variants including the variant of concern B.1.351

The pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. During the years of 2020-2021, millions of humans have died due to SARS-CoV-2 infection and severe economic damage to the global economy has occurred. Unprecedented rapid investments in vaccine development have been made to counter the spread of SARS-CoV-2 among humans. While vaccines are a key pillar of modern medicine, SARS-CoV-2 has mutated as it spread among humans. Vaccines previously developed and approved by regulators are becoming less effective against new variants. One variant of SARS-CoV-2 known as B.1.351 that was first reported to be present in South Africa significantly reduces the efficacy of vaccines developed to date. Therapeutic options that work against the B.1.351 variant are therefore urgently needed to counteract reduced vaccine efficacy. We present here the discovery of recombinant alpaca antibodies that neutralise live virus of B.1.351 and other SARS-CoV-2 variants potently. The antibodies described here may be a useful tool for clinicians who are treating patients infected with B.1.351 and other SARS-CoV-2 for which there is currently no known highly effective treatment.

Randomized, Double-Blind, Placebo-Controlled Phase II Study of Yeast-Brachyury Vaccine (GI-6301) in Combination with Standard-of-Care Radiotherapy in Locally Advanced, Unresectable Chordoma.

BACKGROUND: Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial-to-mesenchymal transition. GI-6301 is a recombinant, heat-killed Saccharomyces cerevisiae yeast-based vaccine targeting brachyury. A previous phase I trial of GI-6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI-6301 vaccine plus radiation. MATERIALS AND METHODS: Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo-controlled trial. Patients received three doses of GI-6301 (80 × 107 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. RESULTS: Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive-free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7-37.5 months) and 25.9 months (95% CI, 9.2-30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38-2.71). Vaccine was well tolerated with no vaccine-related serious adverse events. Preexisting brachyury-specific T cells were detected in most patients in both arms. Most patients developed T-cell responses during therapy, with no difference between arms in frequency or magnitude of response. CONCLUSION: No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual. IMPLICATIONS FOR PRACTICE: Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast-brachyury vaccine (GI-6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.