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Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

The existence of a hypothalamic gonadotropin-inhibiting system has been elusive. A neuropeptide named gonadotropin-inhibitory hormone (GnIH, SIKPSAYLPLRF-NH(2)) which directly inhibits gonadotropin synthesis and release from the pituitary was recently identified in quail hypothalamus. Here we identify GnIH homologs in the human hypothalamus and characterize their distribution and biological activity. GnIH homologs were isolated from the human hypothalamus by immunoaffinity purification, and then identified as MPHSFANLPLRF-NH(2) (human RFRP-1) and VPNLPQRF-NH(2) (human RFRP-3) by mass spectrometry. Immunocytochemistry revealed GnIH-immunoreactive neuronal cell bodies in the dorsomedial region of the hypothalamus with axonal projections to GnRH neurons in the preoptic area as well as to the median eminence. RT-PCR and subsequent DNA sequencing of the PCR products identified human GnIH receptor (GPR147) mRNA expression in the hypothalamus as well as in the pituitary. In situ hybridization further identified the expression of GPR147 mRNA in luteinizing hormone producing cells (gonadotropes). Human RFRP-3 has recently been shown to be a potent inhibitor of gonadotropin secretion in cultured sheep pituitary cells by inhibiting Ca(2+) mobilization. It also directly modulates GnRH neuron firing. The identification of two forms of GnIH (RFRP-1 and RFRP-3) in the human hypothalamus which targets human GnRH neurons and gonadotropes and potently inhibit gonadotropin in sheep models provides a new paradigm for the regulation of hypothalamic-pituitary-gonadal axis in man and a novel means for manipulating reproductive functions.

Kidney cancers are one of the most common malignancies worldwide. Accurate diagnosis is a critical step in the management of kidney cancer patients and is influenced by multiple factors including tumor size or volume, cancer types and stages, etc. For malignant tumors, partial or radical surgery of the kidney might be required, but for clinicians, the basis for making this decision is often unclear. Partial nephrectomy could result in patient death due to cancer if kidney removal was necessary, whereas radical nephrectomy in less severe cases could resign patients to lifelong dialysis or need for future transplantation without sufficient cause. Using machine learning to consider clinical data alongside computed tomography images could potentially help resolve some of these surgical ambiguities, by enabling a more robust classification of kidney cancers and selection of optimal surgical approaches. In this study, we used the publicly available KiTS dataset of contrast-enhanced CT images and corresponding patient metadata to differentiate four major classes of kidney cancer: clear cell (ccRCC), chromophobe (chRCC), papillary (pRCC) renal cell carcinoma, and oncocytoma (ONC). We rationalized these data to overcome the high field of view (FoV), extract tumor regions of interest (ROIs), classify patients using deep machine-learning models, and extract/post-process CT image features for combination with clinical data. Regardless of marked data imbalance, our combined approach achieved a high level of performance (85.66% accuracy, 84.18% precision, 85.66% recall, and 84.92% F1-score). When selecting surgical procedures for malignant tumors (RCC), our method proved even more reliable (90.63% accuracy, 90.83% precision, 90.61% recall, and 90.50% F1-score). Using feature ranking, we confirmed that tumor volume and cancer stage are the most relevant clinical features for predicting surgical procedures. Once fully mature, the approach we propose could be used to assist surgeons in performing nephrectomies by guiding the choices of optimal procedures in individual patients with kidney cancer.

Cystic fibrosis (CF) is commonly complicated by chronic rhinosinusitis (CRS). Despite highly effective management options, CRS in people with CF (PwCF+CRS) may be refractory to medical therapy, eventually requiring endoscopic sinus surgery. The impact of sinus surgery on pulmonary, quality of life (QOL), and other outcomes in PwCF+CRS in the expanding era of highly effective modulator therapy has not been fully elucidated. This study aims to determine if endoscopic sinus surgery can offer superior outcomes for PwCF+CRS when compared to continued medical treatment of CRS. This multi-institutional, observational, prospective cohort study will enroll 150 adults with PwCF+CRS across nine US CF Centers who failed initial medical therapy for CRS and elected to pursue either endoscopic sinus surgery or continue medical treatment. To determine if sinus surgery outperforms continued medical therapy in different outcomes, we will assess changes in pulmonary, CF-specific QOL, CRS-specific QOL, sleep quality, depression, headache, cognition, olfaction, productivity loss, and health utility value after treatment. The influence of highly effective modulator therapy on these outcomes will also be evaluated. This study will provide crucial insights into the impact of endoscopic sinus surgery for PwCF+CRS and aid with development of future treatment pathways and guidelines. This study has been approved by each institution's internal review board, and study enrollment began August 2019. Results will be disseminated in conferences and peer-reviewed journals. This study was registered on ClinicalTrials.gov (NCT04469439).

This study proposes novel and modified conventional flow fields for a high-temperature PEM fuel cell, and predicts the fluid dynamic behavior with a 3D, computational fluid dynamics model. Five base flow field patterns (FFPs) are selected: a 4-channel serpentine, a hybrid design, a 2-channel spiral, a dual-triangle sandwich, and a parallel pin-type flow field. For each base FFP, sub-patterns are developed through modification of the channels and ribs. The 4-channel serpentine is taken as the state-of-the-art reference flow field. Simulations are carried out at two different mass flow rates. The result shows that the incorporation of a dead end in flow channels or the merging of channels into a single channel before connecting to the outlet enhances the average and maximum GDL mass flux, but it also increases the pressure drop. The parallel pin-type design-3 and dual-triangle sandwich design-1 exhibit a more even distribution but yield a lower average GDL mass flux than the 4-channel serpentine, which could be beneficial for reducing MEA degradation and thus used at low load conditions where a high mass flux is not needed. In contrast, the uniform hybrid design and 2-channel spiral design-2 provide a higher average and maximum mass flux with a more non-uniform distribution and greater pressure drop. The high average GDL mass flux would be beneficial during high load conditions to ensure enough reactants reach the catalyst.

This study experimentally investigates various flow field designs for a direct ethanol-based proton exchange membrane (PEM) fuel cell operated at a temperature above the vaporization temperature of water. It expands the designs of flow fields investigated for high-temperature (HT) direct ethanol fuel cells by comparing four designs. It investigates the performance of these designs at various ethanol concentrations and flow rates. A series of polarization, constant current, and impedance spectroscopy experiments were carried out at different combinations of operating conditions. The result shows that all flow fields provide poorer performance at a high ethanol concentration (6 M), regardless of ethanol inlet flow rates. At a low concentration (3 M), the 2-channel spiral flow field exhibits higher cell power output (12–18% higher) with less mass transport loss and charge transfer resistance compared to other flow fields, although it has some voltage instability. As such, it is identified as a promising design, particularly for higher-power applications. The 4-channel serpentine, dual-triangle sandwich, and hybrid flow fields offer similar cell power output (max power: ~23 mW/cm2) and cell potentials. However, the cell potential instability and mass transport losses are higher in the hybrid flow field compared to the other two designs. Thus, it is not as promising a design for ethanol-based HT-PEM fuel cells. Since the dual-triangle has similar performance to the 4-channel serpentine, it could be an alternative to the serpentine for ethanol-based HT-PEM fuel cells.

Purpose A growing body of research has identified time pressure as a key driver of cybersecurity (CS) risks and vulnerabilities. To strengthen CS, organizations use CS documents (e.g. best practices, guidelines and policies) intended to strengthen CS. The purpose of this paper is to provide an overview of how specifically time pressure is addressed by CS documents. Design/methodology/approach The authors conducted a systematic search for CS documents followed by a content analysis of the identified documents. First, the authors carried out a systematic Web search and identified 92 formal and informal CS documents (e.g. security policies, procedures, guidelines, manuals and best practices). Second, they systematically analyzed the resulting documents (n = 92), using a structured approach of data familiarization and low-/high-level coding for the identification and interpretation of themes. Based on this analysis, the authors formulated a conceptual framework that captures the sources and effects of time pressure along the themes of industry, operations and users. Findings The authors developed a conceptual framework that outlines the role of time pressure for the CS industry, threats and operations. This provides a shared frame of reference for researchers and practitioners to understand the antecedents and consequences of time pressure in the organizational CS context. Research limitations/implications While the analyzed documents acknowledge time pressure as an important factor for CS, the documents provide limited information on how to respond to these concerns. Future research could, hence, consult with CS experts and policymakers to inform the development of effective guidelines and policies on how to address time pressure in the identified areas. A dedicated analysis within each area will allow to investigate the corresponding aspects of time pressure in-depth along with a consideration for targeted guidelines and policies. Last, note that a differentiation between CS document types (e.g. formal vs informal and global vs regional) was beyond the scope of this paper and may be investigated by future work. Originality/value This study makes three main contributions to the CS literature. First, this study broadens the understanding of the role of time pressure in CS to consider the organizational perspective along the themes of industry, threats and operations. Second, this study provides the first comprehensive assessment of how organizations address time pressure through CS documents, and how this compares to existing research in academic literature. Third, by developing a conceptual framework, this study provides a shared frame of reference for researchers and practitioners to further develop CS documents that consider time pressure’s role in secure behavior.