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Neurological disorders are often debilitating conditions with no cure. The majority of current therapies are palliative rather than disease-modifying; therefore, new strategies for treating neurological disorders are greatly needed. mRNA-based therapeutics have great potential for treating such neurological disorders; however, challenges with delivery have limited their clinical potential. Lipid nanoparticles (LNPs) are a promising delivery vector for the brain, given their safer toxicity profile and higher efficacy. Despite this, very little is known about LNP-mediated delivery of mRNA into the brain. Here, we employ MC3-based LNPs and successfully deliver Cre mRNA and Cas9 mRNA/Ai9 sgRNA to the adult Ai9 mouse brain; greater than half of the entire striatum and hippocampus was found to be penetrated along the rostro-caudal axis by direct intracerebral injections of MC3 LNP mRNAs. MC3 LNP Cre mRNA successfully transfected cells in the striatum (∼52% efficiency) and hippocampus (∼49% efficiency). In addition, we demonstrate that MC3 LNP Cas9 mRNA/Ai9 sgRNA edited cells in the striatum (∼7% efficiency) and hippocampus (∼3% efficiency). Further analysis demonstrates that MC3 LNPs mediate mRNA delivery to multiple cell types including neurons, astrocytes, and microglia in the brain. Overall, LNP-based mRNA delivery is effective in brain tissue and shows great promise for treating complex neurological disorders.

Aim: Determining specific causes of allograft failure allows a focus on understanding and treating these conditions. Previous studies highlight chronic antibody‐mediated rejection as a leading cause of late allograft failure. We sought to define causes of allograft failure in a large cohort of kidney transplant recipients across multiple centres in Australia and New Zealand, including cases previously attributed to chronic allograft nephropathy (CAN). Methods: All death‐censored allograft failures at 9 participating centres between 1 January 2014 to 31 December 2018 were included. Available clinical and biopsy data were reviewed and the "most likely" cause assigned. Results: There were 642 death‐censored allograft failures in the study period. Of these, 495 (77.1%) had an informative biopsy performed a median of 13.4 months (IQR 2.5–39.1 months) prior to allograft failure. Rejection of any type was the leading cause of allograft failure (47.5%), comprised chiefly of chronic antibody‐mediated rejection (37.4%) and chronic T‐cell mediated rejection (6.4%). Other leading causes were undifferentiated interstitial fibrosis and tubular atrophy (10.8%), late medical and surgical complications (8.1%) and recurrent or de novo glomerulonephritis (7.0%). Polyoma viral nephropathy and calcineurin inhibitor toxicity each contributed to <2%. Causes of allograft failure previously attributed to CAN (n = 419, 65.3%) had a similar distribution to the overall cohort, with 43.9% attributed to chronic antibody‐mediated rejection. Conclusion: To prolong allograft survival, improved strategies are needed to curtail alloimmune responses. Greater understanding of the causes of undifferentiated interstitial fibrosis and tubular atrophy and potential treatments would also be of considerable benefit. Summary at a Glance: In a multicentre, 5‐year, cross‐sectional analysis, rejection, particularly chronic antibody mediated rejection was the leading cause of allograft failure. Further efforts to prevent allo‐immune injury are therefore needed. Interstitial fibrosis and tubular atrophy not due to rejection was also common and requires further exploration into causation and prevention. [ABSTRACT FROM AUTHOR]

The article critiques the public/private rights framework in federal adjudication, focusing on how the distinction between public and private rights has evolved and been challenged, particularly in the context of land claims and administrative adjudication.

STUDY QUESTION What is the prevalence of occupational stress, somatization, and burnout reported by UK and US, embryologists and the impact of work conditions on these well-being outcomes? SUMMARY ANSWER Surveyed UK and US embryologists reported moderate perceived stress, low somatic symptom severity, high levels of burnout, and overall stressful work conditions, but with differences that could be due to country-specific occupational and employment characteristics. WHAT IS KNOWN ALREADY? Spanish, UK, US, and international surveys have identified high levels of occupational stress, somatization, burnout, and occupational health issues among embryologists. These issues have been attributed to embryologists' occupational challenges and work conditions. STUDY DESIGN, SIZE, DURATION A cross-sectional web-based survey was sent to 253 embryologists working in UK ART/IVF clinics and 487 embryologists working in US ART/IVF clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants self-reported their stress levels, somatization, burnout, and work conditions. Proportions across the Perceived Stress Scale (PSS), Patient Health Questionnaire (PHQ-15), Maslach Burnout Inventory-General Survey (MBI-GS), a single-item work unit grade (A–F), and customized occupational and sociodemographic questionnaires were calculated using descriptive statistics. Welch's t -test was utilized to compare PSS and PHQ-15 scores between groups. Risk ratios were calculated using log-binomial regression for all models except for levels of anxiety related to performing cryostorage tasks, for which Poisson models were used. MAIN RESULTS AND THE ROLE OF CHANCE In total, 50.6% (128) of the embryologists in the UK and 50.1% (244) in the US completed the survey. Both groups self-reported moderate PSS and low PHQ-15 scores, although fewer UK embryologists scored high on the MBI cynicism dimension than their US colleagues (43% UK vs 60% US embryologists, P  <   0.05). The UK and US embryologists did not differ on the MBI exhaustion dimension with both scoring high for exhaustion (59% UK vs 62% US). Although 81% and 80% of UK and US embryologists, respectively, reported working overtime, more embryologists in the UK reported being adequately compensated. Increasing levels of anxiety-related to cryostorage showed a dose-dependent increased risk of burnout on at least two MBI-GS dimensions only in the UK group, and, a dose-dependent likelihood of higher PSS and PHQ-15 scores in both groups. LIMITATIONS, REASONS FOR CAUTION Since the two groups were surveyed 9 months apart and were self-reporting, the study is limited by the differences in responsibilities, scheduling, and workload specific to the time of year. WIDER IMPLICATIONS OF THE FINDINGS Work-related health issues and occupational challenges shared by UK and US embryologists could be addressed by organizational enhancements and technology. Lower levels of stress and burnout among UK embryologists might be due to the HFEA-provided structure/certainty. STUDY FUNDING/COMPETING INTEREST(S) This study was supported without any external funding by TMRW Life Sciences Inc. which is developing and commercializing an automated platform for embryology. M.G.C. and M.S.L. are full-time employees and stockholders/shareholders with TMRW Life Sciences, and A.M. of Novavax, Inc. was an employee of TMRW Life Sciences. G.P. is a consultant for TMRW Life Sciences. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER NCT05326802; NCT05708963. [ABSTRACT FROM AUTHOR]

INTRODUCTION The propriety of Bivens (1) actions is part of the debate about federal common law. (2) For some judges and scholars, implied actions are a particularly reprobated form of [...]

The predictive performance equation (PPE) is a mathematicalmodel of learning and retention that uses regularities seen inhuman learning to predict future performance. Previous research(Collins, Gluck, Walsh Krusmark & Gunzelmann, , 2016) foundthat prior data could be used to inform PPE’s free parameterswhen generating predictions of a group’s aggregate performance,allowing for more accurate initial performance predictions. Herewe investigate an extension of this methodology to predictperformance of individuals, rather than aggregate samples. Thispaper documents the results of that investigation, which is on thecritical path to the use of this cognitive technology in educationand training.

INTRODUCTION In upholding standing in Massachusetts v. EPA, Justice Stevens said that states "are not normal litigants for the purposes of invoking federal jurisdiction." (1) While one might agree that [...]