Definition of Implanted Neurological Device Abandonment: A Systematic Review and Consensus Statement.

Importance: Establishing a formal definition for neurological device abandonment has the potential to reduce or to prevent the occurrence of this abandonment. Objective: To perform a systematic review of the literature and develop an expert consensus definition for neurological device abandonment. Evidence Review: After a Royal Society Summit on Neural Interfaces (September 13-14, 2023), a systematic English language review using PubMed was undertaken to investigate extant definitions of neurological device abandonment. Articles were reviewed for relevance to neurological device abandonment in the setting of deep brain, vagal nerve, and spinal cord stimulation. This review was followed by the convening of an expert consensus group of physicians, scientists, ethicists, and stakeholders. The group summarized findings, added subject matter experience, and applied relevant ethics concepts to propose a current operational definition of neurological device abandonment. Data collection, study, and consensus development were done between September 13, 2023, and February 1, 2024. Findings: The PubMed search revealed 734 total articles, and after review, 7 articles were found to address neurological device abandonment. The expert consensus group addressed findings as germane to neurological device abandonment and added personal experience and additional relevant peer-reviewed articles, addressed stakeholders' respective responsibilities, and operationally defined abandonment in the context of implantable neurotechnological devices. The group further addressed whether clinical trial failure or shelving of devices would constitute or be associated with abandonment as defined. Referential to these domains and dimensions, the group proposed a standardized definition for abandonment of active implantable neurotechnological devices. Conclusions and Relevance: This study's consensus statement suggests that the definition for neurological device abandonment should entail failure to provide fundamental aspects of patient consent; fulfill reasonable responsibility for medical, technical, or financial support prior to the end of the device's labeled lifetime; and address any or all immediate needs that may result in safety concerns or device ineffectiveness and that the definition of abandonment associated with the failure of a research trial should be contingent on specific circumstances.

Tracking the British agricultural revolution through the isotopic analysis of dated parchment.

Between the sixteenth and nineteenth century, British agriculture underwent a 'revolutionary' transformation. Yet despite over a century of research and the recognised centrality of agricultural developments to industrialisation and population growth, the character or chronology of any 'revolution' during this period remains contentious. Enquiry has been hampered by the fragmented and locally specific nature of historic accounts and the broad dating of early-modern zooarchaeological assemblages. To address this, we conducted stable isotope analysis on 658 legal documents written on sheepskin parchment; a unique biological resource that records the day, month and year of use (AD 1499 to 1969). We find these provide a high temporal resolution analysis of changing agricultural practices and episodes of disease. Most significantly, they suggest that if an 'Agricultural Revolution' occurred in livestock management, it did so from the mid-nineteenth century, in the aftermath of the Napoleonic Wars.

A modern baseline for the paired isotopic analysis of skin and bone in terrestrial mammals.

We present the isotopic discrimination between paired skin and bone collagen from animals of known life history, providing a modern baseline for the interpretation of archaeological isotopic data. At present, the interpretation of inter-tissue variation (Δ(skin-bone)) in mummified remains is based on comparisons with other archaeological material, which have attributed divergence to their contrasting turnover rates, with rapidly remodelling skin collagen incorporating alterations in environmental, cultural and physiological conditions in the months prior to death. While plausible, the lack of baseline data from individuals with known life histories has hindered evaluation of the explanations presented. Our analysis of a range of animals raised under a variety of management practices showed a population-wide trend for skin collagen to be depleted in 13C by -0.7‰ and enriched in 15N by +1.0‰ relative to bone collagen, even in stillborn animals. These results are intriguing and difficult to explain using current knowledge; however, on the basis of the findings reported here, we caution any results which interpret simply on differing turnover rates. We hypothesize that there may be a consistent difference in the routing of dietary protein and lipids between skin and bone, with potentially on-site synthesis of non-essential amino acids using carbon and nitrogen that have been sourced via different biochemical pathways.

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1-4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

Ambulatory urodynamic monitoring assessment of dorsal genital nerve stimulation for suppression of involuntary detrusor contractions following spinal cord injury: a pilot study.

STUDY DESIGN: A prospective interventional pilot study using within-individual comparisons. OBJECTIVES: To assess the effect of dorsal genital nerve stimulation (DGNS) on urine-storage parameters in participants with spinal cord injury (SCI) and neurogenic detrusor overactivity (NDO) during natural bladder filling. SETTING: The London Spinal Cord Injuries Centre at the Royal National Orthopaedic Hospital, Stanmore, UK. METHODS: Ambulatory urodynamic monitoring (AUM) was carried out with and without DGNS, before and after a week of using DGNS at home. DGNS was applied on-demand by four participants with bladder sensation, and both continuously and intermittently by one participant with absent sensation. A Wilcoxon sign-rank test was used to test paired results of changes within an AUM session. RESULTS: Urodynamic outcomes were improved using DGNS. Bladder capacity was increased from 244 ± 59 to 346 ± 61 ml (p = 0.0078), a mean change of 46 ± 25%. Maximum detrusor pressure was decreased from 58 ± 18 to 47 ± 18 cmH2O (p = 0.0156), a change of 17 ± 13%, and average peak detrusor pressure was decreased from 56 ± 16 to 31 ± 128 cmH2O (p = 0.0156), a mean reduction of 50 ± 19%. There was an increase in the number of detrusor contractions from the first involuntary detrusor contraction to a strong desire, urgency or incontinence, from 1.5 ± 1.4 to 4.3 ± 1.7, and an increase in time of 23 ± 22 min. There were no changes in baseline outcomes following home use of DGNS. CONCLUSIONS: DGNS may be applied on-demand, intermittently or continuously, to increase bladder capacity, decrease storage pressures and provide extra time. Improvements were made in addition to existing antimuscarinic medication regimes.

Comparative Transcriptomics of Ex Vivo, Patient-Derived Endothelial Cells Reveals Novel Pathways Associated With Type 2 Diabetes Mellitus.

In this study low-input RNA-sequencing was used to annotate the molecular identity of endothelial cells isolated and immunopurified with CD144 microbeads. Using this technique, comparative gene expression profiling from healthy subjects and patients with type 2 diabetes mellitus identified both known and novel pathways linked with EC dysfunction. Modeling of diabetes by treating cultured ECs with high glucose identified shared changes in gene expression in diabetic cells. Overall, the data demonstrate how purified ECs from patients can be used to generate new hypotheses about mechanisms of human vascular disease.

Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis.

Atherosclerotic plaques feature local proliferation of leukocytes and vascular smooth muscle cells (VSMCs) and changes in cellular metabolism. Yet the relationship between glucose utilization and proliferation has been technically impossible to study directly in cells of atherosclerotic plaques in vivo. We used multi-isotope imaging mass spectrometry (MIMS), a quantitative imaging platform, to measure coincident cell division and glucose utilization at suborganelle resolution in atherosclerotic plaques. In established plaques, 65% of intimal foam cells and only 4% of medial VSMCs were labeled with 15N-thymidine after 1 week of isotope treatment. Dividing cells demonstrated heightened glucose labeling. MIMS detected 2H-glucose label in multiple subcellular compartments within foam cells, including lipid droplets, the cytosol, and chromatin. Unexpectedly, we identified an intensely focal region of 2H-label in VSMCs underlying plaques. This signal diminished in regions of aorta without atherosclerosis. In advanced plaques, 15N-thymidine and 2H-glucose labeling in foam cells and VSMCs significantly decreased. These data demonstrate marked heterogeneity in VSMC glucose metabolism that was dependent on both proliferative status and proximity of VSMCs to plaques. Furthermore, these results reveal how quantitative mass spectrometry coupled with isotope imaging can complement other methods used to study cell biology directly in the growing atherosclerotic plaque in vivo.

BET bromodomain proteins regulate enhancer function during adipogenesis.

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.