Caffeine, Postoperative Delirium And Change In Outcomes after Surgery (CAPACHINOS)-2: protocol for a randomised controlled trial.

INTRODUCTION: Delirium is a major public health issue for surgical patients and their families because it is associated with increased mortality, cognitive and functional decline, prolonged hospital admission and increased healthcare expenditures. Based on preliminary data, this trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of delirium in older adults after major non-cardiac surgery. METHODS AND ANALYSIS: The CAffeine, Postoperative Delirium And CHange In Outcomes after Surgery-2 (CAPACHINOS-2) Trial is a single-centre, placebo-controlled, randomised clinical trial that will be conducted at Michigan Medicine. The trial will be quadruple-blinded, with clinicians, researchers, participants and analysts all masked to the intervention. The goal is to enrol 250 patients with a 1:1:1: allocation ratio: dextrose 5% in water placebo, caffeine 1.5 mg/kg and caffeine 3 mg/kg as a caffeine citrate infusion. The study drug will be administered intravenously during surgical closure and on the first two postoperative mornings. The primary outcome will be delirium, assessed via long-form Confusion Assessment Method. Secondary outcomes will include delirium severity, delirium duration, patient-reported outcomes and opioid consumption patterns. A substudy analysis will also be conducted with high-density electroencephalography (72-channel system) to identify neural abnormalities associated with delirium and Mild Cognitive Impairment at preoperative baseline. ETHICS AND DISSEMINATION: This study was approved by the University of Michigan Medical School Institutional Review Board (HUM00218290). An independent data and safety monitoring board has also been empanelled and has approved the clinical trial protocol and related documents. Trial methodology and results will be disseminated via clinical and scientific journals along with social and news media. TRIAL REGISTRATION NUMBER: NCT05574400.

Role of Electronic Structure on Nitrate Reduction to Ammonium: A Periodic Journey.

Electrocatalysis is a promising approach to convert waste nitrate to ammonia and help close the nitrogen cycle. This renewably powered ammonia production process sources hydrogen from water (as opposed to methane in the thermal Haber-Bosch process) but requires a delicate balance between a catalyst's activity for the hydrogen evolution reaction (HER) and the nitrate reduction reaction (NO3RR), influencing the Faradaic efficiency (FE) and selectivity to ammonia/ammonium over other nitrogen-containing products. We measure ammonium FEs ranging from 3.6 ± 6.6% (on Ag) to 93.7 ± 0.9% (on Co) across a range of transition metals (TMs; Ti, Fe, Co, Ni, Ni0.68Cu0.32, Cu, and Ag) in buffered neutral media. To better understand these competing reaction kinetics, we develop a microkinetic model that captures the voltage-dependent nitrate rate order and illustrates its origin as competitive adsorption between nitrate and hydrogen adatoms (H*). NO3RR FE can be described via competition for electrons with the HER, decreasing sharply for TMs with a high work function and a correspondingly high HER activity (e.g., Ni). Ammonium selectivity nominally increases as the TM d-band center energy (Ed) approaches and overcomes the Fermi level (EF), but is exceptionally high for Co compared to materials with similar Ed. Density functional theory (DFT) calculations indicate Co maximizes ammonium selectivity via (1) strong nitrite binding enabling subsequent reduction and (2) promotion of nitric oxide dissociation, leading to selective reduction of the nitrogen adatom (N*) to ammonium.

Twin Mitochondrial Sequence Analysis.

When applying genome-wide sequencing technologies to disease investigation, it is increasingly important to resolve sequence variation in regions of the genome that may have homologous sequences. The human mitochondrial genome challenges interpretation given the potential for heteroplasmy, somatic variation, and homologous nuclear mitochondrial sequences (numts). Identical twins share the same mitochondrial DNA (mtDNA) from early life, but whether the mitochondrial sequence remains similar is unclear. We compared an adult monozygotic twin pair using high throughput-sequencing and evaluated variants with primer extension and mitochondrial pre-enrichment. Thirty-seven variants were shared between the twin individuals, and the variants were verified on the original genomic DNA. These studies support highly identical genetic sequence in this case. Certain low-level variant calls were of high quality and homology to the mitochondrial DNA, and they were further evaluated. When we assessed calls in pre-enriched mitochondrial DNA templates, we found that these may represent numts, which can be differentiated from mtDNA variation. We conclude that twin identity extends to mitochondrial DNA, and it is critical to differentiate between numts and mtDNA in genome sequencing, particularly since significant heteroplasmy could influence genome interpretation. Further studies on mtDNA and numts will aid in understanding how variation occurs and persists.

Molecular architecture of CTCFL.

The CTCF-like protein, CTCFL, is a DNA-binding factor that regulates the transcriptional program of mammalian male germ cells. CTCFL consists of eleven zinc fingers flanked by polypeptides of unknown structure and function. We determined that the C-terminal fragment predominantly consists of extended and unordered content. Computational analysis predicts that the N-terminal segment is also disordered. The molecular architecture of CTCFL may then be similar to that of its paralog, the CCCTC-binding factor, CTCF. We speculate that sequence divergence in the unstructured terminal segments results in differential recruitment of cofactors, perhaps defining the functional distinction between CTCF in somatic cells and CTCFL in the male germ line.

CTCF terminal segments are unstructured.

The human CCCTC-binding factor, CTCF, organizes and regulates transcription of the genome by colocalizing distant DNA elements on the same and even different chromosomes. This protein consists of 11 zinc fingers flanked by polypeptide segments of unknown structure and function. We purified recombinant terminal fragments and observed that both are extended, monomeric, and predominantly consist of unordered content. We thus speculate that the role of the terminal extensions, and perhaps all of CTCF, is to act as a scaffold for the assembly of other proteins on a specific binding site.