Understanding the Decamethylferrocene FeIII/IV Oxidation Process in Tris(pentafluoroethyl)trifluorophosphate-Containing Ionic Liquids at Glassy Carbon and Boron-Doped Diamond Electrodes.

Under voltammetric conditions, the neutral decamethylferrocene ([Me10Fc]) to cationic ([Me10Fc]+) FeII/III process is a well-known reversible outer-sphere reaction. A companion cationic [Me10Fc]+ to dicationic [Me10Fc]2+ FeIII/IV process has been reported under direct current (DC) cyclic voltammetric conditions at highly positive potentials in liquid SO2 at low temperatures and in a 1.5:1.0 AlCl3/1-butylpyridinium chloride melt. This study demonstrates that in room-temperature ionic liquids containing the hard to oxidize and hydrophobic tris(pentafluoroethyl)trifluorophosphate anion, the [Me10Fc]+/2+ process can be detected as a quasi-reversible reaction at glassy carbon (GC) and boron-doped diamond (BDD) electrodes. Large amplitude Fourier-transformed alternating current (FT-AC) voltammetry minimizes background current contributions occurring at potentials similar to those of the FeIII/IV process in the second and higher-order harmonics. This enables a straightforward determination of the thermodynamics and kinetics for both the FeII/III and FeIII/IV processes. Unlike the ideal outer-sphere FeII/III process, the parameters of the FeIII/IV process may be impacted by ion-interaction effects. For the faster FeII/III process, heterogeneous rate constants are approximately 10 times smaller at BDD than those at GC electrodes. This electrode dependence is less pronounced for the slower FeIII/IV process. The slower BDD kinetics may be attributed in part to a density of states lower than that at GC.

Unilateral double facial artery: an anatomic variant and clinical implications.

Background: This paper reports a rare anatomical variant of the facial artery (FA) - namely, a double FA pattern - which has significant implications in a wide range of surgical and aesthetic medicine disciplines. Case: The study involves a case report and literature review of the FA and its variants. The case is that of a 61-year-old female cadaver with a unilateral FA variant branching pattern discovered during a cadaveric dissection for an anatomy course. Discussion: The dissection revealed an unusual supply of the typical FA distribution by two separate branches from either side of the maxillary artery. The first branch, termed FA1, followed a typical FA course arising from the external carotid to supply the lower portion of the face via lingual, inferior labial, and mental arterial branches. The second branch, termed FA2, arose superior to the maxillary artery near the origin of a typical transverse facial artery, to supply the upper portion of the face via superior labial, lateral nasal, and angular arterial branches. No direct communication between the two branches was observed grossly via dissection. The observed branching pattern has not previously been reported in literature and has critical implications for surgical planning and intervention. Conclusion: This study emphasizes the importance of understanding variant FA anatomy in procedures requiring precise anatomical knowledge of arterial supply to the face. Duplicate and/or secondary facial arteries necessitate careful consideration for their potential consequences on the success of surgery of the head and neck, dermal fillers, and embolization for epistaxis procedures.

Electrochemical Synthesis of the In Human S-oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications.

The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure-electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With the ability to dial-in under current controlled conditions, the formation of S-oxide and novel S,S-dioxide metabolites has been achieved for the first time on a multi-milligram scale using a direct batch electrode platform. A potential rationale for the electrochemical formation of these metabolites in situ is proposed using molecular docking to a cytochrome P450 enzyme.

Patterns and trends in melanoma mortality in the United States, 1999-2020.

INTRODUCTION: Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades. Despite advancements in treatment, it remains a significant cause of cancer mortality. Understanding demographic trends and variations in melanoma mortality is crucial for addressing disparities and implementing effective interventions. METHODS: Using the Centers for Disease Control Wide Ranging Online Data for Epidemiologic Research (CDC WONDER) database, we analyzed melanoma mortality data in the United States from 1999 to 2020. Data were stratified by demographic and regional variables, and age-adjusted mortality rates were calculated. Descriptive analysis was performed and Joinpoint regression analysis was employed to identify temporal trends. RESULTS: Between 1999 and 2020, there were 184,416 melanoma-related deaths in the United States Overall, the age-adjusted mortality rate declined from 2.7 to 2.0 per 100,000 people at a rate of -1.3% annually, with significant variations across demographic groups and regions. Men, non-Hispanic White individuals, and those aged > 65 experienced higher mortality rates. Non-Hispanic White individuals noted the steepest decrease in AAMR after 2013 at a rate of -6.1% annually. Disparities were seen by geographic density, with rural populations exhibiting higher mortality compared to their urban and suburban counterparts. CONCLUSION: The study highlights a significant reduction in melanoma mortality in the U.S. since 2013, potentially attributed to advancements in diagnostic techniques such as dermoscopy and the introduction of immune checkpoint inhibitors. Disparities persist, particularly among rural populations. Targeted interventions focusing on increased screening and education are warranted to further mitigate melanoma mortality and address demographic disparities.

Chemical approaches to the sulfation of small molecules: current progress and future directions.

Sulfation is one of the most important modifications that occur to a wide range of bioactive small molecules including polysaccharides, proteins, flavonoids, and steroids. In turn, these sulfated molecules have significant biological and pharmacological roles in diverse processes including cell signalling, modulation of immune and inflammation response, anti-coagulation, anti-atherosclerosis, and anti-adhesive properties. This Essay summarises the most encountered chemical sulfation methods of small molecules. Sulfation reactions using sulfur trioxide amine/amide complexes are the most used method for alcohol and phenol groups in carbohydrates, steroids, proteins, and related scaffolds. Despite the effectiveness of these methods, they suffer from issues including multiple-purification steps, toxicity issues (e.g., pyridine contamination), purification challenges, stoichiometric excess of reagents which leads to an increase in reaction cost, and intrinsic stability issues of both the reagent and product. Recent advances including SuFEx, the in situ reagent approach, and TBSAB show the widespread appeal of novel sulfating approaches that will enable a larger exploration of the field in the years to come by simplifying the purification and isolation process to access bespoke sulfated small molecules.

Diagnostic performance of multiplex lateral flow tests in ambulatory patients with acute respiratory illness.

We assessed the performance of three different multiplex lateral flow assays manufactured by SureScreen, Microprofit and Goldsite which provide results for influenza, respiratory syncytial virus (RSV) and SARS-CoV-2. Between 4 April and 20 October 2023, 1646 patients 6 months and older presenting to an outpatient department of a hospital in Hong Kong with ≥2 symptoms or signs of an acute respiratory illness were enrolled. The point estimates for all three multiplex tests had sensitivity >80% for influenza A and SARS-CoV-2 compared to PCR, and the tests manufactured by Microprofit and Goldsite had sensitivity >84% to detect RSV. Specificity was >97% for all three tests except for the SureScreen test which had specificity 86.2% (95% CI: 83.9% to 88.3%) for influenza A. Sensitivity was lower than reported by the manufacturers, resulting in a higher risk of false negatives. The three multiplex tests performed better in patients with high viral loads.

Total Intravenous Anesthesia Is Preferred Over Volatile Agents in Cardiac Surgery.

The choice of maintenance anesthetic during cardiopulmonary bypass has been a subject of ongoing debate. Systematic reviews on the topic have so far failed to demonstrate a difference between volatile agents and total intravenous anesthesia (TIVA) in terms of mortality, myocardial injury, and neurological outcomes. Studies using animal models and noncardiac surgical populations suggest numerous mechanisms whereby TIVA has been associated with more favorable outcomes. However, even if the different anesthetic methods are assumed to equivalent in terms of patient outcomes in the context of cardiac surgery, additional factors, namely variables of occupational exposure and environmental impact, strongly support the preferred use of TIVA.

The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation.

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.

2023 Update on Vascular Anesthesia.

The authors thank the editors for this opportunity to review the recent literature on vascular surgery and anesthesia and provide this clinical update. The last in a series of updates on this topic was published in 2019.1 This review explores evolving discussions and current trends related to vascular surgery and anesthesia that have been published since then. The focus is on the major points discussed in the recent literature in the following areas: carotid artery surgery, infrarenal aortic surgery, peripheral vascular surgery, and the preoperative evaluation of vascular surgical patients.

Dual spatio-temporal regulation of axon growth and microtubule dynamics by RhoA signaling pathways.

RhoA plays a crucial role in neuronal polarization, where its action restraining axon outgrowth has been thoroughly studied. We now report that RhoA has not only inhibitory but also a stimulatory effect on axon development depending on when and where exerts its action and the downstream effectors involved. In cultured hippocampal neurons, FRET imaging revealed that RhoA activity selectively localizes in growth cones of undifferentiated neurites, while in developing axons it displays a biphasic pattern, being low in nascent axons and high in elongating ones. RhoA-Rho kinase (ROCK) signaling prevents axon initiation but has no effect on elongation, while formin inhibition reduces axon extension without significantly altering initial outgrowth. Besides, RhoA-mDia promotes axon elongation by stimulating growth cone microtubule stability and assembly, as opposed to RhoA-ROCK that restrains growth cone microtubule assembly and protrusion.

Preferences and perceptions of 617 migraine patients on acute and preventive migraine treatment attributes and clinical trial endpoints.

BACKGROUND: To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important. DESIGN AND METHODS: The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used. RESULTS: Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients' needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

Proactive cursorial and ambush predation risk avoidance in four African herbivore species.

Most herbivores must balance demands to meet nutritional requirements, maintain stable thermoregulation and avoid predation. Species-specific predator and prey characteristics determine the ability of prey to avoid predation and the ability of predators to maximize hunting success. Using GPS collar data from African wild dogs, lions, impala, tsessebes, wildebeest and zebra in the Okavango Delta, Botswana, we studied proactive predation risk avoidance by herbivores. We considered predator activity level in relation to prey movement, predator and prey habitat selection, and preferential use of areas by prey. We compared herbivore behaviour to lion and wild dog activity patterns and determined the effect of seasonal resource availability and prey body mass on anti-predator behaviour. Herbivore movement patterns were more strongly correlated with lion than wild dog activity. Habitat selection by predators was not activity level dependent and, while prey and predators differed to some extent in their habitat selection, there were also overlaps, probably caused by predators seeking habitats with high prey abundance. Areas favoured by lions were used by herbivores more when lions were less active, whereas wild dog activity level was not correlated with prey use. Prey body mass was not a strong predictor of the strength of proactive predation avoidance behaviour. Herbivores showed stronger anti-predator behaviours during the rainy season when resources were abundant. Reducing movement when top predators are most active and avoiding areas with a high likelihood of predator use during the same periods appear to be common strategies to minimize predation risk. Such valuable insights into predator-prey dynamics are only possible when using similar data from multiple sympatric species of predator and prey, an approach that should become more prevalent given the ongoing integration of technological methods into ecological studies.

One-year limb salvage and quality of life following mechanical aspiration thrombectomy in patients with acute lower extremity ischemia.

OBJECTIVE: Lower extremity acute limb ischemia (LE-ALI) is associated with high morbidity and mortality rates, and a burden on patient quality of life (QoL). There is limited medium- to long-term evidence on mechanical aspiration thrombectomy (MT) in patients with LE-ALI. The STRIDE study was designed to assess safety and efficacy of MT using the Indigo Aspiration System in patients with LE-ALI. Thirty-day primary and secondary endpoints and additional outcomes were previously published. Here, we report 365-day secondary endpoints and QoL data from STRIDE. METHODS: STRIDE was a multicenter, prospective, single-arm, observational cohort study that enrolled 119 patients across 16 sites in the United States and Europe. Patients were treated first-line with MT using the Indigo Aspiration System (Penumbra, Inc). The study completed follow-up in October 2023. Secondary endpoints at 365 days included target limb salvage and mortality. Additionally, the VascuQoL-6 questionnaire, developed for evaluating patient-centered QoL outcomes for peripheral arterial disease, was assessed at baseline and follow-up through 365 days. RESULTS: Seventy-three percent of patients (87/119) were available for 365-day follow-up. Mean age of these patients was 65.0 ± 13.3 years, and 44.8% were female. Baseline ischemic severity was classified as Rutherford I in 12.6%, Rutherford IIa in 51.7%, and Rutherford IIb in 35.6%. In general, baseline and disease characteristics (demographics, medical history, comorbidities, target thrombus) of these patients are similar to the enrolled cohort of 119 patients. The secondary endpoints at 365 days for target limb salvage was 88.5% (77/87) and mortality rate was 12.0% (12/100). VascuQoL-6 improved across all domains, with a median total score improvement from 12.0 (interquartile range, 9.0-15.0) at baseline to 19.0 (interquartile range, 16.0-22.0) at 365 days. CONCLUSIONS: These 365-day results from STRIDE demonstrate that first-line MT with the Indigo Aspiration System for LE-ALI portray continued high target limb salvage rates and improved patient-reported QoL. These findings indicate Indigo as a safe and effective therapeutic option for LE-ALI.

Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.

The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.

Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior.

The intestine is vulnerable to chemotherapy-induced damage due to the high rate of intestinal epithelial cell (IEC) proliferation. We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced IEC damage on T cell behavior. Exposure of intestinal organoids to busulfan, fludarabine, and clofarabine induced damage-related responses affecting both the capacity to regenerate and transcriptional reprogramming. In ex vivo co-culture assays, prior intestinal organoid damage resulted in increased T cell activation, proliferation, and migration. We identified galectin-9 (Gal-9) as a key molecule released by damaged organoids. The use of anti-Gal-9 blocking antibodies or CRISPR/Cas9-mediated Gal-9 knock-out prevented intestinal organoid damage-induced T cell proliferation, interferon-gamma release, and migration. Increased levels of Gal-9 were found early after HSCT chemotherapeutic conditioning in the plasma of patients who later developed acute GVHD. Taken together, chemotherapy-induced intestinal damage can influence T cell behavior in a Gal-9-dependent manner which may provide novel strategies for therapeutic intervention.

Bioconcentration of per- and polyfluoroalkyl substances and precursors in fathead minnow tissues environmentally exposed to aqueous film-forming foam-contaminated waters.

Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with toxicity in wildlife and negative health effects in humans. Decades of fire training activity at Joint Base Cape Cod (MA, USA) incorporated the use of aqueous film-forming foam (AFFF), which resulted in long-term PFAS contamination of sediments, groundwater, and hydrologically connected surface waters. To explore the bioconcentration potential of PFAS in complex environmental mixtures, a mobile laboratory was established to evaluate the bioconcentration of PFAS from AFFF-impacted groundwater by flow-through design. Fathead minnows (n = 24) were exposed to PFAS in groundwater over a 21-day period and tissue-specific PFAS burdens in liver, kidney, and gonad were derived at three different time points. The ∑PFAS concentrations in groundwater increased from approximately 10,000 ng/L at day 1 to 36,000 ng/L at day 21. The relative abundance of PFAS in liver, kidney, and gonad shifted temporally from majority perfluoroalkyl sulfonamides (FASAs) to perfluoroalkyl sulfonates (PFSAs). By day 21, mean ∑PFAS concentrations in tissues displayed a predominance in the order of liver > kidney > gonad. Generally, bioconcentration factors (BCFs) for FASAs, perfluoroalkyl carboxylates (PFCAs), and fluorotelomer sulfonates (FTS) increased with degree of fluorinated carbon chain length, but this was not evident for PFSAs. Perfluorooctane sulfonamide (FOSA) displayed the highest mean BCF (8700 L/kg) in day 21 kidney. Suspect screening results revealed the presence of several perfluoroalkyl sulfinate and FASA compounds present in groundwater and in liver for which pseudo-bioconcentration factors are also reported. The bioconcentration observed for precursor compounds and PFSA derivatives detected suggests alternative pathways for terminal PFAS exposure in aquatic wildlife and humans. Environ Toxicol Chem 2024;00:1-12. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Do acting interns need residents? A comparison of acting intern experience on hospital medicine resident versus nonresident teams.

BACKGROUND: The clinical demands for hospitalist groups have grown at academic medical centers, without similar growth of teaching opportunities for faculty. Traditional resident teaching teams are often crowded with learners which can limit acting intern (or subintern) patient encounters. Medical students are often placed on nonresident teaching teams, although there are few studies on learner experience on a nonresident teaching team model. METHODS: To address these concerns, we created two nonresident teaching teams composed of one attending and two acting interns. We compared acting intern experience on the nonresident teaching teams to the traditional resident teams to determine if there were significant differences in student experience by reviewing course evaluation data on the two team models. RESULTS: Of the 276 students who completed the Internal Medicine Acting Internship from 2019 to 2023, 224 students (81%) completed the course evaluation. The course was highly rated, and the ratings were similar in both models demonstrating that the nonresident teaching team model is an effective option for acting interns. CONCLUSION: The nonresident teaching team model can offload crowded teaching teams, add additional acting intern experiences, and add teaching opportunities for hospital medicine attendings.

Plasma Biomarkers of Brain Injury and Their Association With Brain MRI and Cognition in Type 1 Diabetes.

OBJECTIVE: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS: Plasma amyloid-ß-40, amyloid-ß-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. RESULTS: Participants were 60 (range 44-74) years old with 38 (30-51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-ß measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001). CONCLUSIONS: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms.

Using Microfluidic Hepatic Spheroid Cultures to Assess Liver Toxicity of T-2 Mycotoxin.

The Fusarium fungi is found in cereals and feedstuffs and may produce mycotoxins, which are secondary metabolites, such as the T-2 toxin (T-2). In this work, we explored the hepatotoxicity of T-2 using microfluidic 3D hepatic cultures. The objectives were: (i) exploring the benefits of microfluidic 3D cultures compared to conventional 3D cultures available commercially (Aggrewell plates), (ii) establishing 3D co-cultures of hepatic cells (HepG2) and stellate cells (LX2) and assessing T-2 exposure in this model, (iii) characterizing the induction of metabolizing enzymes, and (iv) evaluating inflammatory markers upon T-2 exposure in microfluidic hepatic cultures. Our results demonstrated that, in comparison to commercial (large-volume) 3D cultures, spheroids formed faster and were more functional in microfluidic devices. The viability and hepatic function decreased with increasing T-2 concentrations in both monoculture and co-cultures. The RT-PCR analysis revealed that exposure to T-2 upregulates the expression of multiple Phase I and Phase II hepatic enzymes. In addition, several pro- and anti-inflammatory proteins were increased in co-cultures after exposure to T-2.