Effects of lithium isotopes on sodium/lithium co-transport and calcium efflux through the sodium/calcium/lithium exchanger in mitochondria.

The effects of lithium (Li) isotopes and their impact on biological processes have recently gained increased attention due to the significance of Li as a pharmacological agent and the potential that Li isotopic effects in neuroscience contexts may constitute a new example of quantum effects in biology. Previous studies have shown that the two Li isotopes, which differ in mass and nuclear spin, have unusual different effects in vivo and in vitro and, although some molecular targets for Li isotope fractionation have been proposed, it is not known whether those result in observable downstream neurophysiological effects. In this work we studied fluxes of Li+, sodium (Na+) and calcium (Ca2+) ions in the mitochondrial sodium/calcium/lithium exchanger (NCLX), the only transporter known with recognized specificity for Li+. We studied the effect of Li+ isotopes on Ca2+ efflux from heart mitochondria in comparison to natural Li+ and Na+ using Ca2+-induced fluorescence and investigated a possible Li isotope fractionation in mitochondria using inductively coupled plasma mass spectrometry (ICP-MS). Our fluorescence data indicate that Ca2+ efflux increases with higher concentrations of either Li+ or Na+. We found that the simultaneous presence of Li+ and Na+ increases Ca2+ efflux compared to Ca2+ efflux caused by the same concentration of Li+ alone. However, no differentiation in the Ca2+ efflux between the two Li+ isotopes was observed, either for Li+ alone or in mixtures of Li+ and Na+. Our ICP-MS data demonstrate that there is selectivity between Na+ and Li+ (greater Na+ than Li+ uptake) and, most interestingly, between the Li+ isotopes (greater 6Li+ than 7Li+ uptake) by the inner mitochondrial membrane. In summary, we observed no Li+ isotope differentiation for Ca2+ efflux in mitochondria via NCLX but found a Li+ isotope fractionation during Li+ uptake by mitochondria with NCLX active or blocked. Our results suggest that the transport of Li+ via NCLX is not the main pathway for Li+ isotope fractionation and that this differentiation does not affect Ca2+ efflux in mitochondria. Therefore, explaining the puzzling effects of Li+ isotopes observed in other contexts will require further investigation to identify the molecular targets for Li+ isotope differentiation.

Utilizing Post-Clerkship Surveys to Optimize Emergency Medicine Program Outcomes in the Match.

Purpose: The Match for Emergency Medicine residency has presented new challenges over the past 2 years (2022-2023). Use of a post-clerkship survey given to clerkship students could improve outcomes in The Match by helping the program identify its different strengths and weaknesses. Methods: A post-clerkship survey, sent after The Match, was sent to Emergency Medicine bound students who completed our Emergency Medicine clerkship. This data was then collected and analyzed and, in collaboration with our faculty and residents, changes were made to the clerkship and residency program with the intention that these changes would improve our program and therefore our competitiveness in the upcoming cycle of The Match. These changes were analyzed in the subsequent post-clerkship survey. The survey included questions that asked students to reflect on their experiences with various aspects of the program and how these experiences influenced their personal ranking of our program compared to other emergency medicine residency programs they might have interacted with. Results: Results from the initial post-clerkship survey revealed that students found our faculty and residents (55% ranked higher), County hospital (55% ranked higher), and SLOE transparency (64% ranked higher) as the main aspects of our program that led them to rank the program higher. Living in Lubbock, TX was found to be the biggest drawback for students, with 55% ranking our program lower. The 2023 post-clerkship survey revealed that the changes we made to our clerkship and program were effective, with an overall decrease of 10 points in students who ranked our program lower based on "Living in Lubbock, TX". We also were able to keep 4 of our rotators, as opposed to 2 the year before. Lastly, we also did not need to go as far down our rank list in the 2023 cycle of The Match. Conclusion: Using a post-clerkship survey to evaluate strengths and weaknesses of a program through a student's perspective can be an effective tool to help programs in their outcomes from The Match. Further study is necessary to validate these findings.

Lithium isotopes differentially modify mitochondrial amorphous calcium phosphate cluster size distribution and calcium capacity.

Lithium is commonly prescribed as a mood stabilizer in a variety of mental health conditions, yet its molecular mode of action is incompletely understood. Many cellular events associated with lithium appear tied to mitochondrial function. Further, recent evidence suggests that lithium bioactivities are isotope specific. Here we focus on lithium effects related to mitochondrial calcium handling. Lithium protected against calcium-induced permeability transition and decreased the calcium capacity of liver mitochondria at a clinically relevant concentration. In contrast, brain mitochondrial calcium capacity was increased by lithium. Surprisingly, 7Li acted more potently than 6Li on calcium capacity, yet 6Li was more effective at delaying permeability transition. The size distribution of amorphous calcium phosphate colloids formed in vitro was differentially affected by lithium isotopes, providing a mechanistic basis for the observed isotope specific effects on mitochondrial calcium handling. This work highlights a need to better understand how mitochondrial calcium stores are structurally regulated and provides key considerations for future formulations of lithium-based therapeutics.

Cascade electrocatalysis via AgCu single-atom alloy and Ag nanoparticles in CO2 electroreduction toward multicarbon products.

Electrocatalytic CO2 reduction into value-added multicarbon products offers a means to close the anthropogenic carbon cycle using renewable electricity. However, the unsatisfactory catalytic selectivity for multicarbon products severely hinders the practical application of this technology. In this paper, we report a cascade AgCu single-atom and nanoparticle electrocatalyst, in which Ag nanoparticles produce CO and AgCu single-atom alloys promote C-C coupling kinetics. As a result, a Faradaic efficiency (FE) of 94 ± 4% toward multicarbon products is achieved with the as-prepared AgCu single-atom and nanoparticle catalyst under ~720 mA cm-2 working current density at -0.65 V in a flow cell with alkaline electrolyte. Density functional theory calculations further demonstrate that the high multicarbon product selectivity results from cooperation between AgCu single-atom alloys and Ag nanoparticles, wherein the Ag single-atom doping of Cu nanoparticles increases the adsorption energy of *CO on Cu sites due to the asymmetric bonding of the Cu atom to the adjacent Ag atom with a compressive strain.

Technical comment on "Reexamination of 2.5-Ga 'whiff' of oxygen interval points to anoxic ocean before GOE".

Many lines of inorganic geochemical evidence suggest transient "whiffs" of environmental oxygenation before the Great Oxidation Event (GOE). Slotznick et al. assert that analyses of paleoredox proxies in the Mount McRae Shale, Western Australia, were misinterpreted and hence that environmental O2 levels were persistently negligible before the GOE. We find these arguments logically flawed and factually incomplete.

Global ocean redox changes before and during the Toarcian Oceanic Anoxic Event.

Mesozoic oceanic anoxic events are recognized as widespread deposits of marine organic-rich mudrocks temporally associated with mass extinctions and large igneous province emplacement. The Toarcian Oceanic Anoxic Event is one example during which expanded ocean anoxia is hypothesized in response to environmental perturbations associated with emplacement of the Karoo-Ferrar igneous province. However, the global extent of total seafloor anoxia and the relative extent of euxinic (anoxic and sulfide-rich) and non-euxinic anoxic conditions during the Toarcian Oceanic Anoxic Event are poorly constrained. Here we present estimates of the global total anoxic and euxinic seafloor areas before and during the Toarcian Oceanic Anoxic Event based on rhenium and molybdenum enrichments, respectively, in organic-rich mudrocks of the Fernie Formation (British Columbia, Canada). We find that mass balance models depict an expansion of up to ~7% total seafloor anoxia, which was dominated by euxinia, at the onset of the Toarcian Oceanic Anoxic Event, followed by a contraction before the end of the event. The global ocean redox trends revealed by the rhenium data mirrors the collapse and recovery patterns of global ammonite and foraminiferal biodiversity.

Impact of a Laboratory-Developed Phenotypic Rapid Susceptibility Test Directly From Positive Blood Cultures on Time to Narrowest Effective Therapy in Patients With Gram-Negative Bacteremia: A Prospective Randomized Trial.

Background: Antimicrobial susceptibility testing (AST) is often needed prior to antimicrobial optimization for patients with gram-negative bloodstream infections (GN-BSIs). Rapid AST (rAST) in combination with antimicrobial stewardship (AS) may decrease time to administration of narrower antibiotics. Methods: This was a prospective, nonblinded, randomized trial evaluating the impact of a phenotypic rAST method vs conventional AST (cAST) in hospitalized patients with GN-BSI and source control. The primary outcome was time to narrowest effective therapy. Results: Two hundred seventy-four patients were randomized and 205 underwent analysis (97 cAST, 108 rAST). Median (interquartile range [IQR]) time to susceptibility results was 23 hours shorter in the rAST group (cAST: 62 [59-67] hours vs rAST: 39 [IQR, 35-46] hours; P < .001). Median (IQR) time to narrowest effective therapy was similar between groups (cAST: 73 [44-138] hours vs rAST: 64 [42-92] hours; P = .10). Median (IQR) time to narrowest effective therapy was significantly shorter in a prespecified subgroup of patients not initially on narrowest therapy and during AS working hours (cAST: 93 [56-154] hours vs rAST: 62 [43-164] hours; P = .004). Significant decreases were observed in median (IQR) time to oral therapy (cAST: 126 [76-209] hours vs rAST: 91 [66-154] hours; P = .02) and median (IQR) length of hospital stay (cAST: 7 [4-13] days vs rAST: 5 [4-8] days; P = .04). Conclusions: In patients with GN-BSI, rAST did not significantly decrease time to narrowest effective therapy but did decrease time to oral antibiotics and length of hospital stay. Rapid AST using existing microbiology platforms has potential to optimize patient outcomes.

Fully oxygenated water columns over continental shelves before the Great Oxidation Event.

Late Archaean sedimentary rocks contain compelling geochemical evidence for episodic accumulation of dissolved oxygen in the oceans along continental margins before the Great Oxidation Event. However, the extent of this oxygenation remains poorly constrained. Here we present thallium and molybdenum isotope compositions for anoxic organic-rich shales of the 2.5 billion-year-old Mount McRae Shale from Western Australia, which previously yielded geochemical evidence of a transient oxygenation event. During this event, we observe an anti-correlation between thalium and molybdenum isotope data, including two shifts to higher molybdenum and lower thalium isotope compositions. Our data indicate pronounced burial of manganese oxides in sediments elsewhere in the ocean at these times, which requires that water columns above portions of the ocean floor were fully oxygenated: all the way from the air-sea interface to well below the sediment-water interface. Well-oxygenated continental shelves were likely the most important sites of manganese oxide burial and mass-balance modeling results suggest that fully oxygenated water columns were at least a regional-scale feature of early-Earth's oceans 2.5 billion years ago.

Extensive marine anoxia during the terminal Ediacaran Period.

The terminal Ediacaran Period witnessed the decline of the Ediacara biota (which may have included many stem-group animals). To test whether oceanic anoxia might have played a role in this evolutionary event, we measured U isotope compositions (δ238U) in sedimentary carbonates from the Dengying Formation of South China to obtain new constraints on the extent of global redox change during the terminal Ediacaran. We found the most negative carbonate δ238U values yet reported (-0.95 per mil), which were reproduced in two widely spaced coeval sections spanning the terminal Ediacaran Period (551 to 541 million years ago). Mass balance modeling indicates an episode of extensive oceanic anoxia, during which anoxia covered >21% of the seafloor and most U entering the oceans was removed into sediments below anoxic waters. The results suggest that an expansion of oceanic anoxia and temporal-spatial redox heterogeneity, independent of other environmental and ecological factors, may have contributed to the decline of the Ediacara biota and may have also stimulated animal motility.

Pleural Effusion Caused by Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer.

Intravesical bacillus Calmette Guérin (BCG) instillation has been used as immunotherapy for early stage bladder cancer for >40 years. Complications from this therapy are rare but may result in a spectrum of infectious sequelae. Here we describe the case of an elderly man who presented with a pleural effusion and subcutaneous nodule several years after treatment with BCG.

Filamentous Fungi.

Filamentous mycoses are often associated with significant morbidity and mortality. Prompt diagnosis and aggressive treatment are essential for good clinical outcomes in immunocompromised patients. The host immune response plays an essential role in determining the course of exposure to potential fungal pathogens. Depending on the effectiveness of immune response and the burden of organism exposure, fungi can either be cleared or infection can occur and progress to a potentially fatal invasive disease. Nonspecific cellular immunity (i.e., neutrophils, natural killer [NK] cells, and macrophages) combined with T-cell responses are the main immunologic mechanisms of protection. The most common potential mold pathogens include certain hyaline hyphomycetes, endemic fungi, the Mucorales, and some dematiaceous fungi. Laboratory diagnostics aimed at detecting and differentiating these organisms are crucial to helping clinicians make informed decisions about treatment. The purpose of this chapter is to provide an overview of the medically important fungal pathogens, as well as to discuss the patient characteristics, antifungal-therapy considerations, and laboratory tests used in current clinical practice for the immunocompromised host.

Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children.

INTRODUCTION: Pneumococcal conjugate vaccines (PCV) have indirect effects due to decreased Streptococcus pneumoniae colonization in vaccine recipients. We sought to determine whether the introduction of PCV13 in children led to changes in the epidemiology and clinical manifestations of invasive pneumococcal disease (IPD) in adults. METHODS: We described demographics, comorbidities, clinical manifestations, and serotypes of IPD in Utah adults before (November 2009-February 2010) and after (March 2010-March 2012) the introduction of PCV13 in children. We also compare serotypes causing IPD in Utah adults and children. RESULTS: After the introduction of PCV13 in the childhood vaccine program, the proportion of IPD due to PCV13 exclusive serotypes decreased significantly in Utah adults (64-40%, p=0.009), primarily due to a decline in serotype 7F (36-15%, p=0.008). There were non-significant increases in IPD due to Pneumococcal polysaccharide 23 (PPV23) unique serotypes and non-vaccine serotypes, most notably serotype 22F. Changes in the proportions of vaccine and non-vaccine serotypes were similar in adults and children. Meningitis was more commonly due to non-vaccine serotypes relative to non-meningitis cases (47% vs. 18%, p=0.007). When stratified by sex, decreases in PCV13 serotype IPD were only noted in men (76-33%, p=0.001). CONCLUSIONS: Serotype epidemiology of IPD in adults closely follows that of children in the PCV13 era. Continued surveillance is needed to confirm whether replacement serotypes will lead to increases in pneumococcal meningitis and whether there are sex differences in the indirect effects of PCV vaccination in children.

Transient episodes of mild environmental oxygenation and oxidative continental weathering during the late Archean.

It is not known whether environmental O2 levels increased in a linear fashion or fluctuated dynamically between the evolution of oxygenic photosynthesis and the later Great Oxidation Event. New rhenium-osmium isotope data from the late Archean Mount McRae Shale, Western Australia, reveal a transient episode of oxidative continental weathering more than 50 million years before the onset of the Great Oxidation Event. A depositional age of 2495 ± 14 million years and an initial (187)Os/(188)Os of 0.34 ± 0.19 were obtained for rhenium- and molybdenum-rich black shales. The initial (187)Os/(188)Os is higher than the mantle/extraterrestrial value of 0.11, pointing to mild environmental oxygenation and oxidative mobilization of rhenium, molybdenum, and radiogenic osmium from the upper continental crust and to contemporaneous transport of these metals to seawater. By contrast, stratigraphically overlying black shales are rhenium- and molybdenum-poor and have a mantle-like initial (187)Os/(188)Os of 0.06 ± 0.09, indicating a reduced continental flux of rhenium, molybdenum, and osmium to seawater because of a drop in environmental O2 levels. Transient oxygenation events, like the one captured by the Mount McRae Shale, probably separated intervals of less oxygenated conditions during the late Archean.

Disseminated Mycobacterial Infection After International Medical Tourism.

International travel for the purpose of receiving medical care is increasing. We report a case of disseminated mycobacterial infection after fetal stem cell infusion.

Evaluation of Outpatient Parenteral Antimicrobial Therapy at a Veterans Affairs Hospital.

We reviewed outpatient parenteral antimicrobial therapy at a Veterans Affairs Medical Center to identify opportunities for antimicrobial stewardship intervention. A definite or possible modification would have been recommended in 60% of courses. Forty-one percent of outpatient parenteral antimicrobial therapy courses were potentially avoidable, including 22% involving infectious diseases consultation.

Update on the epidemiology of pulmonary nontuberculous mycobacterial infections.

For decades, the incidence of pulmonary nontuberculous mycobacteria (NTM) has been reported to be increasing, yet formal epidemiological evaluation of this notion has been lacking until recently. Defining the epidemiology of NTM has been more challenging than with Mycobacterium tuberculosis (MTB). Unlike MTB, NTM are soil and water organisms, and infection is thought to be acquired from the environment rather than transmitted from person-to-person, with very rare exceptions. Due to their nearly ubiquitous presence in municipal water supplies, exposure to NTM is common. Further, NTM can colonize the respiratory tract without causing disease. NTM disease is not reportable to public health authorities; therefore, epidemiological and surveillance data are not readily available. Nonetheless, the prevalence of pulmonary NTM disease has increased dramatically in the United States and globally over the past 3 decades. Mycobacterium avium complex (MAC) accounts for the majority of NTM infections worldwide, but there is significant regional variability of various species. Additionally, novel species have been implicated in several countries in NTM pulmonary disease.