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BACKGROUND: Digital cognitive assessments, particularly those that can be done at home, present as low-burden biomarkers for participants and patients alike, but their effectiveness in the diagnosis of Alzheimer's disease (AD) or predicting its trajectory is still unclear. Here, we assessed what utility or added value these digital cognitive assessments provide for identifying those at high risk of cognitive decline. METHODS: We analyzed >500 Alzheimer's Disease Neuroimaging Initiative participants who underwent a brief digital cognitive assessment and amyloid beta (Aß)/tau positron emission tomography scans, examining their ability to distinguish cognitive status and predict cognitive decline. RESULTS: Performance on the digital cognitive assessment was superior to both cortical Aß and entorhinal tau in detecting mild cognitive impairment and future cognitive decline, with mnemonic discrimination deficits emerging as the most critical measure for predicting decline and future tau accumulation. DISCUSSION: Digital assessments are effective at identifying at-risk individuals, supporting their utility as low-burden tools for early AD detection and monitoring. HIGHLIGHTS: Performance on digital cognitive assessments predicts progression to mild cognitive impairment at a higher proficiency compared to amyloid beta and tau. Deficits in mnemonic discrimination are indicative of future cognitive decline. Impaired mnemonic discrimination predicts future entorhinal and inferior temporal tau.

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BACKGROUND: The Mnemonic Similarity Task (MST) is a popular memory task designed to assess hippocampal integrity. We assessed whether analyzing MST performance using a multinomial processing tree (MPT) cognitive model could detect individuals with elevated Alzheimer's disease (AD) biomarker status prior to cognitive decline. METHOD: We analyzed MST data from >200 individuals (young, cognitively healthy older adults and individuals with mild cognitive impairment [MCI]), a subset of which also had existing cerebrospinal fluid (CSF) amyloid beta (Aß) and phosphorylated tau (pTau) data using both traditional and model-derived approaches. We assessed how well each could predict age group, memory ability, MCI status, Aß, and pTau status using receiver operating characteristic analyses. RESULTS: Both approaches predicted age group membership equally, but MPT-derived metrics exceeded traditional metrics in all other comparisons. DISCUSSION: A MPT model of the MST can detect individuals with AD prior to cognitive decline, making it a potentially useful tool for screening and monitoring older adults during the asymptomatic phase of AD. HIGHLIGHTS: The MST, along with cognitive modeling, identifies individuals with memory deficits and cognitive impairment. Cognitive modeling of the MST identifies individuals with increased AD biomarkers prior to changes in cognitive function. The MST is a digital biomarker that identifies individuals at high risk of AD.

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Denitrification is a key metabolic process in the global nitrogen cycle and is performed by taxonomically diverse microorganisms. Despite the widespread importance of this metabolism, challenges remain in identifying denitrifying populations and predicting their metabolic end-products based on their genotype. Here, genome-resolved metagenomics was used to explore the denitrification genotype of Bacillota enriched in nitrate-amended high temperature incubations with confirmed N2O and N2 production. A set of 12 hidden Markov models (HMMs) was created to target the diversity of denitrification genes in members of the phylum Bacillota. Genomic potential for complete denitrification was found in five metagenome-assembled genomes from nitrate-amended enrichments, including two novel members of the Brevibacillaceae family. Genomes of complete denitrifiers encode N2O reductase gene clusters with clade II-type nosZ and often include multiple variants of the nitric oxide reductase gene. The HMM set applied to all genomes of Bacillota from the Genome Taxonomy Database identified 17 genera inferred to contain complete denitrifiers based on their gene content. Among complete denitrifiers it was common for three distinct nitric oxide reductases to be present (qNOR, bNOR, and sNOR) that may reflect the metabolic adaptability of Bacillota in environments with variable redox conditions.

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The ligands tris(8-quinolyl)stibine and tris(6-methyl-8-quinolyl)stibine have been synthesized and complexed to rhodium using (MeCN)3RhCl3. The resulting complexes feature an unusual [RhSb]VI core as a result of the formal insertion of the antimony center into one of the Rh-Cl bonds. Computational analysis using density functional theory (DFT) methods reveals that the resulting Rh-Sb σ bond is polarized toward the Rh atom, suggesting a description of this linkage as a Rh → Sb Z-type interaction.

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A series of metal-organic frameworks (1-XDI) have been synthesized by imide condensation reactions between an amine-functionalized pentanuclear zinc cluster, Zn4Cl5(bt-NH2)6, (bt-NH2 = 5-aminobenzotriazolate), and organic dianhydrides (pyromellitic dianhydride (PMDA), naphthalenetetracarboxylic dianhydride (NDA), 3,3',4,4'-biphenyltetracarboxylic dianhydride (BPDA) and 4,4'-(hexafluoroisopropylidene)diphthalic anhydride (HFIPA)). The properties of the 1-XDI MOFs have been compared with analogues (2-XDI) prepared using traditional coordination assembly. The resulting materials have been characterized by ATR-IR spectroscopy, acid-digested 1H NMR spectroscopy, elemental analysis, and gas adsorption measurements. N2 adsorption isotherm data reveal modest porosities and BET surface areas (30-552 m2 g-1). All of the new 1-XDI and 2-XDI MOFs show selective adsorption of C2H2 over CO2 while 2-PMDI and 2-BPDI exhibit high selectivity toward C3H6/C3H8 separation. This study establishes imide condensation of preformed metal-organic clusters with organic linkers as a viable route for MOF design.

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In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.

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Cerebral amyloid-beta (Aß) accumulation, a hallmark pathology of Alzheimer's disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aß contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of Aß deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aß deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aß-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aß pathology would be selectively associated with temporal discrimination performance due to Aß's propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aß-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher Aß-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aß accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and may serve as a sensitive behavioral biomarker of emerging AD progression.

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African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12 mg, respectively. Of 34,542 identified variants across 99 genes, 1406 variants were suggestively associated with TAC troughs in univariate models (p-value < 0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome.

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BACKGROUND: The unprecedented COVID-19 pandemic has highlighted the strategic value of wastewater-based surveillance (WBS) of SARS-CoV-2. This multisite 28-month-long study focused on WBS for older residents in 12 long-term care facilities (LTCFs) in Edmonton (AB, Canada) by assessing relationships between COVID-19, WBS, and serostatus during the pandemic. METHODS: Wastewater samples collected two to three times per week were tested for SARS-CoV-2 using RT-quantitative PCR. The serostatus of antibodies was examined using immunoassays. The data of clinical COVID-19 outbreaks based on extensive testing were obtained from local public health officials. Analyses included calculating correlations between 7-day rolling averages for WBS and COVID-19 cases and investigating whether WBS led or lagged confirmed outbreaks using a multinomial test. FINDINGS: Wastewater results correlated well with clinical COVID-19 infections and outbreaks at participating LTCFs. 1058 (36·0%) of 2936 collected wastewater samples were SARS-CoV-2 positive, compared with 1247 people (resident n=671, staff n=572, and unknown n=4) reporting positive test results of 21 673 clinical samples assessed (5·8%). WBS led clinical testing in 32 (60·4%) confirmed outbreaks, which was significantly different from WBS lagged (12 outbreaks [22·6%, 95% CI 11·3-33·7]). Non-detection of WBS SARS-CoV-2 served as a negative predictor for outbreaks. WBS results attested protective immunity in vaccinated individuals before the omicron wave. A parallel increase in the proportions of positive WBS SARS-CoV-2 and anti-nucleocapsid antibodies underlined that omicron was an immunity-evading variant despite high seropositivity of neutralising antibodies after multiple doses of vaccine. INTERPRETATION: Implementation of WBS could enable targeted clinical investigations and improve cost-effectiveness of COVID-19 outbreak management in LTCFs. WBS and serostatus provided informed dynamic changes of infections and immunity. Critical evidence was that LTCF WBS is an effective early warning system to support rapid public health outbreak management and protect vulnerable older populations. FUNDING: Canadian Immunity Task Force for COVID-19 and Alberta Health.

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The transplantation of organ(s) across species may alleviate the shortage of available donor kidneys for an ever-growing number of patients on transplant waiting lists. However, this potential remains limited by uncharacterized physiologic and immune effects of xenotransplants in recipients, which Pan et al.1 investigated in the current study.

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As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain's susceptibility to the effects of aging. As such, non-human primates are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary non-human primate model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical working memory task. Our results demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, highlighting the value of the marmoset as a model for cognitive aging research within the neuroscience community.

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The voltage penalty driving water dissociation (WD) at high current density is a major obstacle in the commercialization of bipolar membrane (BPM) technology for energy devices. Here we show that three materials descriptors, that is, electrical conductivity, microscopic surface area and (nominal) surface-hydroxyl coverage, effectively control the kinetics of WD in BPMs. Using these descriptors and optimizing mass loading, we design new earth-abundant WD catalysts based on nanoparticle SnO2 synthesized at low temperature with high conductivity and hydroxyl coverage. These catalysts exhibit exceptional performance in a BPM electrolyser with low WD overvoltage (ηwd) of 100 ± 20 mV at 1.0 A cm-2. The new catalyst works equivalently well with hydrocarbon proton-exchange layers as it does with fluorocarbon-based Nafion, thus providing pathways to commercializing advanced BPMs for a broad array of electrolysis, fuel-cell and electrodialysis applications.

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This study aimed to compare patient outcomes between prescribing psychologists, psychiatrists, and primary care physicians (PCPs). Private insurance claims (2005-2021; n = 307,478) were used to conduct an active comparator, new user longitudinal cohort study developed using target trial emulation. Inverse propensity for treatment weighting was used to adjust for baseline differences in a range of sociodemographic, clinical, and contextual patient factors. Differences in the 1-year rate of health care visits for adverse drug events (ADEs), psychiatric emergency department (ED) utilization, medication adherence, and psychotropic polypharmacy were identified between prescribing psychologists and the other provider types using doubly robust Cox proportional hazards models. Compared to patients of psychiatrists, patients of prescribing psychologists had a 24% lower rate of ADEs (95% CI [0.60, 0.96]), a 20% lower rate of psychotropic polypharmacy (95% CI [0.74, 0.86]), and similar rates of psychiatric ED utilization and medication nonadherence. Compared to patients of PCPs, patients of prescribing psychologists had 138% higher rates of psychiatric ED utilization (95% CI [1.67, 3.39]), 175% higher rates of psychotropic polypharmacy (95% CI [2.53, 2.99]), 28% lower rates of medication nonadherence (95% CI [0.66, 0.78]), and similar rates of ADEs. Using robust pharmacoepidemiological methods, we noted that among mental health specialists, prescribing psychologists appear to be as safe and efficacious as psychiatrists in a large sample of privately insured patients. Notable differences in safety and efficacy when compared to PCPs may be attributable to differences between specialty and primary care. Future research on prescribing psychologists should move toward studies of care quality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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BACKGROUND: Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR). This study is the first to evaluate LSSs models performance in the context of EHR. METHODS: Adult kidney transplant recipients (n = 84) receiving oral mycophenolate mofetil underwent intensive MPA pharmacokinetic sampling. MPA AUC0-12hr and EHR were determined. Published MPA LSSs in kidney transplant recipients receiving tacrolimus were evaluated for their predictive performance in estimating AUC0-12hr in our full cohort and separately in individuals with high and low EHR. RESULTS: None of the evaluated LSS models (n = 12) showed good precision or accuracy in predicting MPA AUC0-12hr in the full cohort. In the high EHR group, models with late timepoints had better accuracy but low precision, except for 1 model with late timepoints at 6 and 10 hours postdose, which had marginally acceptable precision. For all models, the good guess of predicted AUC0-12hr (±15% of observed AUC0-12hr) was highly variable (range, full cohort = 19%-61.9%; high EHR = 4.5%-65.9%; low EHR = 27.5%-62.5%). CONCLUSIONS: The predictive performance of the LSS models varied according to EHR status. Timepoints ≥5 hours postdose in LSS models are essential to capture EHR. Models and strategies that incorporate EHR during development are required to accurately ascertain MPA exposure.

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BACKGROUND: Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic ß cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and ß cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate ß cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. METHODS: To further explore the role of nephrin YDxV phosphorylation in ß cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. RESULTS: Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. CONCLUSION: Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve ß cell function.

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Digital cognitive assessments, particularly those that can be done at home, present as low burden biomarkers for participants and patients alike, but their effectiveness in diagnosis of Alzheimer's or predicting its trajectory is still unclear. Here, we assessed what utility or added value these digital cognitive assessments provide for identifying those at high risk for cognitive decline. We analyzed >500 ADNI participants who underwent a brief digital cognitive assessment and Aß/tau PET scans, examining their ability to distinguish cognitive status and predict cognitive decline. Performance on the digital cognitive assessment were superior to both cortical Aß and entorhinal tau in detecting mild cognitive impairment and future cognitive decline, with mnemonic discrimination deficits emerging as the most critical measure for predicting decline and future tau accumulation. Digital assessments are effective in identifying at-risk individuals, supporting their utility as low-burden tools for early Alzheimer's detection and monitoring.

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Advancing age is associated with decreased sensitivity to temporal cues in word segments, particularly when target words follow non-informative carrier sentences or are spectrally degraded (e.g., vocoded to simulate cochlear-implant stimulation). This study investigated whether age, carrier sentences, and spectral degradation interacted to cause undue difficulty in processing speech temporal cues. Younger and older adults with normal hearing performed phonemic categorization tasks on two continua: a Buy/Pie contrast with voice onset time changes for the word-initial stop and a Dish/Ditch contrast with silent interval changes preceding the word-final fricative. Target words were presented in isolation or after non-informative carrier sentences, and were unprocessed or degraded via sinewave vocoding (2, 4, and 8 channels). Older listeners exhibited reduced sensitivity to both temporal cues compared to younger listeners. For the Buy/Pie contrast, age, carrier sentence, and spectral degradation interacted such that the largest age effects were seen for unprocessed words in the carrier sentence condition. This pattern differed from the Dish/Ditch contrast, where reducing spectral resolution exaggerated age effects, but introducing carrier sentences largely left the patterns unchanged. These results suggest that certain temporal cues are particularly susceptible to aging when placed in sentences, likely contributing to the difficulties of older cochlear-implant users in everyday environments.

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Muscle-damaging exercise (e.g., downhill running [DHR]) or heat exposure bouts potentially reduce physiological and/or cellular stress during future exertional heat exposure; however, the true extent of their combined preconditioning effects is unknown. Therefore, this study investigated the effect of muscle-damaging exercise in the heat on reducing physiological and cellular stress during future exertional heat exposure. Ten healthy males (mean ± Standard Definition; age, 23 ± 3 years; body mass, 78.7 ± 11.5 kg; height, 176.9 ± 4.7 cm) completed this study. Participants were randomly assigned into two preconditioning groups: (a) DHR in the heat (ambient temperature [Tamb], 35 °C; relative humidity [RH], 40%) and (b) DHR in thermoneutral (Tamb, 20 °C; RH, 20%). Seven days following DHR, participants performed a 45-min flat run in the heat (FlatHEAT [Tamb, 35 °C; RH, 40%]). During exercise, heart rate and rectal temperature (Trec) were recorded at baseline and every 5-min. Peripheral blood mononuclear cells were isolated to assess heat shock protein 72 (Hsp72) concentration between conditions at baseline, immediately post-DHR, and immediately pre-FlatHEAT and post-FlatHEAT. Mean Trec during FlatHEAT between hot (38.23 ± 0.38 °C) and thermoneutral DHR (38.26 ± 0.38 °C) was not significantly different (P = 0.68), with no mean heart rate differences during FlatHEAT between hot (172 ± 15 beats min-1) and thermoneutral conditions (174 ± 8 beats min-1; P = 0.58). Hsp72 concentration change from baseline to immediately pre-FlatHEAT was significantly lower in hot (-51.4%) compared to thermoneutral (+24.2%; P = 0.025) DHR, with Hsp72 change from baseline to immediately post-FlatHEAT also lower in hot (-52.6%) compared to thermoneutral conditions (+26.3%; P = 0.047). A bout of muscle-damaging exercise in the heat reduces cellular stress levels prior to and immediately following future exertional heat exposure.

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To describe the characteristics of patients receiving psychotropic medication from prescribing psychologists, psychiatrists, and primary care physicians. This descriptive study was conducted using private insurance claims of patients from New Mexico and Louisiana receiving psychotropic medications (anticonvulsants, antidepressants, antipsychotics, hypotensive agents, anxiolytics/sedatives/hypnotics, and stimulants) from 2004 to 2021 (N = 307,478). Patient characteristics were captured during the 6 months prior to their first psychotropic medication using administrative information, diagnosis and procedure codes, and medication data. Logistic regression models estimated the associations of patient characteristics with prescriber type. Additional logistic regression models estimated the association of prescriber type with medication classes prescribed. Patients were most likely to see specialists (psychologists or psychiatrists) if they had bipolar disorder (average marginal effect and 95% CI 0.214 [0.196, 0.231]), schizophrenia/psychotic disorders (0.118 [0.097, 0.138]), or had 1-4 visits of psychotherapy (0.267 [0.258, 0.026]). Specialist patients were most likely to see a prescribing psychologist if they had 1-4 visits of psychotherapy (0.196 [0.183, 0.210]) or had insomnia (0.309 [0.203, 0.415]). Prescribing psychologists were more likely to prescribe antidepressants (0.028 [0.011, 0.045]) and less likely to prescribe antipsychotics (-0.016 [-0.020, -0.012]) than psychiatrists. Primary care physicians were less likely to prescribe all psychotropic medications except antidepressants (0.011 [0.002, 0.019]) and anxiolytics (0.074 [0.067, 0.080]). Prescribing psychologists treat patients who are more similar to those of psychiatrists than patients of primary care physicians; they are less likely to prescribe antipsychotics and more likely to prescribe antidepressants. (PsycInfo Database Record (c) 2024 APA, all rights reserved).