Encoding a magic state with beyond break-even fidelity.

To run large-scale algorithms on a quantum computer, error-correcting codes must be able to perform a fundamental set of operations, called logic gates, while isolating the encoded information from noise1-8. We can complete a universal set of logic gates by producing special resources called magic states9-11. It is therefore important to produce high-fidelity magic states to conduct algorithms while introducing a minimal amount of noise to the computation. Here we propose and implement a scheme to prepare a magic state on a superconducting qubit array using error correction. We find that our scheme produces better magic states than those that can be prepared using the individual qubits of the device. This demonstrates a fundamental principle of fault-tolerant quantum computing12, namely, that we can use error correction to improve the quality of logic gates with noisy qubits. Moreover, we show that the yield of magic states can be increased using adaptive circuits, in which the circuit elements are changed depending on the outcome of mid-circuit measurements. This demonstrates an essential capability needed for many error-correction subroutines. We believe that our prototype will be invaluable in the future as it can reduce the number of physical qubits needed to produce high-fidelity magic states in large-scale quantum-computing architectures.

Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses.

Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.

NUDC is critical for rod photoreceptor function, maintenance, and survival.

NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC-/- ). Loss of NUDC in rods led to complete photoreceptor cell death at 6 weeks of age. By 3 weeks of age, rNudC-/- function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC-/- by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. The absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor.

The clinical effectiveness of Fidaxomicin compared to Vancomycin in the treatment of Clostridioides difficile infection, a single center real-world experience.

BACKGROUND: The use of fidaxomicin is recommended as first line therapy for all patients with Clostridioides difficile infection (CDI). However, real-world studies have shown conflicting evidence of superiority. METHODS: We conducted a retrospective single center study of patients diagnosed with CDI between 2011-2021. A primary composite outcome of clinical failure, 30-day relapse or CDI-related death was used. A multivariable cause specific Cox proportional hazards model was used to evaluate fidaxomicin compared to vancomycin in preventing the composite outcome. A separate model was fit on a subset of patients with C. difficile ribotypes adjusting for ribotype. RESULTS: There were 598 patients included, of whom 84 received fidaxomicin. The primary outcome occurred in 8 (9.5%) in the fidaxomicin group compared to 111 (21.6%) in the vancomycin group. The adjusted multivariable model showed fidaxomicin was associated with 63% reduction in the risk of the composite outcome compared to vancomycin (HR = 0.37, 95% CI 0.17-0.80). In the 337 patients with ribotype data after adjusting for ribotype 027, the results showing superiority of fidaxomicin were maintained (HR = 0.19, 95% CI 0.05-0.77). CONCLUSION: In the treatment of CDI, we showed that real-world use of fidaxomicin is associated with lower risk of a composite endpoint of treatment failure.

Sympathetic Cooling and Slowing of Molecules with Rydberg Atoms.

We propose to sympathetically slow and cool polar molecules in a cold, low-density beam using laser-cooled Rydberg atoms. The elastic collision cross sections between molecules and Rydberg atoms are large enough to efficiently thermalize the molecules even in a low-density environment. Molecules traveling at 100 m/s can be stopped in under 30 collisions with little inelastic loss. Our method does not require photon scattering from the molecules and can be generically applied to complex species for applications in precision measurement, quantum information science, and controlled chemistry.

Improvement of Emergency Department Chest Pain Evaluation Using Hs-cTnT and a Risk Stratification Pathway.

BACKGROUND: Chest pain is among the most common reasons for presentation to the emergency department (ED) worldwide. Additional studies on most cost-effective ways of differentiating serious vs. benign causes of chest pain are needed. OBJECTIVES: Our study aimed to evaluate the effectiveness of a novel risk stratification pathway utilizing 5th generation high-sensitivity cardiac troponin T assay (Hs-cTnT) and HEART score (History, Electrocardiogram, Age, Risk factors, Troponin) in assessing nontraumatic chest pain patients in reducing ED resource utilization. METHODS: A retrospective chart review was performed 6 months prior to and after the implementation of a novel risk stratification pathway that combined hs-cTnT with HEART score to guide evaluation of adult patients presenting with nontraumatic chest pain at a large academic quaternary care ED. Primary outcome was ED length of stay (LOS); secondary outcomes included cardiology consult rates, admission rates, number of ED boarders, and number of eloped patients. RESULTS: A total of 1707 patients and 1529 patients were included pre- and postimplementation, respectively. Median overall ED LOS decreased from 317 to 286 min, an absolute reduction of 31 min (95% confidence interval 22-41 min), after pathway implementation (p < 0.001). Furthermore, cardiology consult rate decreased from 26.9% to 16.0% (p < 0.0001), rate of admission decreased from 30.1% to 22.7% (p < 0.0001), and number of ED boarders as a proportion of all nontraumatic chest pain patients decreased from 25.13% preimplementation to 18.63% postimplementation (p < 0.0001). CONCLUSIONS: Implementation of our novel chest pain pathway improved numerous ED throughput metrics in the evaluation of nontraumatic chest pain patients.

The impact of 30-day antecedent antibiotic exposure on Clostridioidesdifficile ribotype patterns and the relationship with clinical outcomes: A single center study.

BACKGROUND: Antibiotic exposure is a known risk factor for Clostridioides difficile infection (CDI) and recurrence and can lead to infection with specific C. difficile strains. In this study, we sought to explore the relationship between antecedent antibiotic exposure and C. difficile antimicrobial resistance, and the impact of resistance on clinical outcomes. METHODS: This was a single center retrospective study evaluating patients with CDI between 2011 and 2021. A logistic regression model was used to evaluate the relationship between antecedent antibiotics in the 30 days prior to CDI and resistance among isolates. In addition, an exploratory analysis using a cause-specific Cox proportional hazards model evaluated the association between resistance and a composite outcome of clinical failure, relapse at 30 days or CDI-related death. RESULTS: we analyzed one isolate from 510 patients; resistance was noted in 339 (66.5 %) of the isolates. Exposure to fluoroquinolones and macrolides was associated with 2.4 (95 % CI 1.4-4.4) and 4.7 (95 % CI 1.1-20.5) increased odds of having resistance compared to other antibiotic class exposure, respectively. There were 58 (17.0 %) patients in the resistance group who developed the composite outcome and 24 (14.2 %) patients who lacked resistance who developed the composite outcome (HR 1.32, 95 % CI 0.81-2.14). CONCLUSION: These findings suggest that fluoroquinolone and macrolide exposure were significantly associated with isolating a resistant strain, but we did not find significant differences in clinical outcomes based on the presence of antimicrobial resistance.

Expectations and perspectives of cognitive behavioural therapy for childhood anxiety and related disorders.

BACKGROUND: Anxiety disorders are the most frequently diagnosed psychiatric conditions in children and adolescents. Cognitive behavioural therapy (CBT) is a well-established and effective treatment for anxiety and related disorders across the lifespan. Expectations of psychotherapy have been demonstrated to affect outcomes, yet there is sparse existing literature on adolescent patient and parent perspectives of CBT prior to engagement with treatment. AIMS: This study aimed to qualitatively explore the expectations and perceptions of CBT for anxiety and related disorders among adolescent patients and parents. METHOD: Fourteen adolescent patients and 16 parents participated in semi-structured individual interviews or focus groups consisting of 2-3 participants. Interview transcripts were analysed using inductive analysis. RESULTS: Three themes were identified: worries about CBT, expectations and knowledge of the CBT process, and the role of parents and families. Overall, we found that adolescents and parents had generally positive views of CBT. The outset of CBT saw adolescents and parents express concern about stigma as well as the ambiguity of CBT. Parents continued to express a lack of understanding of what CBT entailed during their child's treatment course. CONCLUSION: These results suggest that both adolescents and parents would benefit from early discussion and reinforcement of expectations for CBT treatment. Further research efforts are warranted and should be directed towards determining appropriate expectations for parental involvement in a child's CBT course and effective communication of treatment expectations to both adolescents and parents.

Exploring the relationship between child temperament, maternal psychiatric symptoms, family environment and infant feeding.

OBJECTIVES: Infant temperament is assumed to be primarily innate. However, newer research suggests that maternal affection impacts ratings of temperament and environmental factors, including feeding method, can also influence infant temperament. This study investigates child temperament and its relationships with maternal psychiatric symptoms, environmental variables and feeding method longitudinally in a cohort of children followed from 6 to 72 months. Differences in temperament by feeding group are also investigated. We hypothesized that maternal psychiatric symptoms, environmental stressors, and impaired family dynamics would have negative impact on child temperament, whereas breastfeeding would have a positive impact on child temperament. METHOD: Mothers' ratings of child's temperament, own psychiatric symptomatology, environmental stresses and family cohesion were obtained in 504 mother-infant dyads via rating scales completed by mothers. Infants were breastfeed (BF), fed soy-based infant formula (SF) or dairy-based infant formula (MF). Linear mixed effect models investigated the relationship of variables on child's temperament while controlling for significant covariates and repeated measurements. RESULTS: Mothers in this study did not endorse clinical-level psychiatric symptomatology; however, when adjusted for significant covariates, higher psychiatric symptomatology significantly correlated with environmental stressors, impaired family dynamics and elevations in temperament ratings of infants' adaptability and mood. There were no lasting differences for temperament between feeding groups. However, some significant transient increases in rhythmicity and adaptability were found between SF and BF children. CONCLUSION: Positive relationships between family environment stressors and maternal psychiatric ratings were found. Transient differences were found in child temperament based upon feeding method.

Retinal electrophysiologic response to IOP elevation in living human eyes.

PURPOSE: The relationships between intraocular pressure (IOP), ocular perfusion pressure (OPP), retinal perfusion, and retinal electrophysiologic responses have been explored experimentally across several animal models. These studies have demonstrated that elevated IOP reduces OPP, and when this reduction in OPP exceeds the autoregulatory capacity of the retina vasculature, retinal perfusion and electrophysiologic responses are reduced. This study aimed to evaluate these interactions for the first time in the living human eye. METHODS: Five eyes from three research-consented brain-dead organ donors underwent optical coherence tomography with angiographic (OCT/A; Spectralis, Heidelberg Engineering) and electroretinographic (ERG, Diagnosys LLC) measurements while IOP was manometrically-elevated stepwise to pressures of 10, 30 and 50 mmHg. Systemic blood pressure (BP) was monitored continuously during testing. Correlation analysis was applied to assess association between ERG and OPP changes. In a single eye, prolonged IOP elevation was induced with viscoelastic injection and serial ERG measurements were obtained. RESULTS: Reductions in inner retinal function defined by photopic ERG were observed with elevation in IOP and concomitant reduction in OPP. Reductions, especially in b-wave, and photopic negative response (PhNR) amplitudes and implicit times were significantly correlated with elevation in IOP and reduction in OPP. There were more appreciable changes in perfusion and functional responses in eyes tested while systemic blood pressure was lower. With prolonged IOP elevation, selective loss of the PhNR response was observed. CONCLUSIONS: In the living human eye, retinal perfusion and inner retinal function are acutely impacted by elevation of IOP, and this impact is related to systemic BP and OPP. This novel approach provides a viable model to study the autoregulatory responses to IOP elevation in the living human eye.

MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion.

Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.

Do outcomes for heart transplantation differ based on donor and recipient race?

PURPOSE: There are limited data examining the impact of both donor and recipient race on outcomes following orthotopic heart transplant (OHT). The purpose of this study was to evaluate the relationship between donor and recipient race and OHT outcomes. METHODS: The United Network for Organ Sharing (UNOS) database was retrospectively reviewed from January 2000 to March 2018 for donor hearts. A comparison was conducted based on donor and recipient race (White, Black, Hispanic, Other/Unknown). Races for which there were limited numbers were excluded from the analysis (Asian, n = 1292; American Indian, n = 132; Pacific Islander, n = 132, Multiple ethnicities, n = 225). The primary endpoint was survival at 30 days, 1 year survival, and post-transplant rejection. Logistic and Cox models were used to quantify survival endpoints. RESULTS: A total of 41 841 OHT were included. Of the recipients, 29 894 (71%) were White, 8475 (20%) were Black, and 3472 (8%) were Hispanic. Of the donors 27 783 (66%) were White, 6277 (15%) were Black, 6576 (16%) were Hispanic, and 1205 (3%) were Unknown/Other race. In a comparison of recipient demographics, White recipients were older (54.09 ± 12.21 years) compared to Black (49.44 ± 12.83 years) and Hispanic (49.97 ± 13.27 years) recipients. All other differences between groups were not clinically significant. Black recipients were more likely to receive a heart with an "urgent" status (probability .80) compared to White (.73) and Hispanic (.75) recipients (p < .001). Hispanic recipients were more likely to receive a transplant when listed as "non-urgent" (Probability .47) compared to White (.37) and Black (.30) recipients (p < .001). In terms of outcomes, compared to White recipients, Hispanic patients experienced a decreased 30-day survival (OR 1.27; p = .011) and 1-year survival (OR 1.17; p = .016). In comparing Donor/Recipient combinations compared to a White Donor/White Recipient combination, overall survival was decreased in White donor/African American recipient (HR 1.36; p < .001), African American donor/African American recipient (HR 1.41; p < .001) and Hispanic donor/African American recipient (HR 1.30; p < .001) combinations (Table 1). CONCLUSIONS: African American and Hispanic recipients have decreased survival compared to White recipients after heart transplant. The African American donor does not decrease survival. Racial differences still exist in donor and recipient characteristics and recipient outcomes after OHT. Increasing the donor pool for all races and ethnicities would potentially benefit all recipients. Continued study is warranted in order to minimize these differences among recipients and identify factors that could be contributing to decreased survival, in order to optimize outcomes for African American and Hispanic recipients post-transplant and eliminate disparities.

Impact of 2016 UNOS pediatric heart allocation policy changes on VAD utilization, waitlist, and post-transplant survival outcomes in children with CHD versus Non-CHD.

AIMS: We analyzed the impact of the revised pediatric heart allocation policy on types of ventricular assist device (VAD) utilization, and waitlist (WL) and post-heart transplant (HT) survival outcomes in congenital heart disease (CHD) versus non-CHD patients before (Era-1) and after (Era-2) pediatric heart allocation policy implementation. METHODS: We retrospectively reviewed the UNOS database from December 16, 2011, through March 31, 2021, for patients < 18 years old and listed for primary HT. We compared the differences observed between Era-1 and Era-2. RESULTS: 5551 patients were listed for HT, of whom 2447(44%) were in Era-1 and 3104(56%) were in Era-2. CHD patients were listed as status 1A unchanged, but the number of patients listed as status 1B decreased in Era-2, whereas the number of non-CHD patients listed as status 1A decreased, but status 1B increased. In Era-2 compared to Era-1, both temporary (1% to 4%, p < .001) and durable VAD (13.6% to 17.8%, p < .001) utilization increased, and the transplantation rate per 100-patient years increased in both groups. The median WL period for CHD patients increased marginally from 70 to 71 days (p = .06), whereas for non-CHD patients it decreased from 61 to 54 days (p < .001). Adjusted 90-day WL survival increased from 84% to 88%, p = .016 in CHD, but there was no significant change in non-CHD patients (p = .57). There was no significant difference in 1-year post-HT survival in CHD and non-CHD patients between Era-1 and Era-2. CONCLUSIONS: In summary, after the revised heart allocation policy implementation, temporary and durable VAD support increased, HT rate increased, waitlist duration marginally increased in the CHD cohort and decreased in the non-CHD cohort, and 90-day WL survival probability improved in children with CHD without significant change in 1-year post-HT outcomes. Future studies are needed to identify changes to the policy that may further improve the listing criteria to improve WL duration and post-HT survival.

Observer studies of image quality of denoising reduced-count cardiac single photon emission computed tomography myocardial perfusion imaging by three-dimensional Gaussian post-reconstruction filtering and deep learning.

BACKGROUND: The aim of this research was to asses perfusion-defect detection-accuracy by human observers as a function of reduced-counts for 3D Gaussian post-reconstruction filtering vs deep learning (DL) denoising to determine if there was improved performance with DL. METHODS: SPECT projection data of 156 normally interpreted patients were used for these studies. Half were altered to include hybrid perfusion defects with defect presence and location known. Ordered-subset expectation-maximization (OSEM) reconstruction was employed with the optional correction of attenuation (AC) and scatter (SC) in addition to distance-dependent resolution (RC). Count levels varied from full-counts (100%) to 6.25% of full-counts. The denoising strategies were previously optimized for defect detection using total perfusion deficit (TPD). Four medical physicist (PhD) and six physician (MD) observers rated the slices using a graphical user interface. Observer ratings were analyzed using the LABMRMC multi-reader, multi-case receiver-operating-characteristic (ROC) software to calculate and compare statistically the area-under-the-ROC-curves (AUCs). RESULTS: For the same count-level no statistically significant increase in AUCs for DL over Gaussian denoising was determined when counts were reduced to either the 25% or 12.5% of full-counts. The average AUC for full-count OSEM with solely RC and Gaussian filtering was lower than for the strategies with AC and SC, except for a reduction to 6.25% of full-counts, thus verifying the utility of employing AC and SC with RC. CONCLUSION: We did not find any indication that at the dose levels investigated and with the DL network employed, that DL denoising was superior in AUC to optimized 3D post-reconstruction Gaussian filtering.

Inducing SERS activity at graphitic carbon using graphene-covered Ag nanoparticle substrates: Spectroelectrochemical analysis of a redox-active adsorbed anthraquinone.

Graphitic carbon electrodes are central to many electrochemical energy storage and conversion technologies. Probing the behavior of molecular species at the electrochemical interfaces they form is paramount to understanding redox reaction mechanisms. Combining surface-enhanced Raman scattering (SERS) with electrochemical methods offers a powerful way to explore such mechanisms, but carbon itself is not a SERS activating substrate. Here, we report on a hybrid substrate consisting of single- or few-layer graphene sheets deposited over immobilized silver nanoparticles, which allows for simultaneous SERS and electrochemical investigation. To demonstrate the viability of our substrate, we adsorbed anthraquinone-2,6-disulfonate to graphene and studied its redox response simultaneously using SERS and cyclic voltammetry in acidic solutions. We identified spectral changes consistent with the reversible redox of the quinone/hydroquinone pair. The SERS intensities on bare silver and hybrid substrates were of the same order of magnitude, while no discernible signals were observed over bare graphene, confirming the SERS effect on adsorbed molecules. This work provides new prospects for exploring and understanding electrochemical processes in situ at graphitic carbon electrodes.

Vibrational strong coupling in liquid water from cavity molecular dynamics.

We assess the cavity molecular dynamics method for the calculation of vibrational polariton spectra using liquid water as a specific example. We begin by disputing a recent suggestion that nuclear quantum effects may lead to a broadening of polariton bands, finding instead that they merely result in anharmonic red shifts in the polariton frequencies. We go on to show that our simulated cavity spectra can be reproduced to graphical accuracy with a harmonic model that uses just the cavity-free spectrum and the geometry of the cavity as input. We end by showing that this harmonic model can be combined with the experimental cavity-free spectrum to give results in good agreement with optical cavity measurements. Since the input to our harmonic model is equivalent to the input to the transfer matrix method of applied optics, we conclude that cavity molecular dynamics cannot provide any more insight into the effect of vibrational strong coupling on the absorption spectrum than this transfer matrix method, which is already widely used by experimentalists to corroborate their cavity results.

Assessing the role of the gut microbiome in methylmercury demethylation and elimination in humans and gnotobiotic mice.

The risk of methylmercury (MeHg) toxicity following ingestion of contaminated foodstuffs (e.g., fish) is directly related to the kinetics of MeHg elimination among individuals. Yet, the factors driving the wide range of inter-individual variability in MeHg elimination within a population are poorly understood. Here, we investigated the relationship between MeHg elimination, gut microbiome demethylation activity, and gut microbiome composition using a coordinated human clinical trial and gnotobiotic mouse modeling approach together with metagenomic sequence analysis. We first observed MeHg elimination half-lives (t1/2) ranging from 28 to 90 days across 27 volunteers. Subsequently, we found that ingestion of a prebiotic induced changes in the gut microbiome and mixed effects (increased, decrease, and no effect) on elimination in these same individuals. Nonetheless, elimination rates were found to correlate with MeHg demethylation activity in cultured stool samples. In mice, attempts to remove the microbiome via generation of germ-free (GF) animals or through antibiotic (Abx) treatment both diminished MeHg demethylation to a similar extent. While both conditions substantially slowed elimination, Abx treatment resulted in significantly slower elimination than the GF condition, indicating an additional role for host-derived factors in supporting elimination. Human fecal microbiomes transplanted to GF mice restored elimination rates to that seen in control mice. Metagenomic sequence analysis of human fecal DNA did not identify genes encoding proteins typically involved in demethylation (e.g., merB, organomercury lyase). However, the abundance of several anaerobic taxa, notably Alistipes onderdonkii, were positively correlated with MeHg elimination. Surprisingly, mono-colonization of GF free mice with A. onderdonkii did not restore MeHg elimination to control levels. Collectively, our findings indicate the human gut microbiome uses a non-conventional pathway of demethylation to increase MeHg elimination that relies on yet to be resolved functions encoded by the gut microbes and the hostClinical Trial NCT04060212, prospectively registered 10/1/2019.

Quantifying Individual-Level Inaccuracy in Glomerular Filtration Rate Estimation : A Cross-Sectional Study.

BACKGROUND: Although the population-level differences between estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) are well recognized, the magnitude and potential clinical implications of individual-level differences are unknown. OBJECTIVE: To quantify the magnitude and consequences of the individual-level differences between mGFRs and eGFRs. DESIGN: Cross-sectional study. SETTING: Four U.S. community-based epidemiologic cohort studies with mGFR. PATIENTS: 3223 participants in 4 studies. MEASUREMENTS: The GFRs were measured using urinary iothalamate and plasma iohexol clearance; the eGFR was calculated from serum creatinine concentration alone (eGFRCR) and with cystatin C. All GFR results are presented as mL/min/1.73 m2. RESULTS: The participants' mean age was 59 years; 32% were Black, 55% were women, and the mean mGFR was 68. The population-level differences between mGFR and eGFRCR were small; the median difference (mGFR - eGFR) was -0.6 (95% CI, -1.2 to -0.2); however, the individual-level differences were large. At an eGFRCR of 60, 50% of mGFRs ranged from 52 to 67, 80% from 45 to 76, and 95% from 36 to 87. At an eGFRCR of 30, 50% of mGFRs ranged from 27 to 38, 80% from 23 to 44, and 95% from 17 to 54. Substantial disagreement in chronic kidney disease staging by mGFR and eGFRCR was present. Among those with eGFRCR of 45 to 59, 36% had mGFR greater than 60 whereas 20% had mGFR less than 45; among those with eGFRCR of 15 to 29, 30% had mGFR greater than 30 and 5% had mGFR less than 15. The eGFR based on cystatin C did not provide substantial improvement. LIMITATION: Single measurement of mGFR and serum markers without short-term replicates. CONCLUSION: A substantial individual-level discrepancy exists between the mGFR and the eGFR. Laboratories reporting eGFR should consider including the extent of this uncertainty to avoid misinterpretation of eGFR as an mGFR replacement. PRIMARY FUNDING SOURCE: National Institutes of Health.

Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders.

HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS-RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome-lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.