Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a childhood motor neuron disease caused by anomalies in the SMN1 gene. Although therapeutics have been approved for the treatment of SMA, there is a therapeutic time window, after which efficacy is reduced. Hallmarks of motor unit pathology in SMA include loss of motor-neurons and neuromuscular junction (NMJs). Following an increase in Smn levels, it is unclear how much damage can be repaired and the degree to which normal connections are re-established. Here, we perform a detailed analysis of motor unit pathology before and after restoration of Smn levels. Using a Smn-inducible mouse model of SMA, we show that genetic restoration of Smn results in a dramatic reduction in NMJ pathology, with restoration of innervation patterns, preservation of axon and endplate number and normalized expression of P53-associated transcripts. Notably, presynaptic swelling and elevated Pmaip levels remained. We analysed the effect of either early or delayed treated of an antisense oligonucleotide (ASO) targeting SMN2 on a range of differentially vulnerable muscles. Following ASO administration, the majority of endplates appeared fully occupied. However, there was an underlying loss of axons and endplates, which was more prevalent following a delay in treatment. There was an increase in average motor unit size following both early and delayed treatment. Together this work demonstrates the remarkably regenerative capacity of the motor neuron following Smn restoration, but highlights that recovery is incomplete. This work suggests that there is an opportunity to enhance neuromuscular junction recovery following administration of Smn-enhancing therapeutics.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

Do Vancomycin Pharmacokinetics Differ Between Obese and Non-obese Patients? Comparison of a General-Purpose and Four Obesity-Specific Pharmacokinetic Models.

BACKGROUND: Over the past decade, numerous obesity-specific pharmacokinetic (PK) models and dosage regimens have been developed. However, it is unclear whether vancomycin PKs differ between obese and other patients after accounting for weight, age, and kidney function. In this study, the authors investigated whether using obesity-specific population PK models for vancomycin offers any advantage in accuracy and precision over using a recently developed general-purpose model. METHODS: Vancomycin plasma concentrations in a cohort of 49 obese patients (body mass index [BMI] >30 kg/m2), not previously used in the development of any of the evaluated models, were used to validate the performance of 4 obesity-specific models and a general model. Bias and imprecision were calculated for the a priori and a posteriori predictive performance. RESULTS: The bias of the a priori prediction was lowest for one of the obesity-specific models (-1.40%) and that of the general model was a close second (-7.0%). The imprecision was lowest for the general model (4.34 mg/L). The predictive performance for the a posteriori predictions was best for the general model, both for bias (1.96%) and imprecision (2.75 mg/L). CONCLUSIONS: The results of the external validation of vancomycin PK in obese patients showed that currently available obesity-specific models do not necessarily outperform a broadly supported general-purpose model. Based on these results, the authors conclude that there is no advantage in using vancomycin PK models specifically tailored to obese patients over the general-purpose model reported by Colin et al.

Population pharmacokinetic evaluation and optimization of amikacin dosage regimens for the management of mycobacterial infections.

BACKGROUND: There is limited information on amikacin pharmacokinetics (PK) and dose requirements in patients with mycobacterial infections. OBJECTIVES: To conduct a population PK analysis of amikacin data from patients with mycobacterial infections and compare predicted concentrations from standard and modified dosage guidelines with recommended target ranges. METHODS: A population PK model was developed using NONMEM. Cmax, Cmin, concentration 1 h post-infusion (C1h) and AUC0-24 using 15 mg/kg daily (once daily), the WHO table, 25 mg/kg three times weekly (TTW) and modified guidelines were compared using Monte Carlo simulations of 1000 patients. RESULTS: Data were available from 124 patients (684 concentrations) aged 16-92 years. CL was 4.64 L/h per 100 mL/min CLCR; V was 0.344 L/kg. With once-daily regimens, Cmax was 35-45 mg/L in 30%-35% of patients and 35-50 mg/L in 46%-48%; C1h was 25-40 mg/L in 53%-59%. The WHO table produced high Cmax values in patients <60 kg and low in patients >75 kg. With TTW dosing, around 30% of Cmax values were 65-80 mg/L, 40% were 60-80 mg/L, and 48% of C1h were 45-65 mg/L. Increasing the dosage interval for patients with CLCR <50 mL/min reduced Cmin values >2 mg/L from 34% to 25% for once-daily dosing and from 18% to 13% for TTW. In patients whose Cmin was <2 mg/L, 82% of AUC0-24 values were 100-300 mg.h/L. CONCLUSIONS: Standard amikacin dosing guidelines achieve low percentages of target concentrations for mycobacterial infections. Extending the dosing interval in renal impairment and widening target ranges would reduce the need for dose adjustment.

Development and evaluation of a national gentamicin and vancomycin quality improvement programme.

BACKGROUND: Scottish Antimicrobial Prescribing Group (SAPG) recommendations to reduce broad-spectrum antimicrobial use led to an increase in gentamicin and vancomycin prescribing. In 2009, SAPG introduced national guidance to standardize dosage regimens, reduce calculation errors and improve the monitoring of these antibiotics. Studies conducted in 2010 and 2011 identified limitations in guideline implementation. OBJECTIVES: To develop, implement and assess the long-term impact of quality improvement (QI) resources to support gentamicin and vancomycin prescribing, administration and monitoring. METHODS: New resources, comprising revised guidelines, online and mobile app dose calculators, educational material and specialized prescribing and monitoring charts were developed in collaboration with antimicrobial specialists and implemented throughout Scotland during 2013-16. An online survey in 2017 evaluated the use of these resources and a before (2011) and after (2018) point prevalence study assessed their impact. RESULTS: All 12 boards who responded to the survey (80%) were using the guidance, electronic calculators and gentamicin prescription chart; 8 used a vancomycin chart. The percentage of patients who received the recommended gentamicin dose increased from 44% to 89% (OR 10.99, 95% CI = 6.37-18.95) between 2011 and 2018. For vancomycin, the correct loading dose increased from 50% to 85% (OR = 5.69, CI = 2.76-11.71) and the correct maintenance dose from 55% to 90% (OR = 7.17, CI = 3.01-17.07). CONCLUSIONS: This study demonstrated improvements in the national prescribing of gentamicin and vancomycin through the development and coordinated implementation of a range of QI resources and engagement with local and national multidisciplinary teams.

Synaptic withdrawal following nerve injury is influenced by postnatal maturity, muscle-specific properties, and the presence of underlying pathology in mice.

Axonal and synaptic degeneration occur following nerve injury and during disease. Traumatic nerve injury results in rapid fragmentation of the distal axon and loss of synaptic terminals, in a process known as Wallerian degeneration (WD). Identifying and understanding factors that influence the rate of WD is of significant biological and clinical importance, as it will facilitate understanding of the mechanisms of neurodegeneration and identification of novel therapeutic targets. Here, we investigate levels of synaptic loss following nerve injury under a range of conditions, including during postnatal development, in a range of anatomically distinct muscles and in a mouse model of motor neuron disease. By utilising an ex vivo model of nerve injury, we show that synaptic withdrawal is slower during early postnatal development. Significantly more neuromuscular junctions remained fully innervated in the cranial nerve/muscle preparations analysed at P15 than at P25. Furthermore, we demonstrate variability in the level of synaptic withdrawal in response to injury in different muscles, with retraction being slower in abdominal preparations than in cranial muscles across all time points analysed. Importantly, differences between the cranial and thoracoabdominal musculature seen here are not consistent with differences in muscle vulnerability that have been previously reported in mouse models of the childhood motor neuron disease, spinal muscular atrophy (SMA), caused by depletion of survival motor neuron protein (Smn). To further investigate the relationship between synaptic degeneration in SMA and WD, we induced WD in preparations from the Smn2B/- mouse model of SMA. In a disease-resistant muscle (rostral band of levator auris longus), where there is minimal denervation, there was no change in the level of synaptic loss, which suggests that the process of synaptic withdrawal following injury is Smn-independent. However, in a muscle with ongoing degeneration (transvs. abdominis), the level of synaptic loss significantly increased, with the percentage of denervated endplates increasing by 33% following injury, compared to disease alone. We therefore conclude that the presence of a die-back can accelerate synaptic loss after injury in Smn2B/- mice.

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus.

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r-/- rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.

The impact of social capital on patients with multiple sclerosis.

OBJECTIVE: To evaluate the association between social capital (SC) and the physical and psychological impact of multiple sclerosis (MS). MATERIALS & METHODS: A cross-sectional study was conducted among people with MS (pwMS) at The Royal London Hospital, London, UK. Participants completed a survey including the Multiple Sclerosis Impact Scale-29 (MSIS-29), the Hospital Anxiety and Depression Scale (HADS), the self-reported EDSS and a SC questionnaire (SCQ). The SCQ assessed personal relationships, social support networks, civic engagement, and trust and cooperative norms. Kendall's tau correlation test was performed to measure the correlation between SC and MSIS-29 scores, and multiple linear regressions were conducted to find the best outcome prediction model. RESULTS: 236 pwMS participated in the study. Median age was 43.5 years (IQR 35-52). Of the total, 168 (71.2%) were female and 180 (76.3%) had relapsing-remitting MS. Median MSIS-29 scores were 23.7 (IQR 8.8-57.5) for the physical scale and 38.9 (IQR 16.7-55.6) for the psychological scales. Total SC scores were significantly correlated with the MSIS-29 physical (τb = -0.09, P = .02) and psychological scores (τb = -0.23, P < .001). After adjusting for possible confounders, the "personal relationships" domain had a significant effect on the MSIS-29 physical scores (ß = -2.70, SE = 1.34; P = .045). Total SC (ß = -1.08, SE = 0.33; P = .001) and the "personal relationships" (ß = -2.60, SE = 1.20; P = .031) and "trust and cooperative norms" (ß = -1.40, SE = 0.61; P = .024) domains had a significant effect on the MSIS-29 psychological scores. CONCLUSIONS: Higher levels of SC were associated with lower physical and psychological impact of MS. Emerging evidence on SC and its effects on MS should be translated into interventions designed to promote the health and well-being of pwMS.

Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants.

OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

Survival of motor neurone protein is required for normal postnatal development of the spleen.

Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the 'Taiwanese' murine model of severe SMA (Smn-/- ;SMN2tg/0 ), correlated to low levels of cell proliferation and increased cell death. Spleen lacks its distinctive red appearance and presents with a degenerated capsule and a disorganised fibrotic architecture. Histologically distinct white pulp failed to form and this was reflected in an almost complete absence of B lymphocytes necessary for normal immune function. In addition, megakaryoctyes persisted in the red pulp. However, the vascular density remained unchanged in SMA spleen. Assessment of the spleen in SMA patients with the infantile form of the disease indicated a range of pathologies. We conclude that development of the spleen fails to occur normally in SMA mouse models and human patients. Thus, further analysis of immune function is likely to be required to fully understand the full extent of systemic disease pathology in SMA.

How to start a blog.

Blogs that address issues of health and medical education run by clinical and research teams can have a profound impact on how patients access and navigate health information. Regularly updated websites are useful tools to facilitate two-way communication with a range of different audiences from patients to the general public. They provide benefits of supporting patients to learn and self-manage their health, and to educate colleagues and disseminate research. This article describes how to set up a blog, pointing out some simple style and formatting considerations, usable methods and appropriate conduct for healthcare professionals to engage with patients online.

Therapeutic drug monitoring in the past 40 years of the Journal of Antimicrobial Chemotherapy.

Since the Journal of Antimicrobial Chemotherapy was first published in 1975, papers addressing therapeutic drug monitoring (TDM) have been a regular feature. Initially they focused on laboratory aspects of drug concentration measurement then they changed more to the application of TDM in a clinical setting. Over its history, the Journal has provided its readership with the latest technological and scientific advances in TDM and has helped to drive changes in TDM that have directly impacted on patient care. These have varied from improvement in the quality of antimicrobial measurements through better identification of dosage regimens and TDM targets that help predict outcome and adverse events. Despite these advances in our understanding of the science and practice of TDM, there remain many areas of uncertainty. As we move into the next 40 years, it is clear that the Journal will continue to provide the readership with the latest science and opinion in this important area.

Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review.

OBJECTIVES: The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. METHODS: A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion. RESULTS: Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies. CONCLUSIONS: This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin.

Influence of Genotype on Warfarin Maintenance Dose Predictions Produced Using a Bayesian Dose Individualization Tool.

BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. METHODS: The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values. RESULTS: The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations. CONCLUSIONS: Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.

Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations.

OBJECTIVES: To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy. PATIENTS AND METHODS: A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of ≥15%. Doses for subsequent courses were determined using results from the initial course and the patient's clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PK was investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T>MIC for ≥40%, ≥60% or ≥80% of the dose interval. RESULTS: Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kg × [1 - 0.023 × (age - 46)] × [1 - 0.049 × (albumin - 15)], V1 = 0.273 L/kg × [1 - 0.049 × (albumin - 15)], Q = 0.199 L/h/kg and V2 = 0.309 L/kg × [1 - 0.049 × (albumin - 15)]. For a target of ≥80% T>MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min. CONCLUSIONS: Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values ≥4 mg/L.

Multiple sclerosis outpatient future groups: improving the quality of participant interaction and ideation tools within service improvement activities.

BACKGROUND: Improving the patient experience is a key focus within the National Health Service. This has led us to consider how health services are experienced, from both staff and patient perspectives. Novel service improvement activities bring staff and patients together to use design-led methods to improve how health services are delivered. The Multiple Sclerosis Outpatient Future Group study aimed to explore how analogies and props can be used to facilitate rich interactions between staff and patients within these activities. This paper will consider how these interactions supported participants to share experiences, generate ideas and suggest service improvements. METHOD: Qualitative explorative study using 'future groups,' a reinterpretation of the recognised focus groups method directed towards exploring future alternatives through employing analogies and physical props to engage participants to speculate about future service interactions and health experiences. Participants were people with multiple sclerosis (PwMS) and outpatient staff: staff nurses, nursing assistants, junior sisters and reception staff. RESULTS: Use of future groups, analogies and physical props enabled PwMS and outpatient staff to invest their own ideas and feelings in the service improvement activity and envisage alternative health care scenarios. The combination of participants in the groups with their diverse perspectives and knowledge of the service led to a collaborative approach in which staff highlighted potential practical problems and patients ensured ideas were holistic. Service improvements were prototyped and tested in the outpatient clinic. CONCLUSION: Design-led methods such as future groups using analogies and physical props can be used to facilitate interactions between staff and patients in service improvement activities, leading to the generation of meaningful ideas. It is hoped that improving the quality of ideation tools within design-led methods can contribute to developing successful service interventions in service improvement activities.

Tuning of ß-catenin activity is required to stabilize self-renewal of rat embryonic stem cells.

Stabilization of ß-catenin, through inhibition of glycogen synthase kinase 3 (GSK3) activity, in conjunction with inhibition of mitogen-activated protein kinase kinase 1/2 (MEK) promotes self-renewal of naïve-type mouse embryonic stem cells (ESC). In developmentally more advanced, primed-type, epiblast stem cells, however, ß-catenin activity induces differentiation. We investigated the response of rat ESCs to ß-catenin signaling and found that when maintained on feeder-support cells in the presence of a MEK inhibitor alone (1i culture), the derivation efficiency, growth, karyotypic stability, transcriptional profile, and differentiation potential of rat ESC cultures was similar to that of cell lines established using both MEK and GSK3 inhibitors (2i culture). Equivalent mouse ESCs, by comparison, differentiated in identical 1i conditions, consistent with insufficient ß-catenin activity. This interspecies difference in reliance on GSK3 inhibition corresponded with higher overall levels of ß-catenin activity in rat ESCs. Indeed, rat ESCs displayed widespread expression of the mesendoderm-associated ß-catenin targets, Brachyury and Cdx2 in 2i medium, and overt differentiation upon further increases in ß-catenin activity. In contrast, mouse ESCs were resistant to differentiation at similarly elevated doses of GSK3 inhibitor. Interestingly, without feeder support, moderate levels of GSK3 inhibition were necessary to support effective growth of rat ESC, confirming the conserved role for ß-catenin in ESC self-renewal. This work identifies ß-catenin signaling as a molecular rheostat in rat ESC, regulating self-renewal in a dose-dependent manner, and highlights the potential importance of controlling flux in this signaling pathway to achieve effective stabilization of naïve pluripotency.