Rationale & Objective Chronic kidney disease (CKD) and diabetes are comorbid metabolic diseases that share common factors such as insulin resistance. Few studies have examined the association between CKD and incident diabetes, with limited consensus and associated risk factors. We conducted an analysis of participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study to investigate incident diabetes among participants with CKD compared to non-CKD participants. Study Design Prospective cohort study Setting & Participants 7,511 participants who completed 10 years of follow-up were included in the analysis, of whom 994 had CKD (eGFR <60ml/min/1.73m2 or ACR>30mg/g) at baseline. Exposure CKD Outcome Incident diabetes Analytical Approach Logistic regression analysis was performed to estimate the odds of incident diabetes among CKD participants, with odds ratio (OR) and 95% Confidence Interval (Cl). Risk factors for incident diabetes among CKD participants were also examined. Results After 10 years of follow-up, 11.0% (717) of non-CKD participants and 15.8% (157) of CKD participants developed diabetes. Incident diabetes was higher among CKD participants than in non-CKD participants using creatinine-based equations, which was not seen when using a creatinine- and cystatin C-based equation for CKD. Several risk factors such as race, prediabetes, age, body mass index (BMI), hypertension, current smoking, and exercise ≥ 4 times/week increased the odds of incident diabetes, while current alcohol use had a lower risk of incident diabetes. Prediabetes had the highest risk of incident diabetes (OR=4.94, 95% Cl: 4.22, 5.78; p<0.01). Limitations Attrition bias, limited generalizability, and limited diagnostic classification. Conclusions The association between CKD and incident diabetes depends on how CKD is defined. These findings highlight the need for future studies to explore how renal function is assessed when determining adverse outcomes related to CKD.

Studies on the relationship between smoking and cognition yield conflicting results, potentially from survival bias. We examined the effect of smoking status on cognitive evolution, accounting for potential bias in attrition. We analyzed 21 216 Black and White participants from the REGARDS cohort study. In order to account for potential differential attrition, a sensitivity analysis compared the association between smoking status and age-sex-specific composite cognitive trajectories using linear mixed models, robust under missing at random assumption, and joint models, robust under the extended missing at random assumptions. Linear mixed model results indicated current smokers had lower overall composite cognitive scores compared to never smokers at baseline (-0.20, 95% CI, -0.23 to -0.16) and at 14-years duration in the study (-0.26, 95% CI, -0.33 to -0.20), also apparent when comparing current smokers to past smokers, and memory and verbal fluency composite scores. Joint modeling estimates yielded results similar to results from linear mixed models. Joint models are recommended as a potential means to investigate concerns about attrition, particularly in studies of factors associated with both cognition and mortality. This study provides further support that smoking is likely to have negative impacts on cognition.

INTRODUCTION:The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) randomized clinical trial compares the efficacy of revascularization plus intensive medical management (IMM) versus IMM alone for stroke prevention in patients with high-grade asymptomatic carotid stenosis. Innovative strategies are needed to extend clinical follow-up and assess long-term durability of both revascularization and intensive medical therapy. This manuscript describes the methods and early experiences of the Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial (C2LOE). METHODS:C2LOE will extend follow-up in CREST-2 participants for up to 10 years. Patients undergo a scripted, computer-assisted telephone interview every 6 months focused on screening for potential stroke events and any hospitalizations and performing a brief cognitive assessment. If a stroke or transient ischemic attack (TIA) is suspected, or a hospitalization is reported, medical records are retrieved, and vascular neurology video visit assessments are conducted to be used for central adjudication of potential endpoints. CONCLUSION:We describe an ongoing posttrial follow-up study of stroke prevention following IMM with or without carotid revascularization. The study relies on screening for stroke endpoints through periodic telephonic interviews and validation of endpoints through medical record review and vascular neurology video visits. We demonstrate that this technique can be applied effectively to patients enrolled across more than 50 centers. Further research is needed to determine the optimal approach for long-term follow-up studies in stroke-relevant populations.

Background:Mucociliary clearance plays a critical role in pulmonary host defense. Abnormal mucociliary clearance contributes to the pathogenesis of pulmonary disorders, including COPD. In bronchiectasis, treatments targeting mucus obstruction in the airways include the use of high frequency chest wall oscillation (HFCWO) therapy. This prospective outcome based study was designed to investigate the changes in symptoms and quality of life (QOL) to measure the effect of adjunctive HFCWO therapy to standard of care therapy for patients with COPD. Research Question:When HFCWO is indicated and used as intended, will the quality of life for those patients with COPD improve and sustain improvement. Study Design and Methods:We conducted a prospective, openl-label, observational study in COPD patients without concomitant bronchiectasis. Participants had assessments of QOL at baseline (day 0) and then at 30 and 90 days after initiation of HFCWO therapy. The St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) was employed and longitudinally followed at each timepoint. Paired t-tests were used to compare means between each time points adjusted for multiple comparisons. A linear mixed model for the analysis of longitudinal data was then constructed to determine the simultaneous contribution of race, gender, ethnicity, time, and selected interactions in the primary outcome of change in SGRQ-C across 0, 30, and 90 days. Results:The cohort of patients (n=102) demonstrated a significant reduction in the SGRQ-C at 30 and sustained at 90 days compared to baseline. In addition, two component scores of the SGRQ-C questionnaire ("Symptoms" and Impacts") were significantly reduced at 30 and 90 days. Interpretation:This prospective, observational study demonstrates statistically significant and clinically favorable responses to HFCWO as an adjunctive therapy for patients with a primary diagnosis of COPD without concomitant bronchiectasis. Results of this study inform the design of additional additional studies of HFCWO to prove efficacy in COPD patients.

Background:The modest stroke prevention from surgery for asymptomatic carotid disease has prompted a search for predictors that may improve risk stratification beyond luminal stenosis. Plaque disruption and atheroembolization are associated with unique anatomical and histological changes. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) collects information on duplex ultrasound (DUS) plaque biomarkers with the goal of evaluating their relationship to the periprocedural and long-term risks of stroke. In this study, we examine the reliability with which carotid plaque features can be measured from DUS images, and report baseline carotid DUS-derived stenosis and plaque features using semiautomated digital image analysis of patients enrolled in CREST-2. Methods:We studied the first 503 patients in CREST-2. Patients underwent standardized carotid DUS evaluation pre-enrollment. B-Mode images were scaled linearly to normalize brightness. Plaques were outlined manually. Dedicated software automatically measured the longitudinal sectional area (mm2), grayscale median (GSM), Gray-Weale classification, and tissue composition (mm2) of intraplaque hemorrhage (IPH), lipid, fibrous tissue, muscle, and calcium. We present the mean, standard deviation, median, interquartile range, minimum and maximum range, and proportions of carotid peak systolic velocities (PSVs) and plaque morphological features. We tested for autocorrelation among plaque features and computed the proportion of potentially unstable plaques in the cohort. Reliability of the image analysis techniques was tested in 100 patients using Bland-Altman plots and intraclass and interclass correlation coefficients. Results:Most patients were male (58.4%), older (mean age of 69.3 years), White (87.5%), and had a PSV of ≥230 cm/s (98.6%); the 1.4% with a PSV of <230 cm/s were enrolled based on catheter angiography. Plaques in this study were large; the mean longitudinal sectional area was 62 ± 37 mm2 (range, 6.2-256.5 mm2). The mean GSM was 58 ± 30 (unitless) (range, 0-168) and Gray-Weale classification was 3.5 ± 0.9 (range, 1-5). The mean areas of tissue types were IPH 5.3 ± 8.9 mm2, lipid 9.3 ± 8.6 mm2, fibrous tissue 10 ± 10 mm2, muscle 17 ± 12 mm2, and calcium 1.6 ± 4.1 mm2. The PSV of patients showed poor correlation with plaque features. The proportion of plaques with a GSM of ≤35 was 22.8%, IPH of ≥5 mm2 was 30.0%, and a lipid-rich necrotic core of ≥40% was 3.0% of the cohort. Plaque measurements could be performed with high reliability with good interobserver and intraobserver correlations. Conclusions:Site-generated, core laboratory-interpreted ultrasound examination provides a reliable way of characterizing carotid plaque morphological features across studies performed at many CREST-2 sites. The initial cohort of patients randomized in CREST-2 had heterogeneity of plaque features despite causing high-grade stenosis. Completion of the trial will provide an opportunity to assess whether plaque heterogeneity interacts with response to revascularization and medical management. (JVS-Vascular Insights 2024;2:100134.).

Background Rather than considering carotid stenting and endarterectomy to be rival procedures, they ought to be seen as complementary, with some patients more suited to one procedure over another. The respective patient populations best suited for optimal outcomes with stenting and endarterectomy differ substantially. Hence, the CREST‐2 (Carotid Revascularization, Endarterectomy Versus Stent Trial‐2) (study was designed as 2 separate 2‐arm randomized trials run in parallel. One trial compares intensive medical management with and without stenting; the other, intensive medical management with and without endarterectomy. Each trial has a recruitment target of 1240 patients with ≥70% asymptomatic carotid stenosis, randomized 1:1 in each arm. To ensure patient safety and give stenting the best possible chance of demonstrating net benefits in stroke prevention, CREST‐2 adopted a rigorous procedure for evaluating, monitoring, and approving operators to enroll in the trial. The CREST‐2 Registry was established to allow for recent experience for applicant stent operators. Methods The CREST‐2 Registry is a prospective, multicenter, short‐term observational study of carotid stenting allowing use of multiple devices. Results The registry enrolled its first patient in September 2014, and as of October 2, 2023, a total of 9830 patients have been treated by 207 different stent operators from 103 different clinical centers. In this mixed cohort of asymptomatic (61.1% of the cohort) and symptomatic (38.9%) patients, the 30‐day stroke rate is 1.8% and the combined 30‐day stroke or death rate is 2.6%. At its peak in March 2016, the registry achieved an enrollment rate of 142 cases/month. As of October 20, 2023, a total of 104 patients remain to be enrolled in the CREST‐2 stenting trial. Conclusion The registry has facilitated assembly of a high‐performing team of stent operators for the CREST‐2 trial. With continued support of the many operators, we anticipate completing enrollment by the summer of 2024.

AbstractObjectiveWe aimed to determine the longitudinal distribution of hand function skills in individuals with classic Rett syndrome (RTT), an X‐linked dominant neurodevelopmental disorder, and correlate with MECP2 variants.MethodWe conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus of this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups.ResultsFollowing the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C‐terminal truncations) compared with groups composed of individuals with more severe variants.ConclusionsThese temporal variations in hand use represent specific considerations that could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

Abstract Background Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). Methods Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. Results Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5–62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%–94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. Conclusions Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

BACKGROUND:The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport. METHODS:Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment. RESULTS:Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed. CONCLUSIONS:E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Background and Purpose High-grade carotid artery stenosis may alter hemodynamics in the ipsilateral hemisphere, but consequences of this effect are poorly understood. Cortical thinning is associated with cognitive impairment in dementia, head trauma, demyelination, and stroke. We hypothesized that hemodynamic impairment, as represented by a relative time-to-peak (TTP) delay on MRI in the hemisphere ipsilateral to the stenosis, would be associated with relative cortical thinning in that hemisphere. Methods We used baseline MRI data from the NINDS-funded Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics (CREST-H) study. Dynamic contrast susceptibility MR perfusion-weighted images were post-processed with quantitative perfusion maps using deconvolution of tissue and arterial signals. The protocol derived a hemispheric TTP delay, calculated by subtraction of voxel values in the hemisphere ipsilateral minus those contralateral to the stenosis. Results Among 110 consecutive patients enrolled in CREST-H to date, 45 (41%) had TTP delay of at least 0.5 seconds and 9 (8.3%) subjects had TTP delay of at least 2.0 seconds, the maximum delay measured. For every 0.25-second increase in TTP delay above 0.5 seconds, there was a 0.006-mm (6 micron) increase in cortical thickness asymmetry. Across the range of hemodynamic impairment, TTP delay independently predicted relative cortical thinning on the side of stenosis, adjusting for age, sex, hypertension, hemisphere, smoking history, low-density lipoprotein cholesterol, and preexisting infarction (P=0.032). Conclusions Our findings suggest that hemodynamic impairment from high-grade asymptomatic carotid stenosis may structurally alter the cortex supplied by the stenotic carotid artery.

The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) includes two concurrently running two-arm trials assessing intensive medical management (IMM) with or without carotid revascularization for the prevention of stroke.1 One trial tests endarterectomy vs IMM; the other tests stenting vs IMM. Each trial had an original recruitment target of 1240 patients with ≥70% asymptomatic carotid stenosis, randomized 1:1 in each arm. CREST-2 reached an important milestone on September 29, 2023, when the endarterectomy trial achieved its prespecified sample size.

Abstract Purpose To establish criterion and construct validity of a novel, clinically feasible assessment of lower-extremity dexterity for PD patients. Methods Thirty-three PD patients performed a unilateral lower-extremity dexterity task “off” and “on” dopaminergic medications with each leg. The task involves iteratively tapping targets with the foot in a specified pattern, and the measured outcome is the time to complete the movement sequence, with longer times indicating worse performance. We correlated leg movement time with standard, validated measures of gait (comfortable and maximal walk speeds), general mobility (timed up and go), upper-extremity dexterity (9-Hole Pegboard), and elements of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). Results We found significant relationships between lower extremity dexterity and each of these tasks “off” and “on” medications. Task performance also captures known features of PD, including dopamine-mediated improvement in performance and asymmetrical symptom presentation. Conclusions This task provides a simple assessment of lower extremity function that correlates with validated measures of dexterity, gait, and mobility. It provides objective, continuous data, is inexpensive, requires little technical expertise/equipment, has a small physical footprint, and can be administered quickly. These features increase the feasibility of implementing this assessment tool in clinical settings. Implications for rehabilitation We introduce a novel task that captures lower extremity dexterity in individuals with Parkinson’s disease (PD). The task is validated against gold standard measures of upper extremity dexterity, gait, and general mobility. Performance on the task is sensitive to known features of PD, including dopamine-mediated improvements and asymmetrical symptom presentation. The task is easy to implement and provides higher quality data compared to other common clinical assessments (e.g., MDS-UPDRS).

Background Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). Methods Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. Results Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5–62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%–94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. Conclusions Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

We read with considerable interest the systematic review by Dr. Kwok and colleagues regarding the effects of revascularization of extracranial carotid artery disease by carotid endarterectomy or carotid artery stenting on cognition.1 Their systematic review revealed only 7 studies published from January 1985 to December 2022, of which none were randomized clinical trials. This is notable because, as the authors point out, cognitive testing has developed and improved in recent decades, in part driven by pharmaceutical industry funded clinical trials.

ABSTRACTBackgroundDystonia is an under-studied motor feature of Parkinson disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.ObjectivesTo investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in PD patients with and without dystonia.MethodsWe examined the prevalence and distribution of dystonia in PD patients undergoing deep brain stimulation surgery and recorded intracranial electrophysiology from motor cortex and directional electrodes in subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.ResultsDystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0±3.3 and 4.2±2.9 Hz peak frequencies for hand and foot movements respectively). PD patients with dystonia during DBS surgery displayed greater M1 beta power at rest and STN low frequency power during movements versus those without dystonia.ConclusionsSpectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low frequency synchronization, especially in PD patients with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy.

Alzheimer's disease (AD) is the leading cause of dementia and has received considerable research attention, including using neuroimaging biomarkers to classify patients and/or predict disease progression. Generalized linear models, e.g., logistic regression, can be used as classifiers, but since the spatial measurements are correlated and often outnumber subjects, penalized and/or Bayesian models will be identifiable, while classical models often will not. Many useful models, e.g., the elastic net and spike-and-slab lasso, perform automatic variable selection, which removes extraneous predictors and reduces model variance, but neither model exploits spatial information in selecting variables. Spatial information can be incorporated into variable selection by placing intrinsic autoregressive priors on the logit probabilities of inclusion within a spike-and-slab elastic net framework. We demonstrate the ability of this framework to improve classification performance by using cortical thickness and tau-PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to classify subjects as cognitively normal or having dementia, and by using a simulation study to examine model performance using finer resolution images.

Substantial clinical evidence supports the notion that ciliary function in the airways is important in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, the extent or nature of impairment of mucociliary transport (MCT) in in vivo models remains unknown. We hypothesize that SARS-CoV-2 infection results in MCT deficiency in the airways of golden Syrian hamsters that precedes pathological injury in lung parenchyma. Micro-optical coherence tomography was used to quantitate functional changes in the MCT apparatus. Both genomic and subgenomic viral RNA pathological and physiological changes were monitored in parallel. We show that SARS-CoV-2 infection caused a 67% decrease in MCT rate as early as 2 days postinfection (dpi) in hamsters, principally due to 79% diminished airway coverage of motile cilia. Correlating quantitation of physiological, virological, and pathological changes reveals steadily descending infection from the upper airways to lower airways to lung parenchyma within 7 dpi. Our results indicate that functional deficits of the MCT apparatus are a key aspect of COVID-19 pathogenesis, may extend viral retention, and could pose a risk factor for secondary infection. Clinically, monitoring abnormal ciliated cell function may indicate disease progression. Therapies directed toward the MCT apparatus deserve further investigation.

Objective To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. Study design We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. Results Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. Conclusions The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis (CF), resulting in recurrent respiratory infections and exacerbations. Strategies to rehydrate airway mucus including inhibition of the epithelial sodium channel (ENaC) have the potential to improve mucosal defense by enhancing mucociliary clearance (MCC) and reducing the risk of progressive decline in lung function. In the current work, we evaluated the effects of AZD5634, an ENaC inhibitor that shows extended lung retention and safety profile as compared with previously evaluated candidate drugs, in healthy and CF preclinical model systems. We found that AZD5634 elicited a potent inhibition of amiloride-sensitive current in non-CF airway cells and airway cells derived from F508del-homozygous individuals with CF that effectively increased airway surface liquid volume and improved mucociliary transport (MCT) rate. AZD5634 also demonstrated efficacious inhibition of ENaC in sheep bronchial epithelial cells, translating to dose-dependent improvement of mucus clearance in healthy sheep in vivo. Conversely, nebulization of AZD5634 did not notably improve airway hydration or MCT in CF rats that exhibit an MCC defect, consistent with findings from a first single-dose evaluation of AZD5634 on MCC in people with CF. Overall, these findings suggest that CF animal models demonstrating impaired mucus clearance translatable to the human situation may help to successfully predict and promote the successful translation of ENaC-directed therapies to the clinic.