Sleep-wake behavior, perceived fatigability, and cognitive reserve in older adults.

INTRODUCTION: The effects of sleep-wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep-related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below-mean CR. Therefore, improving sleep-wake regulation and leisure activities may protect against fatigability and cognitive decline. HIGHLIGHTS: Clinical fatigue and fatigability cannot be alleviated by rest. Clinical fatigability disrupts daily activities during preclinical Alzheimer's. High cognitive reserve mitigates sleep-wake disturbance effects. High cognitive reserve attenuates clinical fatigability effects on daily functioning. Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain.

Quantifying cell cycle regulation by tissue crowding.

The spatiotemporal coordination and regulation of cell proliferation is fundamental in many aspects of development and tissue maintenance. Cells have the ability to adapt their division rates in response to mechanical constraints, yet we do not fully understand how cell proliferation regulation impacts cell migration phenomena. Here, we present a minimal continuum model of cell migration with cell cycle dynamics, which includes density-dependent effects and hence can account for cell proliferation regulation. By combining minimal mathematical modelling, Bayesian inference, and recent experimental data, we quantify the impact of tissue crowding across different cell cycle stages in epithelial tissue expansion experiments. Our model suggests that cells sense local density and adapt cell cycle progression in response, during G1 and the combined S/G2/M phases, providing an explicit relationship between each cell cycle stage duration and local tissue density, which is consistent with several experimental observations. Finally, we compare our mathematical model predictions to different experiments studying cell cycle regulation and present a quantitative analysis on the impact of density-dependent regulation on cell migration patterns. Our work presents a systematic approach for investigating and analysing cell cycle data, providing mechanistic insights into how individual cells regulate proliferation, based on population-based experimental measurements.

Etiologies of bloody diarrhea in children presenting with acute gastroenteritis to US emergency departments.

Among 111 children presenting with bloody diarrhea in a multicenter study of molecular testing in US emergency departments, we found viral pathogens in 18%, bacteria in 48%, protozoa in 2%, and no pathogens detected in 38%.

The association of range of motion, lower limb strength, and load during jump landings in professional ballet dancers.

This study aimed to investigate the associations between peak plantarflexion ankle joint moments and vertical ground reaction forces (vGRF) during jump landings, and static ankle dorsiflexion range of motion (ROM), three-dimensional ankle excursions, and lower extremity strength in professional ballet dancers. Twenty-seven professional ballet dancers volunteered to participate (men = 14, women = 13). Participants attended one data collection session to measure dorsiflexion ROM and isometric lower extremity strength. Two further sessions were used to establish ankle mechanics and vGRFs during countermovement jump landings in seven foot positions, via a seven-camera motion capture system and piezoelectric force platform. Two linear mixed-effects models were used to investigate associations between the target variables and strength, dorsiflexion ROM, and ankle excursions. Dancer identification, sex, and foot position were entered as random effects. Model fit, when considered independent of random effects, was generally poor with the predictor variables explaining little of the variance of peak plantarflexion ankle joint moments (R2 = 0.02) or vGRF (R2 = 0.01). Model fit improved when random effects were considered (R2 = 0.65 & 0.34). Frontal plane ankle excursion was the only predictor variable with a significant negative association with peak plantarflexion ankle joint moments (p = .016), although coefficient estimates were small. Strength, static ankle dorsiflexion ROM, and three-dimensional ankle excursions are poor predictors of load experienced at a joint and system level in professional ballet dancers. Differences between individuals, sex, and foot position may be better indicators of the load experienced during jump landings.

Switching from Intravenous to Subcutaneous Biological Therapy for Inflammatory Bowel Disease Patients Remains a Challenge.

Biological inflammatory bowel disease (IBD) medications, once limited to intravenous (IV) administration, can now be administered both via IV and subcutaneously (SC). This study investigates patient preferences, willingness to switch from IV to SC, and associated factors. A questionnaire covering demographics, disease-related inquiries, quality of life, and IBD medication preferences was distributed via email, the Israeli Crohn's Disease and Ulcerative Colitis Foundation, infusion centers, and clinics. From 454 IBD patients (median age: 42 years; 55.7% female), responses revealed a preference for SC every 8 weeks, which is comparable to daily oral dosing. Both options were significantly favored over IV every 8 weeks and SC every 2 weeks, with no statistically significant differences between the latter two. However, among patients who were experienced with both SC and IV administration, a clear preference for SC administration every 2 weeks over IV every 8 weeks surfaced. Among IV-treated patients, 54.5% resisted switching to SC. Key reasons for this included medical staff presence (57.7%), a fear of needles (46.4%), belief in infusion efficacy (37.1%), and longer intervals between infusions (36.1%). Findings suggest that transitioning from IV to SC treatment is challenging due to patient resistance, which is influenced by specific factors. Identifying and addressing these obstacles is crucial for optimizing IBD management.

Bioelectric stimulation controls tissue shape and size.

Epithelial tissues sheath organs and electro-mechanically regulate ion and water transport to regulate development, homeostasis, and hydrostatic organ pressure. Here, we demonstrate how external electrical stimulation allows us to control these processes in living tissues. Specifically, we electrically stimulate hollow, 3D kidneyoids and gut organoids and find that physiological-strength electrical stimulation of ∼ 5 - 10 V/cm powerfully inflates hollow tissues; a process we call electro-inflation. Electro-inflation is mediated by increased ion flux through ion channels/transporters and triggers subsequent osmotic water flow into the lumen, generating hydrostatic pressure that competes against cytoskeletal tension. Our computational studies suggest that electro-inflation is strongly driven by field-induced ion crowding on the outer surface of the tissue. Electrically stimulated tissues also break symmetry in 3D resulting from electrotaxis and affecting tissue shape. The ability of electrical cues to regulate tissue size and shape emphasizes the role and importance of the electrical micro-environment for living tissues.

The Cross-talk Between Intestinal Microbiota and MDSCs Fuels Colitis-associated Cancer Development.

Intestinal chronic inflammation is associated with microbial dysbiosis and accumulation of various immune cells including myeloid-derived suppressor cells (MDSC), which profoundly impact the immune microenvironment, perturb homeostasis and increase the risk to develop colitis-associated colorectal cancer (CAC). However, the specific MDSCs-dysbiotic microbiota interactions and their collective impact on CAC development remain poorly understood. In this study, using a murine model of CAC, we demonstrate that CAC-bearing mice exhibit significantly elevated levels of highly immunosuppressive MDSCs, accompanied by microbiota alterations. Both MDSCs and bacteria that infiltrate the colon tissue and developing tumors can be found in close proximity, suggesting intricate MDSC-microbiota cross-talk within the tumor microenvironment. To investigate this phenomenon, we employed antibiotic treatment to disrupt MDSC-microbiota interactions. This intervention yielded a remarkable reduction in intestinal inflammation, decreased MDSC levels, and alleviated immunosuppression, all of which were associated with a significant reduction in tumor burden. Furthermore, we underscore the causative role of dysbiotic microbiota in the predisposition toward tumor development, highlighting their potential as biomarkers for predicting tumor load. We shed light on the intimate MDSCs-microbiota cross-talk, revealing how bacteria enhance MDSC suppressive features and activities, inhibit their differentiation into mature beneficial myeloid cells, and redirect some toward M2 macrophage phenotype. Collectively, this study uncovers the role of MDSC-bacteria cross-talk in impairing immune responses and promoting tumor growth, providing new insights into potential therapeutic strategies for CAC. SIGNIFICANCE: MDSCs-dysbiotic bacteria interactions in the intestine play a crucial role in intensifying immunosuppression within the CAC microenvironment, ultimately facilitating tumor growth, highlighting potential therapeutic targets for improving the treatment outcomes of CAC.

Approach to esophageal absent contractility: can we do better?

Absent contractility (AC), a motility disorder characterized by the absence of esophageal contractions while maintaining normal lower esophageal sphincter relaxation, is recognized as a distinctive major disorder of peristalsis on esophageal high-resolution manometry that warrants comprehensive understanding. This unique motility disorder often co-occurs with connective tissue, rheumatologic or autoimmune diseases, with scleroderma being the classic example. Symptoms of gastroesophageal reflux are common. AC can profoundly impact patients' lives and result in a spectrum of complications, including erosive esophagitis, esophageal candidiasis, Barrett's esophagus, and malnutrition. To address the intricate complexities of AC and its multifaceted complications, a multidisciplinary approach is paramount. This approach considers the distinct clinical presentation and underlying rheumatologic conditions of the individual patient, recognizing the inherent diversity within this disorder. While medical management of gastroesophageal reflux remains the cornerstone of AC treatment, emerging surgical and endoscopic interventions offer additional therapeutic options for those grappling with this challenging condition. This comprehensive review provides an in-depth evaluation of recent advances in our understanding of AC and its management. It endeavors to offer valuable insights into therapeutic strategies for AC and its associated issues.

Spatial heterogeneity in collective electrotaxis: continuum modelling and applications to optimal control.

Collective electrotaxis is a phenomenon that occurs when a cellular collective, for example an epithelial monolayer, is subjected to an electric field. Biologically, it is well known that the velocity of migration during the collective electrotaxis of large epithelia exhibits significant spatial heterogeneity. In this work, we demonstrate that the heterogeneity of velocities in the electrotaxing epithelium can be accounted for by a continuum model of cue competition in different tissue regions. Having established a working model of competing migratory cues in the migrating epithelium, we develop and validate a reaction-convection-diffusion model that describes the movement of an epithelial monolayer as it undergoes electrotaxis. We use the model to predict how tissue size and geometry affect the collective migration of MDCK monolayers, and to propose several ways in which electric fields can be designed such that they give rise to a desired spatial pattern of collective migration. We conclude with two examples that demonstrate practical applications of the method in designing bespoke stimulation protocols.

Parameter identifiability and model selection for partial differential equation models of cell invasion.

When employing mechanistic models to study biological phenomena, practical parameter identifiability is important for making accurate predictions across wide ranges of unseen scenarios, as well as for understanding the underlying mechanisms. In this work, we use a profile-likelihood approach to investigate parameter identifiability for four extensions of the Fisher-Kolmogorov-Petrovsky-Piskunov (Fisher-KPP) model, given experimental data from a cell invasion assay. We show that more complicated models tend to be less identifiable, with parameter estimates being more sensitive to subtle differences in experimental procedures, and that they require more data to be practically identifiable. As a result, we suggest that parameter identifiability should be considered alongside goodness-of-fit and model complexity as criteria for model selection.

Good Short-Term Survivorship of Constrained Condylar Revision Knee Implants With Medial Pivot Kinematics: A Level IV Retrospective Study.

BACKGROUND: The need for revision total knee arthroplasty surgery is increasing worldwide, and, in many cases, a constrained implant is required to provide joint stability. The purpose of this study was to examine the early loosening and functional outcome of a novel constrained condylar (CCK) revision total knee system designed to have medial pivot (MP) kinematics. METHODS: A retrospective cohort study was performed, collecting clinical data from all patients who underwent revision total knee arthroplasty using a novel MP CCK system with a minimum four-year clinical follow-up. Patient demographics, survivorship, complications, and Forgotten Joint Score were analyzed based upon chart review. RESULTS: There were 49 patients available for follow-up, who had a 100% survivorship free of aseptic loosening. All-cause revision survivorship was 92%. There were 4 patients who subsequently underwent rerevision. The causes for rerevision included periprosthetic joint infection in 2 patients, coronal plane instability in one patient, and a traumatic knee dislocation in one patient. There were 45 patients who completed the Forgotten Joint Score, who had an average of 49.8 (± 32.8, range 6.25 to 100). CONCLUSIONS: At 4 years, mid-term follow-up, this novel CCK revision total knee system designed to have MP kinematics had good patient-reported outcomes with no revision for aseptic loosening. Future studies should evaluate the mid- and long-term survivorship of this innovative implant.

E-cadherin biomaterials reprogram collective cell migration and cell cycling by forcing homeostatic conditions.

Cells attach to the world through either cell-extracellular matrix adhesion or cell-cell adhesion, and traditional biomaterials imitate the matrix for integrin-based adhesion. However, materials incorporating cadherin proteins that mimic cell-cell adhesion offer an alternative to program cell behavior and integrate into living tissues. We investigated how cadherin substrates affect collective cell migration and cell cycling in epithelia. Our approach involved biomaterials with matrix proteins on one-half and E-cadherin proteins on the other, forming a "Janus" interface across which we grew a single sheet of cells. Tissue regions over the matrix side exhibited normal collective dynamics, but an abrupt behavior shift occurred across the Janus boundary onto the E-cadherin side, where cells attached to the substrate via E-cadherin adhesions, resulting in stalled migration and slowing of the cell cycle. E-cadherin surfaces disrupted long-range mechanical coordination and nearly doubled the length of the G0/G1 phase of the cell cycle, linked to the lack of integrin focal adhesions on the E-cadherin surface.

Optimal control of collective electrotaxis in epithelial monolayers.

Epithelial monolayers are some of the best-studied models for collective cell migration due to their abundance in multicellular systems and their tractability. Experimentally, the collective migration of epithelial monolayers can be robustly steered e.g. using electric fields, via a process termed electrotaxis. Theoretically, however, the question of how to design an electric field to achieve a desired spatiotemporal movement pattern is underexplored. In this work, we construct and calibrate an ordinary differential equation model to predict the average velocity of the centre of mass of a cellular monolayer in response to stimulation with an electric field. We use this model, in conjunction with optimal control theory, to derive physically realistic optimal electric field designs to achieve a variety of aims, including maximising the total distance travelled by the monolayer, maximising the monolayer velocity, and keeping the monolayer velocity constant during stimulation. Together, this work is the first to present a unified framework for optimal control of collective monolayer electrotaxis and provides a blueprint to optimally steer collective migration using other external cues.

Exploring the association between cognitive activity and symptom resolution following concussion in adolescents aged 11-17 years.

OBJECTIVE: As opposed to postconcussion physical activity, the potential influence of cognitive activity on concussion recovery is not well characterised. This study evaluated the intensity and duration of daily cognitive activity reported by adolescents following concussion and examined the associations between these daily cognitive activities and postconcussion symptom duration. METHODS: This study prospectively enrolled adolescents aged 11-17 years with a physician-confirmed concussion diagnosis within 72 hours of injury from the emergency department and affiliated concussion clinics. Participants were followed daily until symptom resolution or a maximum of 45 days postinjury to record their daily cognitive activity (intensity and duration) and postconcussion symptom scores. RESULTS: Participants (n=83) sustained their concussion mostly during sports (84%), had a mean age of 14.2 years, and were primarily male (65%) and white (72%). Participants reported an average of 191 (SD=148), 166 (SD=151) and 38 (SD=61) minutes of low-intensity, moderate-intensity and high-intensity daily cognitive activity postconcussion while still being symptomatic. Every 10 standardised minutes per hour increase in moderate-intensity or high-intensity cognitive activities postconcussion was associated with a 22% greater rate of symptom resolution (adjusted hazard ratio (aHR) 1.22, 95% CI 1.01 to 1.47). Additionally, each extra day's delay in returning to school postconcussion was associated with an 8% lower rate of symptom resolution (aHR 0.92, 95% CI 0.85 to 0.99). CONCLUSION: In adolescents with concussion, more moderate-high intensity cognitive activity is associated with faster symptom resolution, and a delayed return to school is associated with slower symptom resolution. However, these relationships may be bidirectional and do not necessarily imply causality. Randomised controlled trials are needed to determine if exposure to early cognitive activity can promote concussion recovery in adolescents.

Jumping Asymmetries and Risk of Injuries in Preprofessional Ballet.

BACKGROUND: Preprofessional ballet dancers are exposed to the risk of injuries, primarily in the lower extremities, with most injuries occurring during jumping and landing activities. Interlimb asymmetry during jumping and landing activities has been associated with the injury risk in adolescent athletes, but this has not been examined in dancers. PURPOSE: To investigate associations between interlimb asymmetry during a double-leg countermovement jump (DL-CMJ) and single-leg jump (SLJ) and the injury risk in adolescent preprofessional ballet dancers. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Adolescent preprofessional ballet dancers (N = 255) performed 3 DL-CMJs and 3 SLJs on force plates during annual screening. Absolute and directional (separate values for left and right limb dominance) asymmetries in a set of kinetic variables during a DL-CMJ and in jump height during an SLJ were calculated. Each variable was characterized as having "high" or "normal" asymmetry according to the percentage of asymmetry (greater than or less than or equal to, respectively, the mean ± 0.5 SD) based on the present sample. Risk ratios (RRs) and 95% CIs were calculated based on the injury incidence in the subsequent academic year. RESULTS: Of the 242 dancers that satisfied the inclusion criteria, 128 injuries were observed in the subsequent academic year. In the whole sample, 3 absolute, 7 left limb-dominant, and 1 right limb-dominant kinetic asymmetry in the eccentric, concentric, and landing phases of the DL-CMJ as well as left limb-dominant jump height asymmetry in the SLJ were associated with a significant (P < .001) increase in the injury risk (RR, 1.28-1.69 [95% CI, 1.02-2.37]). Separating by sex, asymmetries in the eccentric and landing phase of the DL-CMJ were not significant in boys, while in girls, RRs for asymmetries in the eccentric and landing phase of the DL-CMJ increased, and SLJ jump height asymmetry was not significant. CONCLUSION: Higher asymmetries in certain kinetic variables during the DL-CMJ and in jump height during the SLJ were associated with an elevated risk of injuries in elite preprofessional ballet dancers with some sex-specific differences. Associations were mainly identified for high left limb-dominant asymmetry in the takeoff phase, suggesting that the injury risk may be specific to a relative right limb deficit.

Covalent inhibition of pro-apoptotic BAX.

BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.

Multidimensional well-being of US households at a fine spatial scale using fused household surveys.

Social science often relies on surveys of households and individuals. Dozens of such surveys are regularly administered by the U.S. government. However, they field independent, unconnected samples with specialized questions, limiting research questions to those that can be answered by a single survey. The presented data comprise the fusion onto the American Community Survey (ACS) microdata of select donor variables from the Residential Energy Consumption Survey (RECS) of 2015, the National Household Travel Survey (NHTS) of 2017, the American Housing Survey (AHS) of 2019, and the Consumer Expenditure Survey - Interview (CEI) for the years 2015-2019. This results in an integrated microdataset of household attributes and well-being dimensions that can be analyzed to address research questions in ways that are not currently possible. The underlying statistical techniques, designed under the fusionACS project, are included in an open-source R package, fusionModel, that provides generic tools for the creation, analysis, and validation of fused microdata.

The discovery and evaluation of [18F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.

PURPOSE: A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1. METHODS: [18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression. RESULTS: Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%. CONCLUSION: A novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.

Spontaneous attentional failures reflect multiplicative interactions of chronic sleep loss with acute sleep loss and circadian misalignment.

OBJECTIVES: Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation. METHODS: Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase. RESULTS: During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day. CONCLUSIONS: A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss-further amplified during the biological night-substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety.

Technical Success in Performing Esophageal High-Resolution Manometry in Patients with an Epiphrenic Diverticulum.

High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders, yet it can be poorly tolerated and technically challenging. Epiphrenic diverticula (ED) are located in the distal esophagus and are associated with underlying motility disorders. ED patients (2008-2022) were retrospectively compared to achalasia patients (2008-2022) and all other patients (2021-2022) who underwent HRM at a single center. Complete success was defined as at least 7 interpretable swallows including measurements throughout the esophagus into the stomach. HRM studies involving children, previously treated achalasia, and sedation or endoscopic-assistance were excluded. 20 ED patients (mean age 66; 60% female) were compared to 76 achalasia patients and 199 controls. HRM was completely successful in 70.0% of ED patients, 85.5% of achalasia (p = 0.106 vs ED), and 91.0% of controls (p = 0.004 vs ED). Most failures in the ED and achalasia groups were due to inability to traverse the esophagogastric junction (EGJ), while patient intolerance was the main reason in controls. Half of the ED group had motility disorders (25% achalasia, 15% hypercontractile esophagus, 10% absent contractility). Large diverticulum size was inversely associated with technical success compared to small diverticulum size (40% vs 100%, p = 0.013), while the presence of a motility disorder did not significantly affect success (60% vs 88.9%, p = 0.303). In conclusion, ED is a predictor of unsuccessful HRM. This appears to be mainly related to an inability to traverse the EGJ due to the size of the diverticulum. Consideration should be given to alternative means of evaluating motility, such as endoscopy-assisted HRM, given the high likelihood of failure with traditional HRM.