Mechanisms underlying distinct subcellular localization and regulation of epithelial long myosin light-chain kinase splice variants.

Intestinal epithelia express two long myosin light-chain kinase (MLCK) splice variants, MLCK1 and MLCK2, which differ by the absence of a complete immunoglobulin (Ig)-like domain 3 within MLCK2. MLCK1 is preferentially associated with the perijunctional actomyosin ring at steady state, and this localization is enhanced by inflammatory stimuli including tumor necrosis factor (TNF). Here, we sought to identify MLCK1 domains that direct perijunctional MLCK1 localization and their relevance to disease. Ileal biopsies from Crohn's disease patients demonstrated preferential increases in MLCK1 expression and perijunctional localization relative to healthy controls. In contrast to MLCK1, MLCK2 expressed in intestinal epithelia is predominantly associated with basal stress fibers, and the two isoforms have distinct effects on epithelial migration and barrier regulation. MLCK1(Ig1-4) and MLCK1(Ig1-3), but not MLCK2(Ig1-4) or MLCK1(Ig3), directly bind to F-actin in vitro and direct perijunctional recruitment in intestinal epithelial cells. Further study showed that Ig1 is unnecessary, but that, like Ig3, the unstructured linker between Ig1 and Ig2 (Ig1/2us) is essential for recruitment. Despite being unable to bind F-actin or direct recruitment independently, Ig3 does have dominant negative functions that allow it to displace perijunctional MLCK1, increase steady-state barrier function, prevent TNF-induced MLCK1 recruitment, and attenuate TNF-induced barrier loss. These data define the minimal domain required for MLCK1 localization and provide mechanistic insight into the MLCK1 recruitment process. Overall, the results create a foundation for development of molecularly targeted therapies that target key domains to prevent MLCK1 recruitment, restore barrier function, and limit inflammatory bowel disease progression.

Biomedical research brings mTBI biomarkers a step closer to the bedside - implementation in clinical practice.

Research in the field of TBI (traumatic brain injury) has long been focused on severe brain injury, while the number of mild injuries far overweigh severe injuries. Mild head injuries constitute up to 95% of all traumatic head injuries. The purpose of this work is to identify mTBI (mild traumatic brain injury) patients who are unlikely to benefit from CT (computed tomography) scanning. Biomarkers capable of clearly discriminating between CT-positive and CT-negative subjects are needed. Biomarkers hold the potential to document whether a concussion occurred, especially when the history is unclear and neurocognitive sequelae persist. Recently, following advances in proteomics analysis, investigators have introduced ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) as two promising brain injury biomarkers. The authors provide an update on the current knowledge of TBI biomarkers, especially protein biomarkers for neuronal cell body injury (UCH-L1) and astroglial injury (GFAP, S100B), and a focused literature review dealing with implementation of mTBI biomarkers in clinical practice.

Differential spatial distribution of white matter lesions in Parkinson's and Alzheimer's diseases and cognitive sequelae.

White Matter Lesions (WML) are a radiological finding common in aged subjects. We explored the impact of WML on underlying neurodegenerative processes. We focused on the impact of WML on two neurodegenerative diseases with different pathology. In this cross-sectional study of 137 subjects (78 female, 59 men, mean age 67.2; 43-87 years), we compared WML in healthy controls (HC; n = 55), patients with Alzheimer's disease and amnestic Mild Cognitive Impairment (aMCI), and Parkinson's disease patients with normal cognition and with MCI. Subjects with AD and aMCI were treated as one group (n = 40), subjects with PD and PDMCI were another group (n = 42). MRI T2_FLAIR sequences were analyzed. WML were divided into periventricular (pWML) or subcortical (sWML) depending on their distance from the ventricles. Subjects from the AD + aMCI group, had a significantly greater volume of WML than both HC and the PD + PDMCI group. The volume of WML was greater in the PD + PDMCI than in HC but the difference was not significant. In AD + aMCI subjects, sWML and not pWML were related to a decrease in global cognitive functioning despite greater volume of pWML. In PD + PDMCI, pWML correlate with decline in executive functions and working memory. In HC, pWML correlated with the multidomain decrease corresponding with the aging. This points to a difference between normal aging and pathological aging due to AD and PD brain pathology. The WML location together with underlying disease related neurodegeneration may play a role in determining the effect of WML on cognition. Our results suggest that the impact of WML is not uniform in all patients; rather, their volume, location and cognitive effect may be disease-specific.

A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Cholera toxin B subunit (CTB) exhibits broad-spectrum biologic activity upon mucosal administration. Here, we found that a recombinant CTB containing an endoplasmic reticulum (ER) retention motif (CTB-KDEL) induces colon epithelial wound healing in colitis via the activation of an unfolded protein response (UPR) in colon epithelial cells. In a Caco2 cell wound healing model, CTB-KDEL, but not CTB or CTB-KDE, facilitated cell migration via interaction with the KDEL receptor, localization in the ER, UPR activation, and subsequent TGF-ß signaling. Inhibition of the inositol-requiring enzyme 1/X-box binding protein 1 arm of UPR abolished the cell migration effect of CTB-KDEL, indicating that the pathway is indispensable for the activity. CTB-KDEL's capacity to induce UPR and epithelial restitution or wound healing was corroborated in a dextran sodium sulfate-induced acute colitis mouse model. Furthermore, CTB-KDEL induced a UPR, up-regulated wound healing pathways, and maintained viable crypts in colon explants from patients with inflammatory bowel disease (IBD). In summary, CTB-KDEL exhibits unique wound healing effects in the colon that are mediated by its localization to the ER and subsequent activation of UPR in epithelial cells. The results provide implications for a novel therapeutic approach for mucosal healing, a significant unmet need in IBD treatment.-Royal, J. M., Oh, Y. J., Grey, M. J., Lencer, W. I., Ronquillo, N., Galandiuk, S., Matoba, N. A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Interprofessional, multitiered daily rounding management in a high-acuity hospital.

PURPOSE: The purpose of this explanatory case study is to explain the implementation of interprofessional, multitiered lean daily management (LDM) and to quantitatively report its impact on hospital safety. DESIGN/METHODOLOGY/APPROACH: This case study explained the framework for LDM implementation and changes in quality metrics associated with the interprofessional, multitiered LDM, implemented at Saint Francis Hospital and Medical Center (SFHMC) at the end of 2018. Concepts from lean, Total Quality Management (TQM) and high reliability science were applied to develop the four tiers and gemba rounding components of LDM. A two-tailed t-test analysis was utilized to determine statistical significance for serious safety events (SSEs) comparing the intervention period (January 2019-December 2019) to the baseline period (calendar years 2017 and 2018). Other quality and efficiency metrics were also tracked. FINDINGS: LDM was associated with decreased SSEs in 2019 compared to 2017 and 2018 (p ≤ 0.01). There were no reportable central line-associated blood stream infection (CLABSI) or catheter-associated urinary tract infection (CAUTI) for first full calendar quarter in the hospital's history. Hospital-acquired pressure injuries were at 0.2 per 1,000 patient days, meeting the annual target of <0.5 per 1,000 patient days. Outcomes for falls with injury, hand hygiene and patient experience also trended toward target. These improvements occurred while also observing a lower observed to expected length of stay (O/E LOS), which is the organizational marker for hospital's efficiency. RESEARCH LIMITATIONS/IMPLICATIONS: LDM may contribute greatly to improve safety outcomes. This observational study was performed in an urban, high-acuity, low cost hospital which may not be representative of other hospitals. Further study is warranted to determine whether this model can be applied more broadly to other settings. PRACTICAL IMPLICATIONS: LDM can be implemented quickly to achieve an improvement in hospital safety and other health-care quality outcomes. This required a redistribution of time for hospital staff but did not require any significant capital or other investment. SOCIAL IMPLICATIONS: As hospital systems move from a volume-based to value-based health-care delivery model, dynamic interventions using LDM can play a pivotal role in helping all patients, particularly in underserved settings where lower cost care is required for sustainability, given limited available resources. ORIGINALITY/VALUE: While many hospital systems promote organizational rounding as a routine quality improvement process, this study shows that a dynamic, intense LDM model can dramatically improve safety within months. This was done in a challenging urban environment for a high-acuity population with limited resources.

Innate immunity at mucosal surfaces: the IRE1-RIDD-RIG-I pathway.

Recent studies have linked the ER stress sensor IRE1α with the RIG-I pathway, which triggers an inflammatory response upon detection of viral RNAs. In response to ER dysfunction, IRE1α cleaves mRNA into single-strand fragments that lack markers of self, which activate RIG-I. Certain microbial products from mucosal pathogens activate this pathway by binding IRE1α directly, and the discovery that IRE1 is amplified at mucosal surfaces by gene duplication suggests an important role for IRE1 in mucosal immunity. Here, we review evidence in support of this hypothesis, and propose a model wherein IRE1 surveys the integrity of the ER, acting as a guard receptor and a pattern recognition receptor, capable both of sensing cellular stress caused by microbial infection and of responding to pathogens directly.

Long-term progressive motor skill training enhances corticospinal excitability for the ipsilateral hemisphere and motor performance of the untrained hand.

It is well established that unilateral motor practice can lead to increased performance in the opposite non-trained hand. Here, we test the hypothesis that progressively increasing task difficulty during long-term skill training with the dominant right hand increase performance and corticomotor excitability of the left non-trained hand. Subjects practiced a visuomotor tracking task engaging right digit V for 6 weeks with either progressively increasing task difficulty (PT) or no progression (NPT). Corticospinal excitability (CSE) was evaluated from the resting motor threshold (rMT) and recruitment curve parameters following application of transcranial magnetic stimulation (TMS) to the ipsilateral primary motor cortex (iM1) hotspot of the left abductor digiti minimi muscle (ADM). PT led to significant improvements in left-hand motor performance immediately after 6 weeks of training (63 ± 18%, P < 0.001) and 8 days later (76 ± 14%, P < 0.001). In addition, PT led to better task performance compared to NPT (19 ± 15%, P = 0.024 and 27 ± 15%, P = 0.016). Following the initial training session, CSE increased across all subjects. After 6 weeks of training and 8 days later, only PT was accompanied by increased CSE demonstrated by a left and upwards shift in the recruitment curves, e.g. indicated by increased MEPmax (P = 0.012). Eight days after training similar effects were observed, but 14 months later motor performance and CSE were similar between groups. We suggest that progressively adjusting demands for timing and accuracy to individual proficiency promotes motor skill learning and drives the iM1-CSE resulting in enhanced performance of the non-trained hand. The results underline the importance of increasing task difficulty progressively and individually in skill learning and rehabilitation training.

Exploring the quiet eye in archery using field- and laboratory-based tasks.

The 'quiet eye' (QE)-a period of extended gaze fixation on a target-has been reported in many tasks that require accurate aiming. Longer quiet eye durations (QEDs) are reported in experts compared to non-experts and on successful versus less successful trials. The QE has been extensively studied in the field; however, the cognitive mechanisms underlying the QE are not yet fully understood. We investigated the QEDs of ten expert and ten novice archers in the field and in the laboratory using a computer-based archery task. The computer task consisted of shooting archery targets using a joystick. Random 'noise' (visual motion perturbation) was introduced at high and low levels to allow for the controlled examination of the effects of task complexity and processing demands. In this computer task, we also tested an additional group of ten non-archers as controls. In both field and computer tasks, eye movements were measured using electro-oculography. The expert archers exhibited longer QED compared to the novice archers in the field task. In the computer task, the archers again exhibited longer QEDs and were more accurate compared to non-archers. Furthermore, expert archers showed earlier QE onsets and longer QEDs during high noise conditions compared to the novices and non-archers. Our findings show skill-based effects on QED in field conditions and in a novel computer-based archery task, in which online (visual) perturbations modulated experts' QEDs. These longer QEDs in experts may be used for more efficient programming in which accurate predictions are facilitated by attention control.

The TMS Map Scales with Increased Stimulation Intensity and Muscle Activation.

One way to study cortical organisation, or its reorganisation, is to use transcranial magnetic stimulation (TMS) to construct a map of corticospinal excitability. TMS maps are reported to be acquired with a wide variety of stimulation intensities and levels of muscle activation. Whilst MEPs are known to increase both with stimulation intensity and muscle activation, it remains to be established what the effect of these factors is on the map's centre of gravity (COG), area, volume and shape. Therefore, the objective of this study was to systematically examine the effect of stimulation intensity and muscle activation on these four key map outcome measures. In a first experiment, maps were acquired with a stimulation intensity of 110, 120 and 130% of resting threshold. In a second experiment, maps were acquired at rest and at 5, 10, 20 and 40% of maximum voluntary contraction. Map area and map volume increased with both stimulation intensity (P < 0.01) and muscle activation (P < 0.01). Neither the COG nor the map shape changed with either stimulation intensity or muscle activation (P > 0.09 in all cases). This result indicates the map simply scales with stimulation intensity and muscle activation.

Maximum tolerable daily dose of mirror movement therapy ankle exercises after stroke: an early phase dose screening study.

BACKGROUND: Mirror movement therapy may reduce lower limb motor impairment after stroke. The dose is unknown. OBJECTIVE: identify the maximum tolerable dose a day (MTD) of lower limb mirror movement therapy DESIGN: 3 + 3 cohort rule-based, dose escalation/de-escalation study. After undertaking baseline measures participants performed mirror movement therapy for 14 consecutive days. Participants then undertook outcome measures. Cohort One trained for 15 minutes daily. Subsequent cohorts exercised at a dose set according to pre-set rules and the modified Fibonacci sequence. The study stopped when the difference between set doses for consecutive cohorts was 10% or less. SETTING: Participants' homes (intervention) and a movement analysis laboratory (measures). PARTICIPANTS: Adults discharged from statutory stroke rehabilitation services. INTERVENTION: Mirror movement therapy ankle exercises. OUTCOME MEASURES: Motricity Index (primary) and bilateral time symmetry from movement onset to peak activation of Tibialis Anterior muscles during standardised sit-to-stand (secondary). RESULTS: Five cohorts of three participants were included (n = 15). Mean (SD) age and time after stroke were 61 (9) years and 35 (42) months respectively. Set daily doses for the five cohorts were: 15, 30, 50, 40 then 35 minutes. The set dose for a subsequent cohort (six) would have been 38 minutes thus the difference from cohort five would have been three minutes i.e., 9% different. Therefore, the study stopped CONCLUSION: The identified MTD of lower limb mirror therapy was 35 minutes daily when frequency was set at seven days a week and duration as two weeks. CLINICAL TRIAL REGISTRATION NUMBER: NCT04339803 (ClinicalTrials.gov) CONTRIBUTION OF THE PAPER: This early phase study found that the maximum tolerable dose per day (MTD) of mirror movement therapy ankle exercises was 35 minutes when frequency was set at seven days a week and duration as two weeks. The optimal therapeutic dose will therefore be somewhere in the range of 15 (starting dose) to 35 minutes per day. Further dose articulation studies are required to identify the optimal therapeutic dose before use of findings in clinical practice. This study is the first step in that research process.

IRE1α recognizes a structural motif in cholera toxin to activate an unfolded protein response.

IRE1α is an endoplasmic reticulum (ER) sensor that recognizes misfolded proteins to induce the unfolded protein response (UPR). We studied cholera toxin (CTx), which invades the ER and activates IRE1α in host cells, to understand how unfolded proteins are recognized. Proximity labeling colocalized the enzymatic and metastable A1 segment of CTx (CTxA1) with IRE1α in live cells, where we also found that CTx-induced IRE1α activation enhanced toxicity. In vitro, CTxA1 bound the IRE1α lumenal domain (IRE1αLD), but global unfolding was not required. Rather, the IRE1αLD recognized a seven-residue motif within an edge ß-strand of CTxA1 that must locally unfold for binding. Binding mapped to a pocket on IRE1αLD normally occupied by a segment of the IRE1α C-terminal flexible loop implicated in IRE1α oligomerization. Mutation of the CTxA1 recognition motif blocked CTx-induced IRE1α activation in live cells, thus linking the binding event with IRE1α signal transduction and induction of the UPR.

Modulation of proprioceptive feedback during functional electrical stimulation: an fMRI study.

Functional electrical stimulation (FES) is sometimes used as a therapeutic modality in motor rehabilitation to augment voluntary motor drive to effect movement that would otherwise not be possible through voluntary activation alone. Effective motor rehabilitation should require that the central nervous system integrate efferent commands and appropriate afferent information to update the internal models of acquired skills. Here, we investigate whether FES-evoked (FES-ev) and FES-assisted (FES-as) movement are associated with the normal integration of motor commands and sensory feedback in a group of healthy participants during functional magnetic resonance imaging (fMRI). Sensory feedback was removed with a peripheral ischaemic nerve block while the participants performed voluntary (VOL), FES-ev or FES-as movement during fMRI. Before the peripheral nerve block, secondary somatosensory area (S2) activation was greater for the FES-ev and FES-as conditions than for the VOL condition. During the ischaemic nerve block, S2 activation was reduced for the FES-ev condition but not for FES-as and VOL conditions. The nerve block also reduced activation during FES in the primary somatosensory cortex and other motor areas including primary motor cortex, dorsal premotor cortex and supplementary motor area. In contrast, superior parietal lobule (area 7A) and precuneus activation was reduced as a consequence of the ischaemic nerve block in the VOL condition. These data suggest FES-related S2 activation is mainly a sensory phenomenon and does not reflect integration of sensory signals with motor commands.

Stressing out over mucus secretion.

In this issue of Cell Host & Microbe, Naama et al. show that autophagy controls mucus secretion in the colons of mice. They demonstrate that autophagy reduces ER stress in mucus-producing goblet cells to enhance mucus production, which shapes the gut microbial community and protects against colitis.

Comparison of ultrasound-guided and palpation-inserted peripheral venous cannula in -patients before primary hip or knee arthroplasty: study protocol for a randomized controlled trial.

BACKGROUND: More than 2 billion peripheral vascular cannulas are introduced globally each year. It is the most frequently performed invasive procedure in medicine worldwide. There is a group of patients with difficult intravenous access (DIVA). In experts' hands, ultrasound-guided vascular access appears to be a significantly better method. Investigators hypothesize that UGVA is superior also in short-term patency of cannula and even for blood draw through cannula. Repeated cannula pricks in the operating room setting not only puts a lot of stress on the patient and medical staff, but they also waste OR time. METHODS: This investigator-initiated prospective randomized monocentric controlled trial is designed to randomly allocate 200 patients undergoing elective primary total joint arthroplasty of hip or knee to one of two groups as follows: Group C (control group) - peripheral venous cannula insertion by palpation or Group USG (intervention) - cannula insertion by ultrasound-guided vascular access. Our primary endpoint is to compare the number of attempts for ultrasound-guided insertion of the peripheral venous cannula with common palpation insertion of the peripheral venous cannula in overweight/obese patients (BMI ≥ 25). The secondary endpoint is a failure rate of the peripheral venous cannula to administer intravenous therapy up to 5 days postoperatively. Tertiary endpoints include a portion of long PVCs that are able to ensure blood draw up to 5 days postoperatively, time needed to insert PVC in each group, number of needle tip redirections in both groups, and reinsertion of PVC needed in both groups for any reason. DISCUSSION: This study is pragmatic and is looking for clinically relevant data. After completion, it will answer the question of whether it is clinically relevant to use ultrasound-guided vascular access in the context of not only short-term benefit of insertion, but also up to 5 days after insertion. Also, if this method can ensure blood draw through a peripheral vein cannula, it can save resources in the perioperative period - valuable especially considering the ongoing shortage of medical staff worldwide. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of ultrasound-guided peripheral vascular access in the perioperative period. TRIAL REGISTRATION: ClinicalTrials.gov NCT05156008. Registered on 13.12.2021.

p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP.

ARHGAP35, which encodes p190A RhoGAP (p190A), is a major cancer gene. p190A is a tumor suppressor that activates the Hippo pathway. p190A was originally cloned via direct binding to p120 RasGAP (RasGAP). Here, we determine that interaction of p190A with the tight-junction-associated protein ZO-2 is dependent on RasGAP. We establish that both RasGAP and ZO-2 are necessary for p190A to activate large tumor-suppressor (LATS) kinases, elicit mesenchymal-to-epithelial transition, promote contact inhibition of cell proliferation, and suppress tumorigenesis. Moreover, RasGAP and ZO-2 are required for transcriptional modulation by p190A. Finally, we demonstrate that low ARHGAP35 expression is associated with shorter survival in patients with high, but not low, transcript levels of TJP2 encoding ZO-2. Hence, we define a tumor-suppressor interactome of p190A that includes ZO-2, an established constituent of the Hippo pathway, and RasGAP, which, despite strong association with Ras signaling, is essential for p190A to activate LATS kinases.

Specialist healthcare services for concussion/mild traumatic brain injury in England: a consensus statement using modified Delphi methodology.

OBJECTIVE: To establish a consensus on the structure and process of healthcare services for patients with concussion in England to facilitate better healthcare quality and patient outcome. DESIGN: This consensus study followed the modified Delphi methodology with five phases: participant identification, item development, two rounds of voting and a meeting to finalise the consensus statements. The predefined threshold for agreement was set at ≥70%. SETTING: Specialist outpatient services. PARTICIPANTS: Members of the UK Head Injury Network were invited to participate. The network consists of clinical specialists in head injury practising in emergency medicine, neurology, neuropsychology, neurosurgery, paediatric medicine, rehabilitation medicine and sports and exercise medicine in England. PRIMARY OUTCOME MEASURE: A consensus statement on the structure and process of specialist outpatient care for patients with concussion in England. RESULTS: 55 items were voted on in the first round. 29 items were removed following the first voting round and 3 items were removed following the second voting round. Items were modified where appropriate. A final 18 statements reached consensus covering 3 main topics in specialist healthcare services for concussion; care pathway to structured follow-up, prognosis and measures of recovery, and provision of outpatient clinics. CONCLUSIONS: This work presents statements on how the healthcare services for patients with concussion in England could be redesigned to meet their health needs. Future work will seek to implement these into the clinical pathway.

Interaction of electrical stimulation and voluntary hand movement in SII and the cerebellum during simulated therapeutic functional electrical stimulation in healthy adults.

The therapeutic application of functional electrical stimulation (FES) has shown promising clinical results in the rehabilitation of post-stroke hemiplegia. It appears that the effect is optimal when the patterned electrical stimulation is used in close synchrony with voluntary movement, although the neural mechanisms that underlie the clinical successes reported with therapeutic FES are unknown. One possibility is that therapeutic FES takes advantage of the sensory consequences of an internal model. Here, we investigate fMRI cortical activity when FES is combined with voluntary effort (FESVOL) and we compare this activity to that produced when FES and voluntary activity (VOL) are performed alone. FESVOL revealed greater cerebellar activity compared with FES alone and reduced activity bilaterally in secondary somatosensory areas (SII) compared with VOL alone. Reduced activity was also observed for FESVOL compared with FES alone in the angular gyrus, middle frontal gyrus and inferior frontal gyrus. These findings indicate that during the VOL condition the cerebellum predicts the sensory consequences of the movement and this reduces the subsequent activation in SII. The decreased SII activity may reflect a better match between the internal model and the actual sensory feedback. The greater cerebellar activity coupled with reduced angular gyrus activity in FESVOL compared with FES suggests that the cortex may interpret sensory information during the FES condition as an error-like signal due to the lack of a voluntary component in the movement.

Decade of Patient Experience Improvement at a Tertiary Care Urban Hospital.

BACKGROUND AND OBJECTIVE: The purpose of this quality management study was to demonstrate how one hospital made a journey from average patient experience to become a regional leader in the experience of patient care for nationally recognized quality and safety metrics. METHODS: Saint Francis Hospital & Medical Center (SFHMC) located in Hartford, Connecticut, serves a diverse sociodemographic community as part of Trinity Health. "Recommend the Hospital" (RTH) has been the main marker of patient experience at SFHMC and Trinity Health across the United States as part of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS). From 2010 to 2019, SFHMC implemented unit-based rounding hospital-wide, adopting charge nurse and executive leadership rounding as standard work. The intense support from senior leadership spurred the implementation of these changes across middle management and all frontline workers. The t test was used to determine differences between the mean RTH scores between SFHMC, Connecticut, and the United States. RESULTS: Patient experience at SFHMC was regularly assessed by Press Ganey surveys and HCAHPS, which demonstrated higher scores than averages for the state of Connecticut and the United States between 2010 and 2019 (both Ps < .001). SFHMC was the top performer with an RTH score of 83%, with the state average being 71% and the national average being 72%. In the years following the implementation of a multipronged low-cost strategy, hospital RTH scores rose linearly from the state and national average. SFHMC observed gains in patient safety and quality scores as measured by national benchmarks, including Leapfrog patient safety scores of 7 A's and 1 B over a 4-year period. SFHMC was the only hospital in Connecticut to receive an A grade 4 years in a row. CONCLUSION: A combination of nurse-led, unit-based rounding and executive team rounding with a consistent focus on patient experience resulted in significant improvement in RTH scores for a busy teaching urban hospital, with only a modest investment of resources. There was also improvement in quality and safety outcomes, which together with patient experience of care drove fiscal stability in an increasingly value-based health care environment.

The epithelial-specific ER stress sensor ERN2/IRE1ß enables host-microbiota crosstalk to affect colon goblet cell development.

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1ß, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free WT mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.