Treatment for Neonatal Abstinence Syndrome using Nonpharmacological Interventions.

OBJECTIVE: Management of neonatal abstinence syndrome includes nonpharmacological interventions, but their effectiveness may not be verified before implemented. The objective of this study is to evaluate the effectiveness of a type of bassinet in the treatment of infants with neonatal abstinence syndrome. STUDY DESIGN: This is a retrospective observational cohort study. Study setting involved a 24-bed open-bay Level III neonatal intensive care unit located in a metropolitan academic trauma facility. Participant inclusion criteria involved prenatally opioid-exposed infants ≥ 35 weeks with confirmed maternal opioid urine toxicology, required pharmacological treatment for withdrawal symptoms, and were admitted to the neonatal intensive care unit. Three subsets of study participants were analyzed over three different time periods: Group 1 were infants admitted during 2019 without nonpharmacological intervention, Group 2 who were admitted from September 2021 to February 2022 and received nonpharmacological interventions, and Group 3 included those admitted from February 2022 to March 2023 who received the same interventions as Group 2 but were managed in bassinets being used in other local facilities for neonatal abstinence syndrome. RESULTS: Group 3 had significant increases in length of stay compared with Group 1 (p = 0.006) and Group 2 (p = 0.013). Group 3 had a significantly greater length of treatment than Group 1 (p = 0.041) and a significantly higher total mg/kg morphine exposure than Group 1 (p = 0.006). CONCLUSION: Addition of the bassinet for nonpharmacological management of infants with neonatal abstinence syndrome appeared to prolong length of stay, length of treatment, and increase total mg/kg morphine exposure. As a retrospective nonrandomized study, weakness of low certainty of causality is of concern but findings strongly warrant further research before devices such as the bassinet used in this study are adopted for routine neonatal abstinence syndrome care. KEY POINTS: · Special bassinets are promoted to enhance sleep and decrease agitation.. · Such bassinets may assist infants undergoing drug withdrawal.. · Study of the bassinet failed to show benefit to this population..

Empowering nursing council implementation science: An appeal to action.

BACKGROUND: In most hospitals, nursing councils are responsible for EBP implementation and evaluation. To enhance the perceived value of council participation by frontline nurses, administrators must promote the impact of council projects on healthcare outcomes. PURPOSE: The purposes of this appeal to action are to describe the role of nursing councils in promoting IS and EBP, and to provide recommendations that enhance the value of IS and/or EBP councils to frontline nurses, thereby incentivizing participation on these councils. METHODS: Nurse researchers from three metropolitan hospitals partnered with a medical librarian to recommend six strategies aimed at enhancing the perceived value of council participation. An argumentative review was conducted to support these strategies. DISCUSSION: Recommendations are inclusion of methods experts on councils; support from nursing administrators in the development, implementation, and evaluation of projects; formation of partnerships with nursing academic departments; expansion of publication opportunities and availability; and connection of projects to measurable quality indicators. CONCLUSION: Enhancing the perceived value of nursing councils by providing tools that optimize time and resource management can result in greater council participation and broader dissemination of IS evidence.

Engagement With mHealth COVID-19 Digital Biomarker Measurements in a Longitudinal Cohort Study: Mixed Methods Evaluation.

BACKGROUND: The COVID-19 pandemic accelerated the interest in implementing mobile health (mHealth) in population-based health studies, but evidence is lacking on engagement and adherence in studies. We conducted a fully remote study for ≥6 months tracking COVID-19 digital biomarkers and symptoms using a smartphone app nested within an existing cohort of adults. OBJECTIVE: We aimed to investigate participant characteristics associated with initial and sustained engagement in digital biomarker collection from a bespoke smartphone app and if engagement changed over time or because of COVID-19 factors and explore participants' reasons for consenting to the smartphone substudy and experiences related to initial and continued engagement. METHODS: Participants in the Fenland COVID-19 study were invited to the app substudy from August 2020 to October 2020 until study closure (April 30, 2021). Participants were asked to complete digital biomarker modules (oxygen saturation, body temperature, and resting heart rate [RHR]) and possible COVID-19 symptoms in the app 3 times per week. Participants manually entered the measurements, except RHR that was measured using the smartphone camera. Engagement was categorized by median weekly frequency of completing the 3 digital biomarker modules (categories: 0, 1-2, and ≥3 times per week). Sociodemographic and health characteristics of those who did or did not consent to the substudy and by engagement category were explored. Semistructured interviews were conducted with 35 participants who were purposively sampled by sex, age, educational attainment, and engagement category, and data were analyzed thematically; 63% (22/35) of the participants consented to the app substudy, and 37% (13/35) of the participants did not consent. RESULTS: A total of 62.61% (2524/4031) of Fenland COVID-19 study participants consented to the app substudy. Of those, 90.21% (2277/2524) completed the app onboarding process. Median time in the app substudy was 34.5 weeks (IQR 34-37) with no change in engagement from 0 to 3 months or 3 to 6 months. Completion rates (≥1 per week) across the study between digital biomarkers were similar (RHR: 56,517/77,664, 72.77%; temperature: 56,742/77,664, 73.06%; oxygen saturation: 57,088/77,664, 73.51%). Older age groups and lower managerial and intermediate occupations were associated with higher engagement, whereas working, being a current smoker, being overweight or obese, and high perceived stress were associated with lower engagement. Continued engagement was facilitated through routine and personal motivation, and poor engagement was caused by user error and app or equipment malfunctions preventing data input. From these results, we developed key recommendations to improve engagement in population-based mHealth studies. CONCLUSIONS: This mixed methods study demonstrated both high initial and sustained engagement in a large mHealth COVID-19 study over a ≥6-month period. Being nested in a known cohort study enabled the identification of participant characteristics and factors associated with engagement to inform future applications in population-based health research.

Development of a prognostic model for mortality in COVID-19 infection using machine learning.

Coronavirus disease 2019 (COVID-19) is a novel disease resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has quickly risen since the beginning of 2020 to become a global pandemic. As a result of the rapid growth of COVID-19, hospitals are tasked with managing an increasing volume of these cases with neither a known effective therapy, an existing vaccine, nor well-established guidelines for clinical management. The need for actionable knowledge amidst the COVID-19 pandemic is dire and yet, given the urgency of this illness and the speed with which the healthcare workforce must devise useful policies for its management, there is insufficient time to await the conclusions of detailed, controlled, prospective clinical research. Thus, we present a retrospective study evaluating laboratory data and mortality from patients with positive RT-PCR assay results for SARS-CoV-2. The objective of this study is to identify prognostic serum biomarkers in patients at greatest risk of mortality. To this end, we develop a machine learning model using five serum chemistry laboratory parameters (c-reactive protein, blood urea nitrogen, serum calcium, serum albumin, and lactic acid) from 398 patients (43 expired and 355 non-expired) for the prediction of death up to 48 h prior to patient expiration. The resulting support vector machine model achieved 91% sensitivity and 91% specificity (AUC 0.93) for predicting patient expiration status on held-out testing data. Finally, we examine the impact of each feature and feature combination in light of different model predictions, highlighting important patterns of laboratory values that impact outcomes in SARS-CoV-2 infection.

RCT of a Comprehensive Outpatient Treatment for Children with Autism Spectrum Disorder.

Objective: This study tested the efficacy of an intensive outpatient psychosocial treatment for children with autism spectrum disorder (ASD) without intellectual disability (ID).Method: Eighty-eight children (ages 7-12 years) were randomly assigned to the treatment or control (waitlist) condition. The 18-week cognitive-behavioral treatment (two 90-min sessions per week) included small-group instruction and therapeutic activities targeting social/social-communication skills, face-emotion recognition, nonliteral language skills, and interest expansion. A behavioral system was used to increase skills development and reduce ASD symptoms. Efficacy was tested immediately following treatment (posttest), with maintenance assessed 4-6 weeks later (follow-up). Measures included parent ratings of the children's social/social-communication skills, ASD symptoms, broad social skills, and behavior symptoms, child tests of social-cognitive skills (emotion recognition and nonliteral language), and behavioral observations.Results:Significant effects favoring the treatment group were found at posttest on the primary measures of ASD symptoms (Social Responsiveness Scale, Second Edition; Constantino & Gruber, 2012) and social/social-communication skills (Adapted Skillstreaming Checklist; Lopata, Thomeer, Volker, Nida & Lee, 2008), and secondary measures of nonliteral language skills, broad social skills, and behavior symptoms (measures of emotion-recognition skills and social behaviors during structured game sessions were non-significant). The significant treatment effects found at posttest were all maintained at follow-up.Conclusions: The outpatient treatment improved several core areas of functioning for children with ASD without ID. Additional elements may be needed to expand the efficacy of the treatment so that the observed skills/symptom improvements generalize to social interactions during gameplay.

Immediate Effects of Immersive Biofeedback on Gait in Children With Cerebral Palsy.

OBJECTIVE: To investigate the immediate response to avatar-based biofeedback on 3 clinically important gait parameters: step length, knee extension, and ankle power in children with cerebral palsy (CP). DESIGN: Repeated measures design. SETTING: Rehabilitation clinic. PARTICIPANTS: Children with spastic paresis (N=22; 10.5±3.1y), able to walk without assistive devices. INTERVENTION: Children walked on a treadmill with a virtual reality environment. Following baseline gait analysis, they were challenged to improve aspects of gait. Children visualized themselves as an avatar, representing movement in real time. They underwent a series of 2-minute trials receiving avatar-based biofeedback on step length, knee extension, and ankle power. To investigate optimization of biofeedback visualization, additional trials in which knee extension was visualized as a simple bar with no avatar; and avatar alone with no specific biofeedback were carried out. MAIN OUTCOME MEASURES: Gait pattern, as measured by joint angles, powers, and spatiotemporal parameters, were compared between baseline and biofeedback trials. RESULTS: Participants were able to adapt gait pattern with biofeedback, in an immediate response, reaching large increases in ankle power generation at push-off (37.7%) and clinically important improvements in knee extension (7.4o) and step length (12.7%). Biofeedback on one parameter had indirect influence on other aspects of gait. CONCLUSION: Children with CP show capacity in motor function to achieve improvements in clinically important aspects of gait. Visualizing biofeedback with an avatar was subjectively preferential compared to a simplified bar presentation of knee angle. Future studies are required to investigate if observed transient effects of biofeedback can be retained with prolonged training to test whether biofeedback-based gait training may be implemented as a therapy tool.

Community Effectiveness RCT of a Comprehensive Psychosocial Treatment for High-Functioning Children With ASD.

This community effectiveness randomized clinical trial examined the feasibility and effectiveness of a comprehensive psychosocial treatment, summerMAX, when implemented by a community agency. Fifty-seven high-functioning children (48 male, 9 female), ages 7-12 years with autism spectrum disorder participated in this study. The 5-week summerMAX treatment included instruction and therapeutic activities targeting social/social-communication skills, interpretation of nonliteral language skills, face-emotion recognition skills, and interest expansion. A behavioral program was also used to increase skills acquisition and decrease autism spectrum disorder symptoms and problem behaviors. Feasibility was supported via high levels of fidelity and parent, child, and staff clinician satisfaction. Significant treatment effects favoring the treatment group over waitlist controls were found on all 5 of the primary outcome measures (i.e., child test of nonliteral language skills and parent ratings of the children's autism spectrum disorder symptoms, targeted social/social-communication skills, broader social performance, and withdrawal). Staff clinician ratings substantiated the improvements reported by parents. Results of this randomized clinical trial are consistent with those of prior studies of summerMAX and suggest that the program was feasible and effective when implemented by a community agency under real-world conditions.

Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.

Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also displayed a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.

The efficacy of functional gait training in children and young adults with cerebral palsy: a systematic review and meta-analysis.

AIM: The aim of this systematic review was to investigate the effects of functional gait training on walking ability in children and young adults with cerebral palsy (CP). METHOD: The review was conducted using standardized methodology, searching four electronic databases (PubMed, Embase, CINAHL, Web of Science) for relevant literature published between January 1980 and January 2017. Included studies involved training with a focus on actively practising the task of walking as an intervention while reporting outcome measures relating to walking ability. RESULTS: Forty-one studies were identified, with 11 randomized controlled trials included. There is strong evidence that functional gait training results in clinically important benefits for children and young adults with CP, with a therapeutic goal of improved walking speed. Functional gait training was found to have a moderate positive effect on walking speed over standard physical therapy (effect size 0.79, p=0.04). Further, there is weaker yet relatively consistent evidence that functional gait training can also benefit walking endurance and gait-related gross motor function. INTERPRETATION: There is promising evidence that functional gait training is a safe, feasible, and effective intervention to target improved walking ability in children and young adults with CP. The addition of virtual reality and biofeedback can increase patient engagement and magnify effects. WHAT THIS PAPER ADDS: Functional gait training is a safe, feasible, and effective intervention to improve walking ability. Functional gait training shows larger positive effects on walking speed than standard physical therapy. Walking endurance and gait-related gross motor function can also benefit from functional gait training. Addition of virtual reality and biofeedback shows promise to increase engagement and improve outcomes.

Acute Mountain Sickness (AMS) Knowledge Among High Altitude Marathon Runners Competing in the Everest Marathon.

OBJECTIVE: Although there are a number of studies on trekkers' knowledge of acute mountain sickness (AMS), there is little current literature on other groups at altitude, for example, marathon runners. Increased knowledge of AMS is associated with a lower incidence of AMS. The purpose of this study was to determine AMS knowledge of marathon runners with an aim to improve AMS information distribution. Incidence of AMS was also determined. METHODS: Participants completed a self-assessment AMS knowledge questionnaire in Kathmandu before starting the acclimatization trek for the Tenzing Hillary Everest Marathon in Nepal. Lake Louise Scoring questionnaires were completed every day of the 12-day acclimatization trek. RESULTS: The majority (86%; 43 of 50) of participants obtained information about AMS before the marathon, with the Internet providing the most common source (50%; 25 of 50). Ninety-two percent (46 of 50) of participants rated their knowledge as average or above, and self-assessment correlated with knowledge questionnaire scores (r = .479, P < .001). However, 48% (24 of 50) did not know it was unsafe to ascend with mild AMS symptoms, and 66% (33 of 50) thought it was safe to go higher with symptoms relieved by medication. Only 50% (25 of 50) knew AMS could occur from 2500 m. Thirty-eight percent (19 of 50) of participants had AMS during the acclimatization trek, and 6% (3 of 50) experienced it during the race. CONCLUSIONS: This study adds to previous literature regarding knowledge and incidence of AMS. It further highlights that more needs to be done to improve knowledge through better information dissemination, with inclusion of scenario-based information to aid application of this knowledge to practical situations.

Advanced Directives and Advanced Care Planning for Healthcare Professionals.

The purposes of this study were to assess healthcare professionals' need for information on advanced directives and to implement and evaluate an educational plan for change in knowledge and behaviors related to advanced directives. End-of-life (EOL) care is an important topic for patients to discuss with their families and healthcare professionals (HP). Needs assessment data were collected from healthcare providers at an urban trauma intensive care unit (ICU) in Louisville, Kentucky on concepts related to end-of-life. Next, healthcare professionals participated in an educational intervention focused on: knowledge about advanced directives; communication techniques for healthcare professionals to use with patients and their families; awareness of the patient's level of illness in advanced care planning; and specifics about living wills in Kentucky and how to complete one. Pre- and post-test data were collected to evaluate change in knowledge, capability an average of 8.7 years (SD = 9.1; range = 1.9-35 years) in healthcare and worked an average of 8.4 years (SD = 9.3; range = 4 months to 35 years) in their respective ICUs. Eighty-seven percent did not have an AD in place even though their perceived knowledge about AD remained moderate throughout pre- and post-test scores (3.3 to 3.8 on a 5 point scale, respectively). Total post-test scores revealed a 2% improvement in correct responses. These findings point to the need for education of healthcare providers in the ICU to increase early AD and ACP discussions with patients and their families.

Orientation and Onboarding Experiences of Internationally Educated Nurses Transitioning to U.S. Nursing Practice.

Nursing professional development practitioners are faced with meeting the onboarding needs of internationally educated nurses (IENs) recruited to work in the United States. The purpose of this secondary data analysis study was to assess differences between demographic characteristics, orientation, and onboarding variables and IEN's length of orientation and retention to a healthcare system. A significant difference in the length of orientation by unit assigned, degree type, and retention were discovered.

Design, Implementation, and Evaluation of a Learning Needs Assessment for Nursing Professional Development Practitioners.

The purpose of this descriptive study was to highlight how a system-level education department operationalized the 2022 Association for Nursing Professional Development Scope and Standards of Practice into a learning needs assessment (LNA) survey. This was a collaborative approach to LNA design, implementation, and evaluation. The LNA conducted among nursing professional development practitioners determined areas for educational improvement, barriers to nursing professional development, and identified standards and competencies critical to improving knowledge acquisition.

Small Bowel Pyloric Metaplasia is Associated with Lower Rates of Earlier Recurrence of Crohn's Disease after Resection.

Recurrence within one or two years is common after Crohn's disease (CD) resection. In this study, we seek to identify histologic features in CD resections that may predict earlier (≤18 months) recurrence to potentially guide post-operative management. A single-institution, retrospective review was performed on patients with first-time CD bowel resection specimens (2002-2007). Patient demographics and CD course were also documented. Slides were reviewed for inflammatory distribution and composition, small bowel (SB) pyloric metaplasia (PM), and presence and characteristics of submucosal fibrosis and granulomas. In our cohort, 14 of 41 patients experienced earlier clinical or endoscopic recurrence after initial resection. In the 38 patients who underwent SB resection (3 were colon only), PM was less common in those with earlier recurrence (6/12 [50%]) compared to those with later (>18 months) or no known recurrence (22/26 [85%]) (P=0.045). PM was present even in patients with < 1 year of known CD. Additionally, therapy with anti-tumor necrosis factor (TNF) prior to surgery was more common in earlier recurrence patients (7/14 [50%]) than later or no recurrence patients (4/27 [15%]) (P = 0.026). There was no significant difference in age, sex, smoking status, duration of CD, post-operative CD medication, distribution or features of inflammation, granulomas, or fibrosis. Overall, our results indicate that SB PM and pre-surgical anti-TNF therapy are possible helpful clinicopathologic features to evaluate for recurrence risk.

Endoscopic submuscular dissection as a rescue for severe fibrosis after incomplete polypectomy.

Video 1Endoscopic submuscular dissection as a rescue for severe fibrosis after incomplete polypectomy.

X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis.

The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)ß-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-ß1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-ß1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fas-mediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.

Active cognitive reserve influences the regional atrophy to cognition link in multiple sclerosis.

Recent research indicates that cognitive reserve mitigates the clinical expression of neuropsychological impairment in multiple sclerosis (MS). This literature primarily uses premorbid intelligence and lifetime experiences as indicators. However, changes in current recreational activities may also contribute to the maintenance of neural function despite brain atrophy. We examined the moderation effects of current changes in recreational activity on the relationship between brain atrophy and information processing speed in 57 relapsing-remitting MS patients. Current enrichment was assessed using the Recreation and Pastimes subscale from the Sickness Impact Profile. In patients reporting current declines in recreational activities, brain atrophy was negatively associated with cognition, but there was no such association in participants reporting stable participation. The MRI metric-by-recreational activity interaction was significant in separate hierarchical regression analyses conducted using third ventricle width, neocortical volume, T2 lesion volume, and thalamic volume as brain measures. Results suggest that recreational activities protect against brain atrophy's detrimental influence on cognition.

Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance deleterious remodelling responses. Thus, EDA cFN may be a therapeutic target for ameliorating fibrosis associated with chronic cardiac allograft rejection.

IL-6 promotes cardiac graft rejection mediated by CD4+ cells.

IL-6 mediates numerous immunologic effects relevant to transplant rejection; however, its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8(+) or CD4(+) cell-dominant responses. In a setting of CD8(+) cell-dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in recipients. IL-6 neutralization markedly prolonged graft survival in the setting of CD4(+) cell-mediated acute rejection and was associated with decreased graft infiltrate, altered Th1 responses, and reduced serum alloantibody. Furthermore, in CD4(+) cell-dominated rejection, IL-6 neutralization was effective when anti-IL-6 administration was delayed by as many as 6 d posttransplant. Finally, IL-6-deficient graft recipients were protected from CD4(+) cell-dominant responses, suggesting that IL-6 production by graft recipients, rather than grafts, is necessary for this type of rejection. Collectively, these observations define IL-6 as a critical promoter of graft infiltration and a shaper of T cell lineage development in cardiac graft rejection. In light of these findings, the utility of therapeutics targeting IL-6 should be considered for preventing cardiac allograft rejection.

Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation.

RATIONALE: Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis. OBJECTIVES: To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs. METHODS: Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured. MEASUREMENTS AND MAIN RESULTS: We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-ß-independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses. CONCLUSIONS: This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner.