MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-ß1 levels.

Mutations in the CD18 gene encoding the common ß-chain of ß2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18-/- wounds by restoring the decreased TGF-ß1 concentrations. TGF-ß1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF-ß1 concentrations at wound sites. Low TGF-ß1 concentrations as occurring in CD18-/- wounds induce TGF-ß1 release from MSCs, whereas high TGF-ß1 concentrations suppress TGF-ß1 production. This regulation depends on TGF-ß receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-ß1 signaling. Inactivation of TGF-ß receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-ß1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.

Local and transient inhibition of p21 expression ameliorates age-related delayed wound healing.

Nonhealing chronic wounds in the constantly growing elderly population represent a major public health problem with high socioeconomic burden. Yet, the underlying mechanism of age-related impairment of wound healing remains elusive. Here, we show that the number of dermal cells expressing cyclin-dependent kinase inhibitor p21 was elevated upon skin injury, particularly in aged population, in both man and mouse. The nuclear expression of p21 in activated wound fibroblasts delayed the onset of the proliferation phase of wound healing in a p53-independent manner. Further, the local and transient inhibition of p21 expression by in vivo delivered p21-targeting siRNA ameliorated the delayed wound healing in aged mice. Our results suggest that the increased number of p21+ wound fibroblasts enforces the age-related compromised healing, and targeting p21 creates potential clinical avenues to promote wound healing in aged population.

A Statewide Program to Improve Management of Suspected Urinary Tract Infection in Long-Term Care.

BACKGROUND/OBJECTIVES: Suspected urinary tract infection (UTI) is the most common indication for antibiotic use in long-term care (LTC). Due to the high prevalence of asymptomatic bacteriuria, for which antibiotics are not warranted, these antibiotics are frequently unnecessary. We implemented a collaborative quality improvement program to improve the management of suspected UTI in LTC residents by increasing awareness of current guidelines, with a focus on decreasing treatment in the absence of symptoms. DESIGN/INTERVENTION: Two separate collaboratives included workshops, webinars, and coaching calls. PARTICIPANTS: A total of 31 facilities participated in the first collaborative, with 17 submitting sufficient data for analysis and 34 in the second, with data analyzed from 25. MEASUREMENTS: Facilities reported monthly numbers of urine cultures, UTI diagnoses, Clostridioides difficile infections (CDIs), and resident days. RESULTS: When comparing the baseline period to the first collaborative period, the intercollaborative period to the second collaborative period, and the first collaborative period to the second, the incident rate ratios (95% confidence intervals) were 0.74 (0.68-0.81), 0.83 (0.73-0.94), and 0.63 (0.57-0.69), respectively, for urine culturing rate; 0.73 (0.64-0.83), 0.86 (0.70-1.05), and 0.60 (0.51-0.69), respectively, for UTI diagnosis rate; and 0.56 (0.40-0.82), 1.61 (0.71-4.14), and 0.45 (0.27-0.74), respectively, for CDI rate. CONCLUSION: The program we implemented was associated with reductions in urine cultures, UTI diagnosis, and CDI; and it suggests that this type of intervention can promote appropriate management of UTI in the LTC setting. J Am Geriatr Soc 68:62-69, 2019.

Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist.

In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+ -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+ -derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+ -derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγ null mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074.

Topical silver and gold nanoparticles complexed with Cornus mas suppress inflammation in human psoriasis plaques by inhibiting NF-κB activity.

New biomaterials based on nanoparticles (NPs) carrying polyphenols-rich extracts (Cornus mas) recently showed promising anti-inflammatory activity in psoriasis. We aimed to understand how topically delivered silver and gold nanoparticles complexed with Cornus mas (Ag-NPs-CM, Au-NPs-CM) modulate inflammation in psoriasis at cellular and molecular level. The impact on psoriatic inflammation was assessed in vitro on pro-inflammatory macrophages, by clinical score, high-frequency ultrasonography and immunohistology of psoriasis plaques treated with Ag-NPs-CM, Au-NPs-CM or control. Incubation of pro-inflammatory macrophages with nanoparticles significantly decreased the release of NO, IL-12 and TNF-α. Immunofluorescence confirmed that nanoparticles significantly reduced CD68-positive macrophages and their IL-12 and TNF-α production in human psoriasis plaques. NPs-CM appear to repress NF-κB activation in macrophages, inhibiting the production of pro-inflammatory factors with causal role in psoriasis. Ag and Au NPs-CM represent a novel nanoparticle-based "green" technology which may provide an efficient tool for modern psoriasis therapy, circumventing immunosuppression-related side effects of biologicals.

A patient-centered primary care practice approach using evidence-based quality improvement: rationale, methods, and early assessment of implementation.

BACKGROUND: Healthcare systems and their primary care practices are redesigning to achieve goals identified in Patient-Centered Medical Home (PCMH) models such as Veterans Affairs (VA)'s Patient Aligned Care Teams (PACT). Implementation of these models, however, requires major transformation. Evidence-Based Quality Improvement (EBQI) is a multi-level approach for supporting organizational change and innovation spread. OBJECTIVE: To describe EBQI as an approach for promoting VA's PACT and to assess initial implementation of planned EBQI elements. DESIGN: Descriptive. PARTICIPANTS: Regional and local interdisciplinary clinical leaders, patient representatives, Quality Council Coordinators, practicing primary care clinicians and staff, and researchers from six demonstration site practices in three local healthcare systems in one VA region. INTERVENTION: EBQI promotes bottom-up local innovation and spread within top-down organizational priorities. EBQI innovations are supported by a research-clinical partnership, use continuous quality improvement methods, and are developed in regional demonstration sites. APPROACH: We developed a logic model for EBQI for PACT (EBQI-PACT) with inputs, outputs, and expected outcomes. We describe implementation of logic model outputs over 18 months, using qualitative data from 84 key stakeholders (104 interviews from two waves) and review of study documents. RESULTS: Nearly all implementation elements of the EBQI-PACT logic model were fully or partially implemented. Elements not fully achieved included patient engagement in Quality Councils (4/6) and consistent local primary care practice interdisciplinary leadership (4/6). Fourteen of 15 regionally approved innovation projects have been completed, three have undergone initial spread, five are prepared to spread, and two have completed toolkits that have been pretested in two to three sites and are now ready for external spread. DISCUSSION: EBQI-PACT has been feasible to implement in three participating healthcare systems in one VA region. Further development of methods for engaging patients in care design and for promoting interdisciplinary leadership is needed.

How can we recognize continuous quality improvement?

OBJECTIVE: Continuous quality improvement (CQI) methods are foundational approaches to improving healthcare delivery. Publications using the term CQI, however, are methodologically heterogeneous, and labels other than CQI are used to signify relevant approaches. Standards for identifying the use of CQI based on its key methodological features could enable more effective learning across quality improvement (QI) efforts. The objective was to identify essential methodological features for recognizing CQI. DESIGN: Previous work with a 12-member international expert panel identified reliably abstracted CQI methodological features. We tested which features met rigorous a priori standards as essential features of CQI using a three-phase online modified-Delphi process. SETTING: Primarily United States and Canada. PARTICIPANTS: 119 QI experts randomly assigned into four on-line panels. INTERVENTION: Participants rated CQI features and discussed their answers using online, anonymous and asynchronous discussion boards. We analyzed ratings quantitatively and discussion threads qualitatively. Main outcome measure(s) Panel consensus on definitional CQI features. RESULTS: /st> Seventy-nine (66%) panelists completed the process. Thirty-three completers self-identified as QI researchers, 18 as QI practitioners and 28 as both equally. The features 'systematic data guided activities,' 'designing with local conditions in mind' and 'iterative development and testing' met a priori standards as essential CQI features. Qualitative analyses showed cross-cutting themes focused on differences between QI and CQI. CONCLUSIONS: We found consensus among a broad group of CQI researchers and practitioners on three features as essential for identifying QI work more specifically as 'CQI.' All three features are needed as a minimum standard for recognizing CQI methods.

TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.

Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-α (TNF-α)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mφ or following injection into wound margins suppressed the release of TNF-α from activated Mφ and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-ß1 (TGF-ß1)/TGF-ß3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mφ activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.

Conducting online expert panels: a feasibility and experimental replicability study.

BACKGROUND: This paper has two goals. First, we explore the feasibility of conducting online expert panels to facilitate consensus finding among a large number of geographically distributed stakeholders. Second, we test the replicability of panel findings across four panels of different size. METHOD: We engaged 119 panelists in an iterative process to identify definitional features of Continuous Quality Improvement (CQI). We conducted four parallel online panels of different size through three one-week phases by using the RAND's ExpertLens process. In Phase I, participants rated potentially definitional CQI features. In Phase II, they discussed rating results online, using asynchronous, anonymous discussion boards. In Phase III, panelists re-rated Phase I features and reported on their experiences as participants. RESULTS: 66% of invited experts participated in all three phases. 62% of Phase I participants contributed to Phase II discussions and 87% of them completed Phase III. Panel disagreement, measured by the mean absolute deviation from the median (MAD-M), decreased after group feedback and discussion in 36 out of 43 judgments about CQI features. Agreement between the four panels after Phase III was fair (four-way kappa=0.36); they agreed on the status of five out of eleven CQI features. Results of the post-completion survey suggest that participants were generally satisfied with the online process. Compared to participants in smaller panels, those in larger panels were more likely to agree that they had debated each others' view points. CONCLUSION: It is feasible to conduct online expert panels intended to facilitate consensus finding among geographically distributed participants. The online approach may be practical for engaging large and diverse groups of stakeholders around a range of health services research topics and can help conduct multiple parallel panels to test for the reproducibility of panel conclusions.

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice.

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.

Qigong for the treatment of tinnitus: a prospective randomized controlled study.

OBJECTIVE: Tinnitus is a frequent disorder which is very difficult to treat. Qigong is a mindful exercise and an important constituent of traditional Chinese medical practice. Here we performed a randomized controlled trial to evaluate the effect of a Qigong intervention on patients with tinnitus. We hypothesized that especially tinnitus patients with somatosensoric components may benefit from the mind-body technique of Qigong. METHODS: Eighty patients with tinnitus of at least 3 months duration were randomly assigned to an intervention group (n=40) consisting of 10 Qigong training sessions in 5 weeks or a waiting-list control group (n=40). Tinnitus severity was assessed with a visual analogue scale (VAS) and with a tinnitus questionnaire (TBF-12) before treatment, immediately after treatment, and 1 and 3 months after treatment. RESULTS: Qigong did not cause any side effects and was completed by 80% of the assigned patients. Compared with the control group, Qigong participants experienced improvement in tinnitus severity, as reflected by a significant reduction in both the VAS and the TBF-12. In the subgroup of patients with somatosensoric tinnitus, Qigong effects were more pronounced, resulting in a highly significant improvement in both scales compared to the waiting-list group. CONCLUSION: These findings suggest that Qigong interventions could be a useful complement to the therapeutic management of patients with tinnitus and especially for those with somatosensoric components. Satisfaction with the intervention, a high degree of completion, and stability of the effects for at least 3 months after the intervention further underscore the potential of Qigong in the treatment of tinnitus.

Economic analysis of a randomized trial of academic detailing interventions to improve use of antihypertensive medications.

The authors estimated the costs and cost savings of implementing a program of mailed practice guidelines and single-visit individual and group academic detailing interventions in a randomized controlled trial to improve the use of antihypertensive medications. Analyses took the perspective of the payer. The total costs of the mailed guideline, group detailing, and individual detailing interventions were estimated at 1000 dollars, 5500 dollars, and 7200 dollars, respectively, corresponding to changes in the average daily per person drug costs of -0.0558 dollars (95% confidence interval, -0.1365 dollars to 0.0250 dollars) in the individual detailing intervention and -0.0001 dollars (95% confidence interval, -0.0803 dollars to 0.0801 dollars) in the group detailing intervention, compared with the mailed intervention. For all patients with incident hypertension in the individual detailing arm, the annual total drug cost savings were estimated at 21,711 dollars (95% confidence interval, 53,131 dollars savings to 9709 dollars cost increase). Information on costs of academic detailing could assist with health plan decision making in developing interventions to improve prescribing.

Clinical and nonclinical correlates of adherence to prescribing guidelines for hypertension in a large managed care organization.

To examine correlates of guideline adherence in a population with access to health care and prescription drug benefits, the authors conducted a cross-sectional analysis among 5789 patients undergoing hypertension treatment with a single medication in a large New England managed care organization. Logistic regression was used to determine correlates of adherence, defined as use of diuretics or beta blocker as antihypertensive monotherapy during the 1-year study period. Women were more likely than men to receive guideline-adherent therapy (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.45-1.85). Compared with patients covered by health maintenance organization plans, Medicare coverage was positively associated with guideline adherence (OR, 1.38; 95% CI, 1.13-1.69), but fee-for-service coverage was negatively associated (OR, 0.66; 95% CI, 0.48-0.91). Patient age was not a significant correlate of adherence to guidelines (OR, 1.01; 95% CI, 0.94-1.09). Understanding these observations may lead to strategies to improve guideline adherence and reduce health care disparities.

Group versus individual academic detailing to improve the use of antihypertensive medications in primary care: a cluster-randomized controlled trial.

PURPOSE: To compare group versus individual academic detailing to increase diuretic or beta-blocker use in hypertension. METHODS: We conducted a cluster-randomized controlled trial in a large health maintenance organization. Subjects (N=9820) were patients with newly treated hypertension in the year preceding the intervention (N=3692), the 9 months following the intervention (N=3556), and the second year following intervention (N=2572). We randomly allocated 3 practice sites to group detailing (N=227 prescribers), 3 to individual detailing (N=235 prescribers), and 3 to usual care (N=319 prescribers). Individual detailing entailed a physician-educator meeting individually with clinicians to address barriers to prescribing guideline-recommended medications. The group detailing intervention incorporated the same social marketing principles in small groups of clinicians. RESULTS: In the first year following the intervention, the rates of diuretic or beta-blocker use increased by 13.2% in the group detailing practices, 12.5% in the individual detailing practices, and 6.2% in the usual care practices. As compared with usual care practices, diuretic or beta-blocker use was more likely in group detailing practices (adjusted odds ratio (OR), 1.40; 95% confidence interval (CI), 1.11 - 1.76) and individual detailing practices (adjusted OR, 1.30; 95% CI, 0.95 - 1.79). Neither intervention affected blood pressure control. Two years following this single-visit intervention, there was still a trend suggesting a persistent effect of individual (OR, 1.22; 95% CI, 0.92 - 1.62), but not group, detailing (OR, 1.06; 95% CI, 0.80 - 1.39), as compared with usual care. CONCLUSION: Both group and individual academic detailing improved antihypertensive prescribing over and above usual care but may require reinforcement to sustain improvements.

Barriers to first-week follow-up of newborns: findings from parent and clinician focus groups.

BACKGROUND: Monitoring newborns within the first week is critical to assess the adequacy of feeding and weight gain and to identify instances of hyperbilirubinemia. As systems of maternal and newborn care have become increasingly fragmented, infants are at increased risk of poor outcomes because of poor follow-up. Structured focus groups were conducted in June--July 2001 to provide information about the barriers to timely newborn follow-up and strategies to address them. METHODS: One focus group for physicians and one for nurses were held at the Henry Ford Health System, Detroit, and two focus groups of parents were recruited by Blue Cross Blue Shield of Texas, Dallas. RESULTS: Barriers were identified in communication and information, systems and processes of care, and parental knowledge and education. Concerns raised by clinicians and parents were consistent and complementary. Some organizations have begun implementing some of the suggested strategies to achieve timely follow-up. DISCUSSION: Implementing the AAP guideline and improving safe care in the first week of newborn life will require attention to linkages and transitions between these various microsystems.