Human movement and environmental barriers shape the emergence of dengue.

Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.

BACKGROUND: Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. AIM: This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. METHODS: Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. CONCLUSIONS: This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges.

Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.

Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases 2023.

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade increasing evidence from preclinical models suggests that cells, which are not normally resident in the lung can be utilized to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathologic remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of "-omics" technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

Transarterial microembolization for the management of refractory chronic joint pain in osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease significantly impacting both patient quality of life and socioeconomics. Traditional treatment options, including pharmacological and surgical interventions, are often limited. Advancements in our understanding of the pathological mechanisms behind OA indicate the involvement of pathological angiogenesis. Transarterial microembolization (TAME), a minimally invasive radiological procedure, may present an innovative therapeutic approach. This review aims to consolidate current knowledge and experiences regarding TAME as a therapeutic modality for alleviating chronic joint pain associated with OA. It explores the role of TAME, focusing on its indications, patient selection, clinical outcomes, and future perspectives. Potential complications and associated risks are systematically addressed, alongside proposed strategies for risk mitigation and effective management.The presented patient cases originate from our institution, supplemented by a thorough review of relevant literature retrieved from PubMed.TAME represents a promising therapeutic approach, providing relief from the burden of joint diseases and substantially enhancing patient quality of life. Clinical outcomes emphasize the efficacy and safety of TAME in mitigating pain and improving functional capabilities in patients with chronic joint pain associated with OA. With mounting evidence of its therapeutic benefits and applicability to numerous joint-related pathologies, TAME offers a valuable addition to the arsenal of treatments for these conditions. · TAME is an innovative therapy for treating chronic joint pain related to OA.. · TAME is a technically challenging minimally invasive intervention requiring a high level of expertise.. · Understanding the challenges and complications of TAME can reduce risk and enhance procedural outcomes.. · Wilms LM, Jannusch K, Weiss D et al. Transarterial microembolization for the management of refractory chronic joint pain in osteoarthritis. Fortschr Röntgenstr 2024; DOI 10.1055/a-2288-5743.

Safety and efficacy of coated flow diverters in the treatment of ruptured intracranial aneurysms: a retrospective multicenter study.

BACKGROUND: This multicenter study evaluated the safety and efficacy of coated flow diverters (cFDs) for the treatment of ruptured intracranial aneurysms. METHODS: Consecutive patients treated with different cFDs for ruptured aneurysms under tirofiban at eight neurovascular centers between 2016 and 2023 were retrospectively analyzed. The majority of patients were loaded with dual antiplatelet therapy after the treatment. Aneurysm occlusion was determined using the O'Kelly-Marotta (OKM) grading scale. Primary outcome measures were major procedural complications and aneurysmal rebleeding during hospitalization. RESULTS: The study included 60 aneurysms (posterior circulation: 28 (47%)) with a mean size of 5.8±4.7 mm. Aneurysm morphology was saccular in 28 (47%), blister-like in 12 (20%), dissecting in 13 (22%), and fusiform in 7 (12%). Technical success was 100% with a mean of 1.1 cFDs implanted per aneurysm. Adjunctive coiling was performed in 11 (18%) aneurysms. Immediate contrast retention was observed in 45 (75%) aneurysms. There was 1 (2%) major procedural complication (a major stroke, eventually leading to death) and no aneurysmal rebleeding. A good outcome (modified Rankin Scale 0-2) was achieved in 40 (67%) patients. At a mean follow-up of 6 months, 27/34 (79%) aneurysms were completely occluded (OKM D), 3/34 (9%) had an entry remnant (OKM C), and 4/34 (12%) had residual filling (OKM A or B). There was 1 (3%) severe in-stent stenosis during follow-up that was treated with balloon angioplasty. CONCLUSIONS: Treatment of ruptured aneurysms with cFDs was reasonably safe and efficient and thus represents a valid treatment option, especially for complex cases.

[How the implementation of a school for people with Parkinson's disease can succeed-Results of a consensus study and a formative evaluation]. / Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann ­ Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation.

BACKGROUND: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson's disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson's disease with skills to manage the disease better and to participate in shared decision making. MATERIAL AND METHODS: To prepare the implementation of a concept for patient education for people with Parkinson's disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. RESULTS: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6-8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. DISCUSSION: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.

Identification of tyrosine brominated extracellular matrix proteins in normal and fibrotic lung tissues.

Peroxidasin (PXDN) is a secreted heme peroxidase that catalyzes the oxidative crosslinking of collagen IV within the extracellular matrix (ECM) via intermediate hypobromous acid (HOBr) synthesis from hydrogen peroxide and bromide, but recent findings have also suggested alternative ECM protein modifications by PXDN, including incorporation of bromide into tyrosine residues. In this work, we sought to identify the major target proteins for tyrosine bromination by HOBr or by PXDN-mediated oxidation in ECM from mouse teratocarcinoma PFHR9 cells. We detected 61 bromotyrosine (BrY)-containing peptides representing 23 proteins in HOBr-modified ECM from PFHR9 cells, among which laminins displayed the most prominent bromotyrosine incorporation. Moreover, we also found that laminin α1, laminin ß1, and tubulointerstitial nephritis antigen-like (TINAGL1) contained BrY in untreated PFHR9 cells, which depended on PXDN. We extended these analyses to lung tissues from both healthy mice and mice with experimental lung fibrosis, and in lung tissues obtained from human subjects. Analysis of ECM-enriched mouse lung tissue extracts showed that 83 ECM proteins were elevated in bleomycin-induced fibrosis, which included various collagens and laminins, and PXDN. Similarly, mRNA and protein expression of PXDN and laminin α/ß1 were enhanced in fibrotic mouse lung tissues, and also in mouse bone-marrow-derived macrophages or human fibroblasts stimulated with transforming growth factor ß1, a profibrotic growth factor. We identified 11 BrY-containing ECM proteins, including collagen IV α2, collagen VI α1, TINAGL1, and various laminins, in both healthy and mouse fibrotic lung tissues, although the relative extent of tyrosine bromination of laminins was not significantly increased during fibrosis. Finally, we also identified 7 BrY-containing ECM proteins in human lung tissues, again including collagen IV α2, collagen VI α1, and TINAGL1. Altogether, this work demonstrates the presence of several bromotyrosine-modified ECM proteins, likely involving PXDN, even in normal lung tissues, suggesting a potential biological function for these modifications.

Behcet disease: A case report on the utilization of T1-weighted black blood fat-suppressed sequences for the detection of venous vasculitis.

T1-weighted black blood FS sequences may provide a useful addition to imaging protocols in detection of subtle changes in venous vasculitides and, therefore, may have an impact on treatment options.

Extracellular Matrix as a Driver of Chronic Lung Diseases.

The extracellular matrix (ECM) is not just a three-dimensional scaffold that provides stable support for all cells in the lungs, but also an important component of chronic fibrotic airway, vascular, and interstitial diseases. It is a bioactive entity that is dynamically modulated during tissue homeostasis and disease, that controls structural and immune cell functions and drug responses, and that can release fragments that have biological activity and that can be used to monitor disease activity. There is a growing recognition of the importance of considering ECM changes in chronic airway, vascular, and interstitial diseases, including 1) compositional changes, 2) structural and organizational changes, and 3) mechanical changes and how these affect disease pathogenesis. As altered ECM biology is an important component of many lung diseases, disease models must incorporate this factor to fully recapitulate disease-driver pathways and to study potential novel therapeutic interventions. Although novel models are evolving that capture some or all of the elements of the altered ECM microenvironment in lung diseases, opportunities exist to more fully understand cell-ECM interactions that will help devise future therapeutic targets to restore function in chronic lung diseases. In this perspective article, we review evolving knowledge about the ECM's role in homeostasis and disease in the lung.

Socioeconomic, Demographic, and Environmental Factors May Inform Malaria Intervention Prioritization in Urban Nigeria.

Urban population growth in Nigeria may exceed the availability of affordable housing and basic services, resulting in living conditions conducive to vector breeding and heterogeneous malaria transmission. Understanding the link between community-level factors and urban malaria transmission informs targeted interventions. We analyzed Demographic and Health Survey Program cluster-level data, alongside geospatial covariates, to describe variations in malaria prevalence in children under 5 years of age. Univariate and multivariable models explored the relationship between malaria test positivity rates at the cluster level and community-level factors. Generally, malaria test positivity rates in urban areas are low and declining. The factors that best predicted malaria test positivity rates within a multivariable model were post-primary education, wealth quintiles, population density, access to improved housing, child fever treatment-seeking, precipitation, and enhanced vegetation index. Malaria transmission in urban areas will likely be reduced by addressing socioeconomic and environmental factors that promote exposure to disease vectors. Enhanced regional surveillance systems in Nigeria can provide detailed data to further refine our understanding of these factors in relation to malaria transmission.

Diagnostic Value of Perfusion Parameters for Differentiation of Underlying Etiology in Internal Carotid Artery Occlusions.

PURPOSE: Occlusions of the internal carotid artery (ICA) may be caused by dissection, embolic or macroangiopathic pathogenesis, which partially influences the treatment; however, inferring the underlying etiology in computed tomography angiography can be challenging. In this study, we investigated whether computed tomography perfusion (CT-P) parameters could be used to distinguish between etiologies. METHODS: Patients who received CT­P in acute ischemic stroke due to ICA occlusion between 2012 and 2019 were retrospectively analyzed. Group comparisons between etiologies regarding the ratios of CT­P parameters between both hemispheres for relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), time to maximum (Tmax), and mean transit time (MTT) were calculated by one-factorial analysis of variance (ANOVA) and compared by pairwise Bonferroni post hoc tests. An receiver operating characteristics (ROC) analysis was performed if differences in group comparisons were found. Multinomial logistic regression (MLR) including pretherapeutic parameters was calculated for etiologies. RESULTS: In this study 69 patients (age = 70 ± 14 years, dissection = 10, 14.5%, embolic = 19, 27.5% and macroangiopathic = 40, 58.0%) were included. Group differences in ANOVA were only found for MTT ratio (p = 0.003, η2 = 0.164). In the post hoc test, MTT ratio showed a differentiability between embolic and macroangiopathic occlusions (p = 0.002). ROC analysis for differentiating embolic and macroangiopathic ICA occlusions based on MTT ratio showed an AUC of 0.77 (p < 0.001, CI = 0.65-0.89) and a cut-off was yielded at a value of 1.15 for the MTT ratio (sensitivity 73%, specificity 68%). The MLR showed an overall good model performance. CONCLUSION: It was possible to differentiate between patients with embolic and macroangiopathic ICA occlusions based on MTT ratios and to define a corresponding cut-off. Differentiation from patients with dissection versus the other etiologies was not possible by CT­P parameters in our sample.

The Impact of Pseudomonas aeruginosa Infection in Adult Cystic Fibrosis Patients-A Single Polish Centre Study.

BACKGROUND: Pseudomonas aeruginosa (PA) is one of the most predominant pathogens of lung infections, often causing exacerbations in adult patients with cystic fibrosis (CF). MATERIALS AND METHODS: Microbiological characterization of 74 PA isolates and to evaluate the correlations between the bacterial features and 44 adult Polish CF cohort clinical parameters. RESULTS: The most common variant in the CF transmembrane conductance regulator (CFTR) gene was F508del (76.3%), followed by 3849+10kbC>T (26.3%). A total of 39.4% of the PA isolates showed multiple resistances. In patients with parameters pointing to a decline in lung function, there was a statistically significant moderate correlation with ß-lactam resistance and a weak correlation between hospital frequency and colistin resistance. The mucoidity did not correlate with the biofilm formation ability, which showed 41.9% of the isolates. Proteolytic activity, observed in 60.8% of the clinical isolates, was weakly associated with motility detected in 78.4% of the strains. The genetic profiles of the PA were highly heterogeneous, and a weak positive correlation was established between cluster group and biofilm formation. CONCLUSION: The findings suggest that there is a high variety in P. aeruginosa populations in adult CF patients. There is a need to monitor PA strains in groups of patients with cystic fibrosis, in particular, in terms of the occurrence of antibiotic resistance related to a decline in lung function.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Revealed versus potential spatial accessibility of healthcare and changing patterns during the COVID-19 pandemic.

BACKGROUND: Timely access to healthcare is essential but measuring access is challenging. Prior research focused on analyzing potential travel times to healthcare under optimal mobility scenarios that do not incorporate direct observations of human mobility, potentially underestimating the barriers to receiving care for many populations. METHODS: We introduce an approach for measuring accessibility by utilizing travel times to healthcare facilities from aggregated and anonymized smartphone Location History data. We measure these revealed travel times to healthcare facilities in over 100 countries and juxtapose our findings with potential (optimal) travel times estimated using Google Maps directions. We then quantify changes in revealed accessibility associated with the COVID-19 pandemic. RESULTS: We find that revealed travel time differs substantially from potential travel time; in all but 4 countries this difference exceeds 30 minutes, and in 49 countries it exceeds 60 minutes. Substantial variation in revealed healthcare accessibility is observed and correlates with life expectancy (⍴=-0.70) and infant mortality (⍴=0.59), with this association remaining significant after adjusting for potential accessibility and wealth. The COVID-19 pandemic altered the patterns of healthcare access, especially for populations dependent on public transportation. CONCLUSIONS: Our metrics based on empirical data indicate that revealed travel times exceed potential travel times in many regions. During COVID-19, inequitable accessibility was exacerbated. In conjunction with other relevant data, these findings provide a resource to help public health policymakers identify underserved populations and promote health equity by formulating policies and directing resources towards areas and populations most in need.

Spatial access to healthcare facilities (i.e., how long people need to travel to reach care) is important for understanding public health, but hard to measure. Most research so far has focused on theoretical (potential) travel times. Using anonymized smartphone location history data, we measure actual (revealed) travel times to healthcare facilities in over 100 countries. We find that revealed travel times exceed theoretical travel times in many regions of the world, meaning that in reality people travel longer to get healthcare. Our data also show that inequities in travel time became worse during the COVID-19 pandemic. When combined with other data, these results can help policymakers identify areas and populations at need, and direct resources to improve public health.

Endovascular coil-embolization of an unruptured, true UAA during early pregnancy- a case report.

BACKGROUND: True uterine artery aneurysms, especially during pregnancy, are a rare entity and not well understood. Clinical symptoms are unspecific pelvic pain and pressure. Diagnosis can be confirmed by transvaginal color-coded-sonography and/or magnetic resonance imaging. Because of potential risk of rupture, immediate interdisciplinary discussion and treatment planning in the best interests of both mother and child is crucial. CASE PRESENTATION: We present a 31-year-old pregnant woman with increasing pelvic pain and pressure. Diagnosis of an unruptured uterine artery aneurysm was confirmed by color-coded-sonography and magnetic resonance angiography. After interdisciplinary consultation, successful endovascular super-selective coil-embolization was performed by using X-ray fluoroscopy. Thus, fetal radiation dose during treatment with 4.33 mGy (VirtualDoseTM) was as low as possible with no immediate harm to the fetus. CONCLUSIONS: Unruptured true uterine artery aneurysms can be successfully treated by endovascular super-selective coil-embolization during early pregnancy with no immediate harm to the fetus.

Dissection and Isolation of Region-Specific Decellularized Lung Tissue.

Lung transplantation is often the only option for patients in the later stages of severe lung disease, but this is limited both due to the supply of suitable donor lungs and both acute and chronic rejection after transplantation. Ascertaining novel bioengineering approaches for the replacement of diseased lungs is imperative for improving patient survival and avoiding complications associated with current transplantation methodologies. An alternative approach involves the use of decellularized whole lungs lacking cellular constituents that are typically the cause of acute and chronic rejection. Since the lung is such a complex organ, it is of interest to examine the extracellular matrix components of specific regions, including the vasculature, airways, and alveolar tissue. The purpose of this approach is to establish simple and reproducible methods by which researchers may dissect and isolate region-specific tissue from fully decellularized lungs. The current protocol has been devised for pig and human lungs, but may be applied to other species as well. For this protocol, four regions of the tissue were specified: airway, vasculature, alveoli, and bulk lung tissue. This procedure allows for the procurement of samples of tissue that more accurately represent the contents of the decellularized lung tissue as opposed to traditional bulk analysis methods.

Resting state EEG as biomarker of cognitive training and physical activity's joint effect in Parkinson's patients with mild cognitive impairment.

BACKGROUND: Cognitive decline is a major factor for the deterioration of the quality of life in patients suffering from Parkinson's disease (PD). Recently, it was reported that cognitive training (CT) in PD patients with mild cognitive impairment (PD-MCI) led to an increase of physical activity (PA) accompanied by improved executive function (EF). Moreover, PA has been shown to alter positively brain function and cognitive abilities in PD. Both observations suggest an interaction between CT and PA. OBJECTIVES: A previous multicenter (MC) study was slightly significant when considering independent effects of interventions (CT and PA) on EF. Here, we use MC constituent single center data that showed no effect of interventions on EF. Thus, this exploratory study considers pooling data from both interventions to gain insight into a recently reported interaction between CT and PA and provide a proof of principle for the usefulness of resting state EEG as a neurophysiological biomarker of joint intervention's effect on EF and attention in PD-MCI. METHODS: Pre- and post-intervention resting state EEG and neuropsychological scores (EF and attention) were obtained from 19 PD-MCI patients (10 (CT) and 9 (PA)). We focused our EEG analysis on frontal cortical areas due to their relevance on cognitive function. RESULTS: We found a significant joint effect of interventions on EF and a trend on attention, as well as trends for the negative correlation between attention and theta power (pre), the positive correlation between EF and alpha power (post) and a significant negative relationship between attention and theta power over time (post-pre). CONCLUSIONS: Our results support the role of theta and alpha power at frontal areas as a biomarker for the therapeutic joint effect of interventions.

Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma.

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).