Search

Background Acute exacerbations of fibrosing interstitial lung diseases (ILDs) are associated with high mortality. We used prospective data from the INBUILD trial to investigate risk factors for acute exacerbations and the impact of these events in patients with progressive pulmonary fibrosis. Methods Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib or placebo. Associations between baseline characteristics and time to first acute exacerbation were assessed using pooled data from both treatment groups using Cox proportional hazard models, firstly univariable models and then a multivariable model using forward stepwise selection. The risk of death was estimated based on the Kaplan−Meier method. Results Over a median follow-up of approximately 19 months, acute exacerbations were reported in 58 (8.7%) of 663 patients. In the risk factor analysis, the final model included diffusing capacity of the lung for carbon monoxide (DLCO) % predicted, treatment and age. Lower DLCO % predicted was associated with an increased risk of acute exacerbation with a hazard ratio (HR) of 1.56 (95% CI 1.21–2.02) per 10 units lower (p

The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer’s Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (100 x 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).

Background: β-Thalassemia is an inherited blood disorder requiring lifetime management of anemia and its complications., Objective: This study aimed to determine the indirect costs and humanistic burden of β-thalassemia., Design: A systematic literature review was conducted., Data Sources and Methods: Searches were conducted in Embase, MEDLINE, MEDLINE In-Process, and EconLit (November 1, 2010, to November 25, 2020). Studies reporting indirect costs and health-related quality of life (HRQoL) for patients with β-thalassemia were eligible., Results: Seventy-five publications were included. Mean annual days lost due to transfusion-related absenteeism ranged from 15.6 to 35 days. Patients spent a mean of 592 min (standard deviation (SD): 349) daily on disease management on transfusion days and 91 min (SD: 221) daily on non-transfusion days. Patients with non-transfusion-dependent β-thalassemia (NTDT) showed worse HRQoL versus those with transfusion-dependent β-thalassemia (TDT) on the 36-item Short Form Health Survey (75.8 vs 66.5; p  = 0.021). Caregivers of patients with TDT had more severe stress compared with patients (20.17 vs 18.95; p  = 0.006), as measured by the standardized Cohen Perceived Stress Questionnaire., Conclusion: TDT is associated with substantial indirect costs and caregiver burden, and NTDT is associated with worse HRQoL. There is an unmet need for novel treatments in both TDT and NTDT that minimize patient and caregiver burden., Competing Interests: Yesim Aydinok has participated on advisory boards for Bristol Myers Squibb, CRISPR Therapeutics/Vertex, and Silence Therapeutics; has participated in speakers bureaus for Cerus, Chiesi, and Novartis; and has received research funding from Agios Pharmaceuticals, Bristol Myers Squibb, Imara, Ionis Pharmaceuticals, Novartis, and Resonance Health. Sneha Purushotham, Sohan Deshpande, Barbara Potrata, and Myrto Trapali declare employment at Evidera. Aylin Yucel and Mrudula Glassberg declare employment at and stock/stock options ownership in Bristol Myers Squibb. Farrukh Shah has received consulting fees from Bristol Myers Squibb; and has participated in speakers bureaus for Abfero Pharmaceuticals, Agios Pharmaceuticals, Bluebird Bio, Chiesi, Global Blood Therapeutics, Novartis, Roche, Silence Therapeutics, and Vertex Pharmaceuticals; and reports membership in an adjunction committee/data monitoring committee for Abfero Pharmaceuticals, Agios Pharmaceuticals, and IQVIA., (© The Author(s), 2024.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT , RTEL1 , common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Challenges for the effective management of interstitial lung diseases (ILDs) include difficulties with the early detection of disease, accurate prognostication with baseline data, and accurate and precise response to therapy. The purpose of this Review is to describe the clinical and research gaps in the diagnosis and prognosis of ILD, and how machine learning can be applied to image biomarker research to close these gaps. Machine-learning algorithms can identify ILD in at-risk populations, predict the extent of lung fibrosis, correlate radiological abnormalities with lung function decline, and be used as endpoints in treatment trials, exemplifying how this technology can be used in care for people with ILD. Advances in image processing and analysis provide further opportunities to use machine learning that incorporates deep-learning-based image analysis and radiomics. Collaboration and consistency are required to develop optimal algorithms, and candidate radiological biomarkers should be validated against appropriate predictors of disease outcomes., Competing Interests: Declaration of interests SMH reports grants from Boehringer Ingelheim and NHLBI; service contracts from Calyx outside the present work; the US patent 10,706,533 Systems and Methods for Automatic Detection and Quantification of Pathology Using Dynamic Feature Classification (assigned to National Jewish Health and not licensed); grants and consulting fees from Veracyte; consulting fees from Lyra Therapeutics and IMIDEX; and payment or honorarium for attending the 2021 World Association of Sarcoidosis and Other Granulomatous Disease Conference. PMG reports consulting fees from Boehringer Ingelheim; payment or honoraria from Boehringer Ingelheim, Roche Pharmaceuticals, Teva, Cipla, and AstraZeneca; support for attending meetings or travel from Brainomix; and stock options in Brainomix. DA reports consulting fees and speaker fees from Boehringer Ingelheim and Roche; and grants or contracts from Boehringer Ingelheim and Fonds de Recherche Québec–Santé. TJC reports grants or contracts from Boehringer Ingelheim, Roche, Biogen, and Three Lakes Foundation; consulting fees from, and participation on a Data Safety Monitoring Board or Advisory Board for, Boehringer Ingelheim, Roche and Bristol Myers Squibb; payment or honoraria from Boehringer Ingelheim; and is the cochair of Australian ILD Registry. KAJ reports grants or contracts from the University of Calgary Cumming School of Medicine, Three Lakes Foundation, and the Chest Foundation; consulting fees from Boehringer Ingelheim, Roche, Pliant Therapeutics, Three Lakes Foundation, and Thyron; payment or honoraria from Boehringer Ingelheim and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for the PFOX trial. LC reports payments or honoraria from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for Boehringer Ingelheim. AW reports personal fees from Boehringer Ingelheim, Roche, and Veracyte outside the submitted work; payment or honoraria from Roche and Boehringer Ingelheim; and support for attending meetings or travel from Boehringer Ingelheim (or both). SW reports grants from National Institute for Health Research Clinician Scientist Award CS-2018-18-ST2-004; consulting fees and payment or honoraria from Boehringer Ingelheim and Roche; a leadership or fiduciary role on NHS England AI Award Advisory Panel; and is the Radiology Lead for the Open Source Imaging Consortium. IG reports consulting fees from Ad Alta, Amplia, Accendatech, and Lassen; participation on a data safety monitoring board or advisory board for Boehringer Ingelheim; and is the cochair of Australian ILD Registry. HB, JAM, MG, FF report no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Migraine is one of the leading causes of disability worldwide. Erenumab is a fully human monoclonal antibody that targets the calcitonin gene-related peptide (CGRP) receptor. This study aimed to evaluate real-world evidence on the impact of erenumab on acute medication usage and health care resource utilization (HCRU) among migraine patients., Methods: This retrospective effectiveness study utilized the US Optum's de-identified Clinformatics® Data Mart database to identify migraine patients initiating erenumab between May 1, 2018 and September 30, 2019. Patients had to be at least 18 years old, with a minimum of three doses for erenumab in the 6-month post-index period and continuous medical/pharmacy coverage in the 12-month pre- and 6-month post-index period. The date of the first claim for erenumab served as the index date. Use of acute medications overall and at different drug class level, and HCRU were compared during the 6-month pre- vs. post-index period. Impact of erenumab on a composite endpoint of three possible events: 1) outpatient visit with a diagnosis of migraine and an associated acute medication claim within 7 days of the visit, 2) hospital admission with a primary diagnosis for migraine, or 3) emergency room visit with a primary diagnosis for migraine (any events that occurred ≤3 days apart were counted only once) was also evaluated., Results: The analysis included 3171 identified patients. At 6 months, following initiation of erenumab, acute medication use including the number of types of acute medication, number of claims of each medication and % of patients who received acute medication, and HCRU were significantly decreased. For the composite outcome, the mean number of events decreased from 1.03 to 0.77 (rate ratio: 0.75; 95% CI: 0.71 to 0.79; P < 0.0001). A decrease in the proportion of patients with any of the three events was also observed (52.7% vs. 39.5%, P < 0.0001)., Conclusion: In this retrospective analysis, erenumab was associated with significantly reduced acute medication use and HCRU in a real-world setting, hence significantly reducing the burden of the disease. A composite endpoint could be used as a proxy to evaluate the burden of migraine attacks; however, further research is needed.

The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 10 6 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH)., Competing Interests: Conflict of Interest All authors declare that there are no conflicts of interest regarding the publication of this manuscript.

The ex vivo human skin wound model is a widely accepted model to study wound epithelialization. Due to a lack of animal models that fully replicate human conditions, the ex vivo model is a valuable tool to study mechanisms of wound reepithelialization, as well as for preclinical testing of novel therapeutics. The current standard for assessment of wound healing in this model is histomorphometric analysis, which is labor intensive, time consuming, and requires multiple biological and technical replicates in addition to assessment of different time points. Optical coherence tomography (OCT) is an emerging noninvasive imaging technology originally developed for noninvasive retinal scans that avoids the deleterious effects of tissue processing. This study investigated OCT as a novel method for assessing reepithelialization in the human ex vivo wound model. Excisional ex vivo wounds were created, maintained at air-liquid interface, and healing progression was assessed at days 4 and 7 with OCT and histology. OCT provided adequate resolution to identify the epidermis, the papillary and reticular dermis, and importantly, migrating epithelium in the wound bed. We have deployed OCT as a noninvasive tool to produce, longitudinal "optical biopsies" of ex vivo human wound healing process, and we established an optimal quantification method of re-epithelialization based on en face OCT images of the total wound area. Pairwise statistical analysis of OCT and histology based quantifications for the rate of epithelialization have shown the feasibility and superiority of OCT technology for noninvasive monitoring of human wound epithelialization. Furthermore, we have utilized OCT to evaluate therapeutic potential of allogeneic adipose stem cells revealing their ability to promote reepithelialization in human ex vivo wounds. OCT technology is promising for its applications in wound healing and evaluation of novel therapeutics in both the laboratory and the clinical settings., (© 2017 by the Wound Healing Society.)

Unlabelled: Postmenopausal women are more susceptible to poor wound healing. This phenomenon can be reversed by estrogen replacement therapy in non-diabetic individuals. Postmenopausal women with type 2 diabetes are more susceptible to wound healing complications, potentially secondary to an estrogen deficiency. Few studies have examined the mechanism of action and effects of estrogens on diabetic wound healing in females. It appears that multiple factors influence delayed wound healing among individuals with diabetes including: an imbalance in cytokines, growth factors, extracellular matrix (ECM) turnover, and oxidant stress (OS). Estrogens have been shown to regulate the expression of genes important for extracellular matrix turnover, including collagen and matrix metalloproteinases (MMP)., Methods: For this reason, the effects of 17β-estradiol (E2) on MMP-2, MMP-13, and MMP-14 and estrogen receptor alpha and beta (ER-α and -β) expression in the wound tissue of estrogen-deficient female mice with established type 2 diabetes mellitus (C57BL/6J-m Leprdb/2+) were studied., Results: Topical E2 upregulates ERα in wound tissue thereby improving and accelerating diabetic wound healing in estrogen deficient mice., Conclusion: The mechanism appears to decrease MMP-2, MMP-13, and MMP-14 mediated tissue matrix destruction and increasing collagen content. .

We evaluated the contribution of spousal feedback to a parent education curriculum designed for parents of children with autism. A modified multiple baseline design across 3 husband-and-wife dyads was used to examine the effects of teaching parents to give each other feedback on their teaching performance. For 5 of 6 participants, improvement in teaching performance occurred following didactic presentations. However, additional improvement was observed for 5 participants when the spousal feedback component was implemented.

Objective: To determine the concentrations of immunoreactive (IR) endothelin-1 in human follicular fluid (FF) and whether IR-endothelin-1 levels are different in women with endometriosis-associated infertility., Design: Follicular fluid and plasma samples, obtained from women with and without endometriosis undergoing IVF-ET, were collected at the time of oocyte aspiration and analyzed for IR-endothelin-1 levels., Setting: Infertility clinic in an academic research environment., Results: Overall, 90% of FF samples and 60% of plasma samples contained IR-endothelin-1 detectable above the threshold of assay sensitivity. Immunoreactive endothelin-1 levels (mean +/- SEM) in FF samples from women with and without endometriosis-associated infertility were 74 +/- 12 and 37 +/- 6 pg/mL, respectively. There was no difference in IR-endothelin-1 levels in FF samples between controlled ovarian hyperstimulation cycles with or without leuprolide acetate. No significant differences were detected in plasma IR-endothelin-1 levels in women with endometriosis-associated infertility when compared with those without., Conclusions: These results demonstrate the presence of IR-endothelin-1 in human FF obtained at the time of oocyte aspiration for IVF-ET and higher levels of IR-endothelin-1 in FF of women with endometriosis-associated infertility.

The effect of reversible blood-brain barrier modification on the delivery of Adriamycin to the brain was studied in a rodent and canine model. Pharmacokinetic and physiological studies were done in these animals after a wide range of doses of Adriamycin (0.1 to 1.0 mg/kg) were administered into the carotid artery following osmotic barrier modification with mannitol. In the absence of barrier modification, no immunoreactive Adriamycin was detected in the cerebrum; whereas, following barrier modification, up to 4.5 micrograms of drug and/or metabolites per g of brain were found. Optimum tissue levels of Adriamycin and metabolites were achieved following barrier modification when the drug was administered by either bolus or slow continuous (15-min) infusion. Immunoreactive drug was identified in brain for up to 6 hr after administration. Significant functional neurotoxicity occurred at all dose levels, even at 0.1 mg/kg, a level at which Adriamycin concentration in the brain was below the level of detectability. Neuropathological examination revealed the presence of necrosis and hemorrhagic infarcts. Thus, these pharmacological and toxicity studies suggest that Adriamycin (or its metabolites) may produce significant clinical neurotoxicity when even small amounts penetrate the blood-brain barrier.