Severe cases of COVID‐19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID‐19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo‐capillary barriers. The authors performed a systematic literature review and random‐effects meta‐analysis to determine the potential value of MSC therapy for treating COVID‐19‐infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2/FiO2 ratio, alveolo‐capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.

Transcription networks and epigenetic mechanisms including DNA methylation, histone modifications, and noncoding RNAs control lineage commitment of multipotent mesenchymal progenitor cells. Proteins that read, write, and erase histone tail modifications curate and interpret the highly intricate histone code. Epigenetic reader proteins that recognize and bind histone marks provide a crucial link between histone modifications and their downstream biological effects. Here, we investigate the role of bromodomain‐containing (BRD) proteins, which recognize acetylated histones, during osteogenic differentiation. Using RNA‐sequencing (RNA‐seq) analysis, we screened for BRD proteins (n = 40) that are robustly expressed in MC3T3 osteoblasts. We focused functional follow‐up studies on Brd2 and Brd4 which are highly expressed in MC3T3 preosteoblasts and represent “bromodomain and extra terminal domain” (BET) proteins that are sensitive to pharmacological agents (BET inhibitors). We show that small interfering RNA depletion of Brd4 has stronger inhibitory effects on osteoblast differentiation than Brd2 loss as measured by osteoblast‐related gene expression, extracellular matrix deposition, and alkaline phosphatase activity. Similar effects on osteoblast differentiation are seen with the BET inhibitor +JQ1, and this effect is reversible upon its removal indicating that this small molecule has no lasting effects on the differentiation capacity of MC3T3 cells. Mechanistically, we find that Brd4 binds at known Runx2 binding sites in promoters of bone‐related genes. Collectively, these findings suggest that Brd4 is recruited to osteoblast‐specific genes and may cooperate with bone‐related transcription factors to promote osteoblast lineage commitment and maturation.

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Dorsal root ganglion stimulation (DRG-S) is a form of selective neuromodulation therapy that targets the dorsal root ganglion. DRG-S offers analgesia in a variety of chronic pain conditions and is approved for treatment of complex regional pain syndrome (CRPS) by the US Food and Drug Administration (FDA). There has been increasing utilization of DRG-S to treat various neuropathic pain syndromes of the lower extremity, although evidence remains limited to one randomized controlled trial and 39 observational studies. In this review, we appraised the current evidence for DRG-S in the treatment of lower extremity neuropathic pain using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The primary outcome was change in pain intensity after DRG-S compared to baseline. We stratified presentation of results based of type of neuropathy (CRPS, painful diabetic neuropathy, mononeuropathy, polyneuropathy) as well as location of neuropathy (hip, knee, foot). Future powered randomized controlled trials with homogeneous participants are warranted.

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