Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.

OBJECTIVE: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p. Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. METHODS: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were performed by both Sanger and amplicon-based deep sequencing, mRNA studies were performed by both cDNA subcloning and mRNA sequencing. RESULTS: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis from patients' samples demonstrated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. CONCLUSION: Here we describe the abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and support for a complete gene evaluation in those candidate patients for VEXAS syndrome.

Neutrophilic dermatosis in a patient with an IKZF1 variant and a review of monogenic autoinflammatory disorders presenting with neutrophilic dermatoses.

Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2-year-old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants. IKZF1 variants could potentially lead to aberrant neutrophil chemotaxis and development of neutrophilic dermatoses. Long-term surveillance is required to monitor the development of hematologic malignancy, autoimmunity, immunodeficiency, and infection in patients with pathogenic IKZF1 germline variants.

Submuscular Placement of Baclofen Infusion Pumps: Case Series and Technique.

BACKGROUND: Baclofen pumps provide treatment of symptoms of spasticity for disease processes such as cerebral palsy and traumatic brain injury. These devices provide continuous infusion or periodic dosing of intrathecal baclofen (ITB). Traditionally, these pumps have been placed subcutaneously. Subcutaneous device placement has been associated with infection and extrusion. Baclofen pumps are large and range from 8 to 10 cm in diameter and 4 to 8 cm in width. Patients requiring device placement typically have a paucity of subcutaneous tissue. Cachexia coupled with the size and bulk of these devices leads to increased protusion and friction. Submuscular placement provides a well-vascularized pocket that directs the device inward eliminating protrusion and decreasing the potential for soft tissue breakdown. METHODS: A retrospective chart review of ITB pump placement in a submuscular plane by a single plastic surgeon at a major academic center in conjunction with a neurosurgeon was performed. Inclusion criteria were cases of primary placement or replacement of ITB pumps and spasticity requiring ITB. Major complications included infection, extrusion, and reoperation. RESULTS: Five patients during a 5-month period were treated with submuscular placement of ITB pumps. Average age of patients included was 18.4 years. Average preoperative body mass index was 18.8 kg/m, with values ranging from 15.8 to 20.1 kg/m. Medical histories of patients included diagnoses of cerebral palsy and traumatic brain injury causing spasticity. The most frequently cited reason for plastic surgical consultation preoperatively was cachexia. Two patients had previous baclofen pumps placed subcutaneously. Average follow-up was 6 months and ranged from 3 to 13 months. There were no major complications. One patient had a small seroma that spontaneously resolved. No patient had wound healing problems, and there were no extrusions of implanted devices or reoperations. CONCLUSION: Submuscular placement of baclofen pumps provides a well-vascularized and stable environment for device placement that minimizes the dangers of pump extrusion and infection. Patients who require treatment with ITB commonly have severe cachexia, which makes subcutaneous device placement high risk. Submuscular placement should be performed in all patients with body mass index less than 20 kg/m.

Translating current biomedical therapies for long duration, deep space missions.

It is been shown that spaceflight-induced molecular, cellular, and physiologic changes cause alterations across many modalities of the human body, including cardiovascular, musculoskeletal, hematological, immunological, ocular, and neurological systems. The Twin Study, a multi-year, multi-omic study of human response to spaceflight, provided detailed and comprehensive molecular and cellular maps of the human response to radiation, microgravity, isolation, and stress. These rich data identified epigenetic, gene expression, inflammatory, and metabolic responses to spaceflight, facilitating a better biomedical roadmap of features that should be monitored and safe-guarded in upcoming missions. Further, by exploring new developments in pre-clinical models and clinical trials, we can begin to design potential cellular interventions for exploration-class missions to Mars and potentially farther. This paper will discuss the overall risks astronauts face during spaceflight, what is currently known about human response to these risks, what pharmaceutical interventions exist for use in space, and which tools of precision medicine and cellular engineering could be applied to aerospace and astronaut medicine.

Aerodigestive sampling reveals altered microbial exchange between lung, oropharyngeal, and gastric microbiomes in children with impaired swallow function.

BACKGROUND: Children with oropharyngeal dysphagia have impaired airway protection mechanisms and are at higher risk for pneumonia and other pulmonary complications. Aspiration of gastric contents is often implicated as a cause for these pulmonary complications, despite being supported by little evidence. The goal of this study is to determine the relative contribution of oropharyngeal and gastric microbial communities to perturbations in the lung microbiome of children with and without oropharyngeal dysphagia and aspiration. METHODS: We conducted a prospective cohort study of 220 patients consecutively recruited from a tertiary aerodigestive center undergoing simultaneous esophagogastroduodenoscopy and flexible bronchoscopy. Bronchoalveolar lavage, gastric and oropharyngeal samples were collected from all recruited patients and 16S sequencing was performed. A subset of 104 patients also underwent video fluoroscopic swallow studies to assess swallow function and were categorized as aspiration/no aspiration. To ensure the validity of the results, we compared the microbiome of these aerodigestive patients to the microbiome of pediatric patients recruited to a longitudinal cohort study of children with suspected GERD; patients recruited to this study had oropharyngeal, gastric and/or stool samples available. The relationships between microbial communities across the aerodigestive tract were described by analyzing within- and between-patient beta diversities and identifying taxa which are exchanged between aerodigestive sites within patients. These relationships were then compared in patients with and without aspiration to evaluate the effect of aspiration on the aerodigestive microbiome. RESULTS: Within all patients, lung, oropharyngeal and gastric microbiomes overlap. The degree of similarity is the lowest between the oropharynx and lungs (median Jensen-Shannon distance (JSD) = 0.90), and as high between the stomach and lungs as between the oropharynx and stomach (median JSD = 0.56 for both; p = 0.6). Unlike the oropharyngeal microbiome, lung and gastric communities are highly variable across people and driven primarily by person rather than body site. In patients with aspiration, the lung microbiome more closely resembles oropharyngeal rather than gastric communities and there is greater prevalence of microbial exchange between the lung and oropharynx than between gastric and lung sites (p = 0.04 and 4x10-5, respectively). CONCLUSIONS: The gastric and lung microbiomes display significant overlap in patients with intact airway protective mechanisms while the lung and oropharynx remain distinct. In patients with impaired swallow function and aspiration, the lung microbiome shifts towards oropharyngeal rather than gastric communities. This finding may explain why antireflux surgeries fail to show benefit in pediatric pulmonary outcomes.

Bis(monoacylglycero)phosphate as a Macrophage Enriched Phospholipid.

Bis(monoacylglycero)phosphate (BMP) is a structural isomer of phosphatidylglycerol (PtdGro) with an unusual sn-1:sn-1' fatty acyl configuration and is found almost exclusively in late endosomes/lysosomes. BMP comprises only about 1-2% of the total phospholipids in most mammalian cells, but accumulates in tissues of humans and animals with lysosomal storage disorders including the gangliosidoses. Total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin. BMP composition was similar in tumorigenic/metastatic macrophages and non-tumorigenic macrophages/microglia. Finally, BMP fatty acid composition differed between cells grown in culture and obtained in vivo suggesting an influence from growth environment.