Citations

Abstract Pre and post-licensure studies have supported the safety of the intranasally administered live, attenuated influenza vaccine (LAIV). The objective of this study was to measure changes to the nasal microbiome in subjects who received LAIV. We hypothesized that administration would result in only a transient alteration of the nasal microbiome. To test this hypothesis, we swabbed the anterior nares just before vaccination (Day 0), and on Day 7 and Day 28. We performed next-generation sequencing on amplified 16s rRNA genes. There was a significant increase in alpha diversity (Observed, CHAO, and ACE) from Days 0 to 7 (p = 0.02, 0.00, 0.01; respectively) and Days 0 to 28 (p = 0.05, 0.03, 0.05; respectively). When measuring differences in specific observed taxanomic units (OTUs), we identified a significant increase in Flavobacteriaceae and Enterobacteriaceae after vaccination. These data suggest that LAIV may increase the ability of these less abundant OTUs to establish a community niche and, therefore, could be clinically relevant. We have begun to investigate the second objective of this study, which is to correlate microbiome composition with mucosal immunity to influenza virus. To our knowledge, this is the first study to investigate LAIV-induced alterations to the human microbiome. These data may lead to a better understanding of the influences of the host microbiome on the response to vaccine, and perhaps infection.

Abstract Prevalence of chronic lung diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease, have been found to increase with age. Pulmonary disease can occur from failure to maintain alveolar type (AT) 1 and alveolar type 2 cells located in the epithelium of the lung. It is currently known that AT2 cells are the facultative stem cells of the lung, and can transform into AT1 cells which make up the structure of the alveoli. This process happens throughout embryonic development, but AT2 cells can also replenish AT1 cell populations post lung injury. This research investigates whether this process that normally occurs during development can also occur in mature AT2 cells, and studies this question using genetically engineered mouse models at a postnatal stage. Using a double inhibition mechanism, we attempted to increase cellular proliferation by administering an agonist and conducted cellular lineage tracing with an SpcCreER lox system via tamoxifen-induced GFP expression. Through lineage labeling, we saw AT1 cells arising from AT2 cells that became plastic, mirroring the plasticity observed in development. Further research is needed to determine if this agonist can be used to epigenetically unlock mature AT2 cells. This result would provide a mechanism to temporarily induce plasticity in a patient’s own AT2 cells in an attempt to regenerate their lungs in disease.

AbstractBackgroundDelirium and dementia are common causes of cognitive impairment in older adults and frequently co‐exist. Delirium is associated with poor clinical outcomes when comorbid with dementia. Identifying delirium superimposed on dementia (DSD) is clinically challenging given the overlap in symptoms, including inattention, cognitive impairment, and altered level of consciousness, especially in advanced stages of dementia. Recognition of delirium is also critical in ADRD (Alzheimer’s Disease and Related Dementias) clinical trials for both validity and safety reasons. The ECT‐AD study is one such trial investigating the safety and efficacy of electroconvulsive therapy (ECT) for treatment‐refractory agitation and aggression in individuals with advanced ADRD. Herein we review the Confusion Assessment Method (CAM) for identifying delirium in the ECT‐AD study.MethodInclusion criteria for ECT‐AD are hospitalized individuals diagnosed with ADRD (ages 55–89, MMSE ≤ 15) and refractory agitation/aggression, as measured by the Cohen‐Mansfield Agitation Inventory (CMAI). Procedures for detecting baseline and treatment‐emergent delirium involve a 3‐step approach conducted by raters trained in the CAM, which assesses inattention, disorganized thinking, altered levels of consciousness, and fluctuating mental status. Step 1 involves gathering information from nurse informants regarding the patient’s mental status over the past 24 hours. Step 2 involves collecting observational data through informal patient interaction (e.g., brief conversation). Step 3 is an objective assessment of cognitive status using the Severe Impairment Battery – 8 Item (SIB‐8), while also making qualitative observations about delirium features (e.g., level of consciousness). The rater then codes the CAM and determines delirium status based on these 3 steps.ResultOf our 6 consented subjects, 1 experienced delirium detected by the CAM during the Randomization Phase. The subject received three positive CAMs on consecutive treatment days, citing change in mental status, inability to arouse, restlessness, psychomotor agitation, and swearing. ECT/S‐ECT was held each treatment day and the subject was withdrawn from the Randomization Phase.ConclusionIdentifying DSD is challenging due to overlapping symptoms and the fluctuating nature of delirium. The CAM may be useful in this regard by using a multi‐step approach that incorporates observations from reliable informants, direct patient interactions, and structured cognitive assessments.

Abstract Purpose Professional identity formation (PIF) is a dynamic process by which an individual internalizes the core values and beliefs of a specific profession. Within medical education, PIF begins in medical school and continues throughout training and practice. Transitions affect PIF, with a critical transition occurring between medical training and unsupervised practice. This study aims to characterize PIF during the transition from resident to early-career faculty physician and explores the relationship between PIF and burnout during this transition. Method The authors conducted a qualitative study using constructivist grounded theory. They conducted semistructured interviews with early-career faculty physicians (defined as practicing for ≤ 5 years) from the Department of Medicine, Mayo Clinic. Deidentified interview transcripts were processed through open and axial coding. The authors organized themes and identified relationships between themes that were refined through discussion and constant comparison with newly collected data. During data analysis, the authors identified self-determination theory, with the concepts of autonomy, competence, and relatedness, as a framework to support the organization and analysis of the data. Results Eleven early-career faculty physicians participated in the interviews. Their PIF was characterized by the dual desires to fit in and stand out. Striving for these desires was characterized by imposter syndrome, driving physicians to question their decision making and overall competence. Participants associated imposter syndrome and academic pressures with burnout. Autonomy support by the institution to pursue opportunities important for career development helped mitigate burnout and support PIF. Conclusions Early-career faculty physicians face identity challenges when transitioning from training to unsupervised practice, including striving to fit in and stand out. They link this tension to imposter syndrome, which they associated with burnout. Institutional awareness and support, including addressing structural and cultural contributors to imposter syndrome, are paramount as new faculty explore their identities and navigate new challenges.

Abstract The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.