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Importance: Chronic rhinosinusitis (CRS) is a common inflammatory disease of the paranasal sinuses with significant quality of life impairments. There is a need to implement outcome-based metrics to evaluate the outcomes of CRS treatment with endoscopic sinus surgery or biologics. Objective: We aimed to understand Canadian otolaryngologists' opinions on patient-related outcome measures (PROM) for CRS and identify potential barriers to implementation. Design: Qualitative research. Setting and Participants: A cross-sectional survey was distributed via the Canadian Society of Otolaryngology-Head and Neck Surgery and direct emailing. Measures: Participants' demographics, practice information, and opinions on PROM were collected. Results: Of 346 (23%) Canadian otolaryngologists, 78 responded to the survey (26 rhinology fellowship–trained, 51 non-fellowship-trained, and 1 missing data). Thirty-eight responded that they collect PROM (69% with fellowship-trained, 39% non-fellowship-trained, P =.029). Regarding opinions on PROM, 74% of respondents agreed that it helps patients report their symptoms, 42% agreed that it improves the efficiency of the patient encounter, 54% agreed that it is easy for patients to understand, 62% agreed that it improves management and monitoring of clinical outcomes, and 71% disagreed that PROM is not helpful. Fellowship-trained otolaryngologists were 4 times more likely to agree that PROM improves management and monitoring of clinical outcomes (P =.014), and no other differences in opinions were significant. The most-frequently-identified barriers to PROM usage were lack of time for 67% of respondents, difficulty integrating into clinical workflow for 64%, and lack of integration into the electronic medical record for 47%. If these barriers were addressed, 86% of respondents said they would use PROM in their practice. Conclusions and Relevance: Despite the low uptake of PROM among otolaryngologists without rhinology fellowship, opinions were generally favorable. We identified barriers that, if addressed, may increase their use in clinical practice. As resource-limited therapies such as biologics become more prevalent in CRS management, PROM may find more applications in shared clinical decision making. [ABSTRACT FROM AUTHOR]

This study investigated dietary supplementation as a prophylactic for neuroinflammation following traumatic brain injury (TBI) in a preclinical model. Adult male Sprague-Dawley rats received 30 days of supplementation with either water or two dietary supplements. The first consisted of high-dose omega-3 fatty acid (O3FA) (supplement A) along with vitamin D3 and vitamin E. The second had the same ingredients at different doses with an addition of cannabidiol (supplement B). Rats were subjected to an impact TBI and then euthanized 7 days post-injury and neuroinflammation quantified by histological detection of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and CD68, a marker of microglial activity. There was a trend toward increased GFAP staining in injured, unsupplemented animals as compared to sham, unsupplemented animals, consistent with increased activation of astrocytes in response to trauma which was reversed by supplement A but not by supplement B. The pattern of CD68 staining across groups was similar to that of GFAP staining. There was a trend toward an increase in the injured unsupplemented group, relative to sham which was reversed by supplement A but not by supplement B. CD68 staining in injured animals was concentrated in the perivascular domain. The consistency between trends across different measures of neuroinflammation showing benefits of high-dose O3FA supplementation following TBI suggests that the observed effects are real. These findings are preliminary, but they justify further study to determine the functional benefits associated with improvements in histological outcomes and understand associated dose-response curves.

The alternatively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in similar amounts in most tissues and have largely redundant functions. This redundancy suggests that diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that are caused by prelamin A-specific mutations could be treated by shifting the output of LMNA more toward lamin C. Here, we investigated mechanisms that regulate LMNA mRNA alternative splicing and assessed the feasibility of reducing prelamin A expression in vivo. We identified an exon 11 antisense oligonucleotide (ASO) that increased lamin C production at the expense of prelamin A when transfected into mouse and human fibroblasts. The same ASO also reduced the expression of progerin, the mutant prelamin A protein in HGPS, in fibroblasts derived from patients with HGPS. Mechanistic studies revealed that the exon 11 sequences contain binding sites for serine/arginine-rich splicing factor 2 (SRSF2), and SRSF2 knockdown lowered lamin A production in cells and in murine tissues. Moreover, administration of the exon 11 ASO reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduction of prelamin A as a potential strategy to treat prelamin A-specific diseases.

Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called "laminopathies," mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low-due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why "prelamin A diseases" such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.

Lamins B1 and B2 have a high degree of sequence similarity and are widely expressed from the earliest stages of development. Studies of Lmnb1 and Lmnb2 knockout mice revealed that both of the B-type lamins are crucial for neuronal migration in the developing brain. These observations naturally posed the question of whether the two B-type lamins might play redundant functions in the development of the brain. To explore that issue, Lee and coworkers generated "reciprocal knock-in mice" (knock-in mice that produce lamin B1 from the Lmnb2 locus and knock-in mice that produce lamin B2 from the Lmnb1 locus). Both lines of knock-in mice manifested neurodevelopmental abnormalities similar to those in conventional knockout mice, indicating that lamins B1 and B2 have unique functions and that increased production of one B-type lamin cannot compensate for the loss of the other.

Lamins B1 and B2 (B-type lamins) have very similar sequences and are expressed ubiquitously. In addition, both Lmnb1- and Lmnb2-deficient mice die soon after birth with neuronal layering abnormalities in the cerebral cortex, a consequence of defective neuronal migration. The similarities in amino acid sequences, expression patterns, and knockout phenotypes raise the question of whether the two proteins have redundant functions. To investigate this topic, we generated "reciprocal knock-in mice"-mice that make lamin B2 from the Lmnb1 locus (Lmnb1(B2/B2)) and mice that make lamin B1 from the Lmnb2 locus (Lmnb2(B1/B1)). Lmnb1(B2/B2) mice produced increased amounts of lamin B2 but no lamin B1; they died soon after birth with neuronal layering abnormalities in the cerebral cortex. However, the defects in Lmnb1(B2/B2) mice were less severe than those in Lmnb1-knockout mice, indicating that increased amounts of lamin B2 partially ameliorate the abnormalities associated with lamin B1 deficiency. Similarly, increased amounts of lamin B1 in Lmnb2(B1/B1) mice did not prevent the neurodevelopmental defects elicited by lamin B2 deficiency. We conclude that lamins B1 and B2 have unique roles in the developing brain and that increased production of one B-type lamin does not fully complement loss of the other.

The use of brain-computer interface (BCI) technologies is a rapidly developing area of interest in neurosurgery. Studies investigating the use of BCIs have primarily focused on surface electrodes; however, subcortically implanted microchips may provide novel, non-pharmacological approaches for managing nervous system disorders. Accessing subcortical regions without disrupting surrounding tissues remains a significant challenge. Accordingly, we conducted an observational, proof-of-concept study to evaluate the use of a modified BrainPath® device to implant subcortical microchips in a rodent model. All animals survived the procedure and lived with a microchip in situ for one or three months with no apparent neurological effects. Histological examination revealed that implantation of a small chip was associated with some tissue damage, tract formation, and surrounding reactive changes. Gliosis and hemosiderin-laden macrophages were evident surrounding tract marks after one month and focal cystic cavitation consistent with infarcted tissue was evident after three months. While a more extensive cellular proliferation response was apparent one month after implantation of a large microchip, there was no significant collagen deposition suggestive of fibrosis. This study is the first demonstration of subcortical microchip implantation using a novel neurosurgical technique that may facilitate the development of BCI technologies for treatment of neurological disorders. [ABSTRACT FROM AUTHOR]