Objective
Previous studies examining changes in central sleep apnea (CSA) following adenotonsillectomy (T&A) performed for obstructive sleep apnea (OSA) in children have been limited by sample size ...and analysis of only certain populations. The aim of this study was to determine whether CSA improves following T&A and what factors mediate this change.
Methods
This was a retrospective case series from 1994 to 2020 of children undergoing primary T&A for OSA (obstructive apnea‐hypopnea index ≥1) with CSA (central apnea index CAI ≥1) and preoperative and postoperative polysomnograms within 12 months of T&A. Polysomnograms were analyzed for improvement in CSA, defined as: 1) if preoperative CAI >5, a postoperative CAI <5; or 2) if preoperative CAI <5, a postoperative CAI <1.
Results
One hundred twenty‐three patients were included. Median age was 5.5 years (interquartile range, 2.9–8.4). Most patients were overweight/obese (58.5%). Nineteen (15.4%) had a syndromic condition. Preoperative CAI was ≥5 in 21 (17.1%) patients. CAI significantly decreased following T&A (preoperative 2.1, postoperative 0.4; P < .001). Thirty‐two (26.0%) patients had CSA postoperatively. Improvement in the microarousal index and older age were significantly associated with improvement in CSA.
Conclusions
T&A led to resolution of CSA in most children with OSA. Improvement in the microarousal index was associated with improvement in CAI, suggesting that preoperative central apneas may be postarousal and thus resolve following T&A.
Level of Evidence
4 Laryngoscope, 132:478–484, 2022
Understanding of repair outcomes after Cas9-induced DNA cleavage is still limited, especially in primary human cells. We sequence repair outcomes at 1,656 on-target genomic sites in primary human T ...cells and use these data to train a machine learning model, which we have called CRISPR Repair Outcome (SPROUT). SPROUT accurately predicts the length, probability and sequence of nucleotide insertions and deletions, and will facilitate design of SpCas9 guide RNAs in therapeutically important primary human cells.
Human Immunodeficiency Virus (HIV) relies on host molecular machinery for replication. Systematic attempts to genetically or biochemically define these host factors have yielded hundreds of ...candidates, but few have been functionally validated in primary cells. Here, we target 426 genes previously implicated in the HIV lifecycle through protein interaction studies for CRISPR-Cas9-mediated knock-out in primary human CD4+ T cells in order to systematically assess their functional roles in HIV replication. We achieve efficient knockout (>50% of alleles) in 364 of the targeted genes and identify 86 candidate host factors that alter HIV infection. 47 of these factors validate by multiplex gene editing in independent donors, including 23 factors with restrictive activity. Both gene editing efficiencies and HIV-1 phenotypes are highly concordant among independent donors. Importantly, over half of these factors have not been previously described to play a functional role in HIV replication, providing numerous novel avenues for understanding HIV biology. These data further suggest that host-pathogen protein-protein interaction datasets offer an enriched source of candidates for functional host factor discovery and provide an improved understanding of the mechanics of HIV replication in primary T cells.
•Environmental enrichment stimulates expansion of natural killer (NK) cells in fat.•Hypothalamic BDNF is the upstream brain mediator underlying this stimulation.•Adipocyte-derived IL-15 is the ...downstream mediator of the brain-fat axis.•IL-15 gene transfer to visceral fat expands adipose NK cells and inhibits melanoma.
Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.
The association between patients' confidence in their ability to attend appointments and future retention in care has not previously been studied in a general HIV clinic. A survey of potential and ...known risk factors for poor retention was developed using validated screening tools and administered to 105 patients at an HIV clinic. Retention in care was assessed prospectively using two definitions: (1) two appointments at least three months apart within one year ("HRSA/HAB retention") and (2) no missed appointments within one year ("missed visits retention"). Most patients were African American (86%) and male (59%). Although most patients were confident they could keep their HIV appointments (89%), fewer were retained (HRSA/HAB: 73%; missed visits: 56%). Patients' confidence in their ability to keep future appointments was not associated with retention. Employment was associated with lower odds of HRSA/HAB retention (aOR 0.26 95% CI 0.09-0.77), and childcare was a common barrier that was associated with lower odds of missed visits retention (aOR 0.06 95% CI 0.006-0.62). Other known risk factors for poor retention were inconsistently associated with retention in care.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
In the era of free flap reconstruction, mandibular defects are routinely reconstructed with osseous free flaps, and non‐free flap bony reconstruction options are limited. A patient with T4N0 ...mandibular squamous cell carcinoma underwent resection with fibula free flap reconstruction of a parasymphyseal to angle defect. After free flap failure due to venous congestion, the flap was explanted. He declined additional free flap reconstruction and elected to proceed with pedicled osteomyocutaneous pectoralis major with rib. In this case presentation, we discuss the technical details of harvest of this flap using the 6th rib. The pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest, which is infrequently described in the literature, remains a viable option for bony reconstruction, particularly in the salvage setting.
•Environmental enrichment (EE) modulates thymocyte maturation and selection in mice.•Hypothalamic BDNF mediates the EE-induced thymic phenotypes.•Adrenalectomy and thymocyte glucocorticoid receptor ...knockout block EE’s thymic effects.•EE protects mice against autoimmune EAE via regulation of type 1 T helper cells.•Adoptive transfer and thymocyte GR knockout link EE thymic modulation to EAE outcome.
Environmental and social factors have profound impacts on immune homeostasis. Our work on environmental enrichment (EE) has revealed a novel anti-obesity and anticancer phenotype associated with enhanced activity of CD8+ cytotoxic T lymphocytes in secondary lymphoid tissues. Here we investigated how an EE modulated thymus and thymocyte development. EE decreased thymus mass and cellularity, decreased the double positive thymocyte population, increased the proportion of CD8+ T cells, reduced the CD4:CD8 ratio, and downregulated CD69 expression in T cells. In a model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE), EE alleviated symptoms, inhibited spinal cord inflammation through regulation of type 1 T-helper cells mediated by glucocorticoid receptor signaling, and prevented EAE-induced thymic disturbance. Our mechanistic studies demonstrated that hypothalamic BDNF activated a hypothalamic-pituitary-adrenal axis mediating the EE’s thymic effects. Our results indicate that a lifestyle intervention links the nervous, endocrine, and adaptive immune system, allowing the body to adapt to internal and external environments.
To assess the usefulness of numeric grading scales of middle ear risk in predicting ossiculoplasty hearing outcomes.
Retrospective review.
Tertiary care, academic medical center.
Adults and children ...undergoing ossiculoplasty between May 2013 and May 2019 including: synthetic ossicular replacement prosthesis, autograft interposition, bone cement repair, and mobilization of lateral chain fixation.
Cases were scored via middle ear risk index (MERI), surgical prosthetic infection tissue eustachian tube (SPITE) method, and ossiculoplasty outcome scoring parameter (OOPS) scale. Preoperative and postoperative hearing outcomes were recorded.
Statistical correlation between risk score and postoperative pure-tone average air-bone gap (PTA-ABG).
The 179 included cases had average pre and postoperative PTA-ABGs of 30.3dB (standard deviation SD 12.7) and 20.3dB (SD 11.1), respectively. Mean MERI, SPITE, and OOPS scores were 4.5 (SD 2.3), 2.8 (SD 1.7), and 3.1 (SD 1.8), respectively. Statistically significant correlations with hearing outcome were noted for all three methods (MERI r = 0.22, p = 0.003; OOPS r = 0.19, p = 0.012; SPITE r = 0.27, p < 0.001). No scale predicted poor (PTA-ABG > 30dB) outcomes; only low SPITE scores predicted excellent (PTA-ABG < 10dB) outcomes (odds ratio OR 0.74 Confidence Interval: 0.57 - 0.97, p = 0.032).
Significant weak correlations between each middle ear risk score and hearing outcomes were encountered. Although only the SPITE method predicted postoperative PTA-ABG, it was not overwhelmingly superior. Current grading scale selection may be justified by familiarity or ease of use.
Unlike humans, mice are unable to support HIV-1 infection. This is due, in part, to a constellation of defined minor, species-specific differences in conserved host proteins needed for viral gene ...expression. Here, we used precision CRISPR/Cas9 gene editing to engineer a "mousified" version of one such host protein, cyclin T1 (CCNT1), in human T cells. CCNT1 is essential for efficient HIV-1 transcription, making it an intriguing target for gene-based inactivation of virus replication. We show that isogenic cell lines engineered to encode CCNT1 bearing a single mouse-informed amino acid change (tyrosine in place of cysteine at position 261) exhibit potent, durable, and broad-spectrum resistance to HIV-1 and other pathogenic lentiviruses, and with no discernible impact on host cell biology. These results provide proof of concept for targeting
in the context of one or more functional HIV-1 cure strategies.
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