Safety of Ambulatory Surgery For Obstructive Sleep Apnea: A Retrospective Review.

OBJECTIVE: Assess the safety of ambulatory surgery performed for obstructive sleep apnea. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. METHODS: Demographic data including age, gender, race, body mass index, insurance status, socioeconomic status, and distance traveled for surgery was collected, as well as comorbidities, and apnea-hypopnea index (AHI). Outcome variables included continuous positive airway pressure reinitiation, planned/unplanned postoperative admission, emergency department (ED) presentation, or readmission within 7 and 14 days of surgery. RESULTS: A total of 601 patients were included, who underwent sleep surgery between 2017 and 2022. The median age was 55 years [interquartile range: 19]. A total of 437 patients (73%) were male, 502 (84%) were Caucasian, and the median distance traveled was 20 miles [27]. The median AHI was 27.1 [26]. A total of 286 hypoglossal nerve stimulators, 12 tonsillectomies, 160 expansion sphincteroplasties (ESP), and 201 nasal procedures were performed. There were 9 (1%) planned and 23 (4%) total admissions postoperatively. Sixteen patients (2%) presented to ED within 7 days, and 22 (3%) within 14 days. Nine (1%) were readmitted within 7 days, and 12 (2%) within 14 days. There were significantly more planned admissions, unplanned admissions, ED presentations, and readmissions for ESP. There were no significant differences in demographic or clinical data between patients who underwent single versus multiple surgeries. CONCLUSION: Outpatient sleep surgery is generally safe. Close postoperative monitoring is necessary and overnight observation should be considered in those with very severe sleep apnea and/or significant comorbidities. The distance a patient travels should also be considered for overnight admission.

A silver bullet for ageing medicine?: clinical relevance of T-cell checkpoint receptors in normal human ageing.

Immunosenescence describes dysregulation of the immune system with ageing manifested in both the innate and adaptive immunity, including changes in T-cell checkpoint signaling. Through complex and nuanced process, T-cells lose excitatory signaling pathways and upregulate their inhibitory signaling, leading to ineffective immune responses that contribute to the formation of the ageing phenotype. Here we expand on the expression, function, and clinical potential of targeting the T-cell checkpoint signaling in age and highlight interventions offering the most benefits to older adults' health. Notably, modifications in vaccination such as with mTOR inhibitors show immediate clinical relevance and good tolerability. Other proposed treatments, including therapies with monoclonal antibodies fail to show clinical efficacy or tolerability needed for implementation at present. Although T-cell co-signaling fits a valuable niche for translational scientists to manage immunosenescence, future study would benefit from the inclusion of older adults with multiple long-term conditions and polypharmacy, ensuring better applicability to actual patients seen in clinical settings.

Management of an obstructing calculus in an anticoagulated patient with a ureteral hernia.

Introduction: Ureteral hernias are a rare urologic occurrence and can complicate otherwise straightforward management of commonly encountered urologic emergencies. Methods: We review the incidence and identification of ureteroinguinal hernias and present a novel and easily reproducible technique using a modified bander stent to decompress the upper tracts. Results: The technique allowed for decompression of the upper tract secondary to an obstructing stone in a ureteral hernia. No complications were documented. Conclusion: We propose a novel and easily reproducible technique to allow for emergent upper tract decompression in patients with ureteral hernias who are not candidates for percutaneous access.

Microvascular reconstruction of medication related osteonecrosis of the head and neck.

BACKGROUND: Medication related osteonecrosis of the jaw (MRONJ) requiring free flap (FF) reconstruction is uncommon with limited reported findings. METHODS: Multicenter, retrospective case series of 49 consecutive adult patients presenting with advanced MRONJ requiring FF reconstruction from 2010 to 2022. Perioperative complications and outcomes were analyzed. RESULTS: Eighty-two percent (n = 40) of cases were of the mandible and 18% (n = 9) were of the maxilla. The mean follow-up was 15 months (±19.6). The majority of FF survived (96%, n = 47). FF reconstructions of the maxilla were more likely to require postoperative debridement (56%, 95% CI [27, 81%] vs. 15%, 95% CI [7, 25%], p = 0.008) or develop intraoral bone exposure (56%, 95% CI [27, 81%] vs. 18%, 95% CI [9, 27%], p = 0.02). Most patients (71%, n = 35) received preoperative antibiotics which was associated with a higher rate of FF survival (100% vs. 86%, 95% CI [60, 96%], p = 0.02) and fewer complications. CONCLUSIONS: Patients undergoing FF reconstruction for MRONJ do well with high rates of FF success. MRONJ of the maxilla have a higher rate of some complications. Preoperative antibiotics correlated with higher FF survival and fewer postoperative complications.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

Perioperative opioids and survival outcomes in resectable head and neck cancer: A systematic review.

BACKGROUND: Opioids are a mainstay in pain control for oncologic surgery. The objective of this systematic review is to evaluate the associations of perioperative opioid use with overall survival (OS) and disease-free survival (DFS) in patients with resectable head and neck cancer (HNC). METHODS: A systematic review of PubMed, SCOPUS, and CINAHL between 2000 and 2022 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating perioperative opioid use for patients with HNC undergoing surgical resection and its association with OS and DFS were included. RESULTS: Three thousand three hundred seventy-eight studies met initial inclusion criteria, and three studies representing 562 patients (intraoperative opioids, n = 463; postoperative opioids, n = 99) met final exclusion criteria. One study identified that high intraoperative opioid requirement in oral cancer surgery was associated with decreased OS (HR = 1.77, 95% CI 0.995-3.149) but was not an independent predictor of decreased DFS. Another study found that increased intraoperative opioid requirements in treating laryngeal cancer was demonstrated to have a weak but statistically significant inverse relationship with DFS (HR = 1.001, p = 0.02) and OS (HR = 1.001, p = 0.02). The last study identified that patients with chronic opioid after resection of oral cavity cancer had decreased DFS (HR = 2.7, 95% CI 1.1-6.6) compared to those who were not chronically using opioids postoperatively. CONCLUSION: An association may exist between perioperative opioid use and OS and DFS in patients with resectable HNC. Additional investigation is required to further delineate this relationship and promote appropriate stewardship of opioid use with adjunctive nonopioid analgesic regimens.

The exercise IL-6 enigma in cancer.

Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the 'exercise IL-6 enigma'. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory cytokines, mobilising immune cells, and reducing DNA damage in early malignant cells. By contrast, IL-6 continuously produced by leukocytes in inflammatory sites drives tumorigenesis by promoting chronic inflammation and activating tumour-promoting signalling pathways. How can a molecule have such opposing effects on cancer? Here, we review the roles of IL-6 in chronic inflammation, tumorigenesis, and exercise-associated cancer prevention and define the factors that underpin the exercise IL-6 enigma.

Predictors of opioid requirement among patients receiving free flap reconstruction to the head and neck.

BACKGROUND: Opioids are a part of standard of care treatment of acute, severe postoperative pain. However, increased opioid requirements have been shown to be associated with increased postoperative complications, morbidity, and mortality. The aim of this study was to identify potential predictive factors associated with increased or decreased opioid requirements after free tissue transfer (FTT) to the head and neck. MATERIALS/METHODS: A retrospective review was conducted on subjects who underwent head and neck reconstruction (HNR) from 2015 to 2021 at a single tertiary care center. Patients with inpatient stay over 10 days and those receiving fentanyl for sedation purposes were excluded due to EMR limitations and confounding, respectively. The total dose of opioid medication each patient received was calculated and summed using morphine milligram equivalents (MME). Statistical analysis was conducted using poisson regression and multivariable regression models. RESULTS: Two hundred and ninety-one patients were included. The mean opioid requirement for all subjects was 228.6 (SD 250.0) MMEs during their entire postoperative stay and the mean length of stay was 6.0 (SD 1.7) days. An established opioid prescription prior to surgical resection was the greatest predictor of increased risk for opioid requirement according univariate and multivariate analysis 2.356 (2.321-2.392), p ≤ 0.0001 and 1.833 (1.802-1.863), p ≤ 0.0001, respectively. Fibula transfers were associated with higher opioid requirements while scapula transfers were associated with decreased opioid requirements compared to other free tissue transfer types. CONCLUSION: Preoperative opioid use was associated with higher postoperative opioid requirements. Multimodal pain management (MMPM) was not associated with a decreased opioid requirement; however, further studies are needed to investigate the hierarchy, dosing, and timing of MMPM in relation to opioid requirements and pain control.

Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach.

Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.

Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

miRNA Expression in Fibroblastic Foci within Idiopathic Pulmonary Fibrosis Lungs Reveals Novel Disease-Relevant Pathways.

miRNAs are 22 nucleotides long and belong to a class of noncoding RNAs that plays an important role in regulating gene expression at a post-transcriptional level. Studies show aberrant levels of miRNAs to be associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis was artificially induced. The current study used laser microdissection to collect fibroblastic foci (FF), the key pathologic lesion in IPF, isolated miRNAs, and compared their expression levels with those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated, and data generated were bioinformatically analyzed. A total of 18 miRNAs were significantly overexpressed in FF tissue when compared with whole IPF tissue. Of those, 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miRNA composition that impacted several signaling pathways. The miRNA composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterizing FF biology as a phenotypically and functionally discrete tissue microenvironment.

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation.

BACKGROUND: Molecular characterisation of hepatocellular carcinoma (HCC) is central to the development of novel therapeutic strategies for the disease. We have previously demonstrated mutagenic consequences of Long-Interspersed Nuclear Element-1 (LINE1s/L1) retrotransposition. However, the role of L1 in HCC, besides somatic mutagenesis, is not well understood. METHODS: We analysed L1 expression in the TCGA-HCC RNAseq dataset (n = 372) and explored potential relationships between L1 expression and clinical features. The findings were confirmed by immunohistochemical (IHC) analysis of an independent human HCC cohort (n = 48) and functional mechanisms explored using in vitro and in vivo model systems. RESULTS: We observed positive associations between L1 and activated TGFß-signalling, TP53 mutation, alpha-fetoprotein and tumour invasion. IHC confirmed a positive association between pSMAD3, a surrogate for TGFß-signalling status, and L1 ORF1p (P < 0.0001, n = 32). Experimental modulation of L1 ORF1p levels revealed an influence of L1 ORF1p on key hepatocarcinogenesis-related pathways. Reduction in cell migration and invasive capacity was observed upon L1 ORF1 knockdown, both in vitro and in vivo. In particular, L1 ORF1p increased PIN1 cytoplasmic localisation. Blocking PIN1 activity abrogated L1 ORF1p-induced NF-κB-mediated inflammatory response genes while further activated TGFß-signalling confirming differential alteration of PIN1 activity in cellular compartments by L1 ORF1p. DISCUSSION: Our data demonstrate a causal link between L1 ORF1p and key oncogenic pathways mediated by PIN1, presenting a novel therapeutic avenue.

Chronic liver diseases: From development to novel pharmacological therapies: IUPHAR Review 37.

Chronic liver diseases comprise a broad spectrum of burdensome diseases that still lack effective pharmacological therapies. Our research group focuses on fibrosis, which is a major precursor of liver cirrhosis. Fibrosis consists in a progressive disturbance of liver sinusoidal architecture characterised by connective tissue deposition as a reparative response to tissue injury. Multifactorial events and several types of cells participate in fibrosis initiation and progression, and the process still needs to be completely understood. The development of experimental models of liver fibrosis alongside the identification of critical factors progressing fibrosis to cirrhosis will facilitate the development of more effective therapeutic approaches for such condition. This review provides an overlook of the main process leading to hepatic fibrosis and therapeutic approaches that have emerged from a deep knowledge of the molecular regulation of fibrogenesis in the liver. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

c-Rel-dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC. APPROACH AND RESULTS: Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo , global ( Rel-/- ) and epithelial specific ( RelAlb ) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type (WT) controls 30 weeks after N-diethylnitrosamine injury. However, tumor burden was comparable when c-Rel was deleted in hepatocytes once tumors were established, suggesting c-Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro , Rel-/- hepatocytes were more susceptible to genotoxic injury than WT controls. ATM-CHK2 DNA damage response pathway proteins were suppressed in Rel-/- hepatocytes following genotoxic injury, suggesting that c-Rel is required for effective DNA repair. To determine if c-Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy-induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT-603 (c-Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone. CONCLUSION: Hepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.

Unusual Cause of Artificial Urinary Sphincter Malfunction: Device Entanglement Resulting in Urethral Constriction and Urinary Retention.

Urinary retention following placement of an artificial urinary sphincter (AUS) is not an uncommon complication. We describe a unique case of urinary retention due to AUS entanglement causing urethral constriction in a 72-year-old male. He presented to the emergency department postoperatively following AUS placement with pelvic pain and incomplete emptying. Eventual cystourethroscopy demonstrated severe extrinsic urethral constriction despite the deactivation of the AUS device. Surgical exploration revealed an unexpected looping of the occlusive cuff, causing urethral constriction. Although the precise cause is not clearly known, we suspect that it may have been related to the process of connecting the tubing at the level of the abdomen. Regardless of the underlying etiology, this case highlights a unique complication and supports an assessment of the cuff with direct perineal inspection prior to wound closure and/or with cystourethroscopy.

TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation.

BACKGROUND & AIMS: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis. METHODS: TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed. RESULTS: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism. CONCLUSIONS: TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target. LAY SUMMARY: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.

COVID-19 and laryngological surgery.

In 2019, the emergence of the novel SARS-CoV-2 virus in Wuhan, China transformed society and caused major changes in medical care. Efforts to implement protocols to keep providers and their staffs safe during care of all patients ensued. Within the field of laryngology, the risk of aerosol generation and viral spread was among the highest in medicine. It is important to understand the impact of COVID-19 on presurgical and surgical laryngoscopic care as well as the evolution of knowledge that led to our current practices and protocols.

CXCR2 inhibition enables NASH-HCC immunotherapy.

OBJECTIVE: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. DESIGN: Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. RESULTS: Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. CONCLUSION: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions.

HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.