Dental Surgical Activity in Hospitals during COVID-19: A Nationwide Observational Cohort Study.

INTRODUCTION: The number of surgical extractions performed in hospitals in England remains unclear. This study reports the volume of surgical extractions conducted in hospitals and change in activity during the COVID-19 pandemic. METHODS: We conducted a nationwide observational cohort study using Hospital Episode Statistics (HES) in England for patients undergoing surgical removal of a tooth (defined using OPSC-4 code F09) between April 1, 2015, and December 31, 2020. Procedures were stratified by age, gender, and urgency (elective or nonelective), reported using descriptive statistics, number, and percentage. We conducted post hoc modeling to predict surgical activity to December 2023. In addition, we contrasted this with aggregate national data on simple dental extraction procedures and drainage of dental abscesses in hospital as well as dental activity in general practice. RESULTS: We identified a total of 569,938 episodes for the surgical removal of a tooth (females 57%). Of these, 493,056/569,938 (87%) were for adults and 76,882/569,938 (13%) children ≤18 years. Surgical extractions were most frequent in adult females. Elective cases accounted for 96% (n = 548,805/569,938) of procedures. The median number of procedures carried out per quarter was 27,256, dropping to 12,003 during the COVID-19 pandemic, representing a 56% reduction in activity. This amounted to around 61,058 cancelled procedures. Modeling predicts that this activity has not returned to prepandemic levels. CONCLUSIONS: The number of surgical extractions taking place in hospitals during the pandemic fell by 56%. The true impact of this reduction is unknown, but delayed treatment increases the risk of complications, including life-threatening infections. KNOWLEDGE TRANSFER STATEMENT: The result of this study provides an evidence-based overview of the trends relating to surgical extractions of teeth in England taking place in hospitals. This information can be used to inform service and workforce planning to meet the needs of patients requiring surgical extractions. The data also provide an insight into the oral health needs of the population in England.

Bacillus anthracis spores are internalized in human lung epithelial cells by Rab GTPase-supported macropinocytosis.

Inhalation anthrax, the deadliest form of the disease, requires inhaled B. anthracis spores to escape from the alveolar space and travel to the mediastinal lymph nodes, from where the vegetative form of the pathogen disseminates, resulting in a rapidly fatal outcome. The role of epithelia in alveolar escape is unclear, but previous work suggests these epithelial cells are involved in this process. Using confocal microscopy, we found that B. anthracis spores are internalized more rapidly by A549 type II alveolar epithelial cells compared to hAELVi type I alveolar epithelial cells. Internalization of spores by alveolar epithelial cells requires cytoskeletal rearrangement evidenced by significant inhibition by cytochalasin D, an actin inhibitor. Chemical inhibitors of macropinocytosis significantly downregulated B. anthracis spore internalization in human alveolar cells, while inhibitors of other endocytosis pathways had minimal effects. Additional studies using a macropinosome marker and electron microscopy confirmed the role of macropinocytosis in spore uptake. By colocalization of B. anthracis spores with four endocytic Rab proteins, we demonstrated that Rab31 played a role in B. anthracis spore macropinocytosis. Finally, we confirmed that Rab31 is involved in B. anthracis spore internalization by enhanced spore uptake in Rab31-overexpressing A549 cells. This is the first report that shows B. anthracis spore internalization by macropinocytosis in human epithelial cells. Several Rab GTPases are involved in the process.

RIG-I agonist SLR10 promotes macrophage M1 polarization during influenza virus infection.

Rationale: A family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection. Methods: Mice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV. Results: SLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. In vitro testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization. Conclusions: Our data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.

A method for beam's eye view breath-hold monitoring during breast volumetric modulated arc therapy.

Background and purpose: Deep inspiration breath-hold (DIBH) is a technique that is widely utilised to spare the heart and lungs during breast radiotherapy. In this study, a method was developed to validate directly the intrafraction accuracy of DIBH during breast volumetric modulated arc therapy (VMAT) via internal chest wall (CW) monitoring. Materials and methods: In-house software was developed to automatically extract and compare the treatment position of the CW in cine-mode electronic portal image device (EPID) images with the planned CW position in digitally reconstructed radiographs (DRR) for breast VMAT treatments. Feasibility of this method was established by evaluating the percentage of total dose delivered to the target volume when the CW was sufficiently visible for monitoring. Geometric accuracy of the approach was quantified by applying known displacements to an anthropomorphic thorax phantom. The software was used to evaluate (offline) the geometric treatment accuracy for ten patients treated using real-time position management (RPM)-guided DIBH. Results: The CW could be monitored within the tangential sub-arcs which delivered a median 89% (range 73% to 97%) of the dose to target volume. The phantom measurements showed a geometric accuracy within 1 mm, with visual inspection showing good agreement between the software-derived and user-determined CW positions. For the RPM-guided DIBH treatments, the CW was found to be within ±5 mm of the planned position in 97% of EPID frames in which the CW was visible. Conclusion: An intrafraction monitoring method with sub-millimetre accuracy was successfully developed to validate target positioning during breast VMAT DIBH.

Disturbance of primary producer communities disrupts the thermal limits of the associated aquatic fauna.

Environmental fluctuation forms a framework of variability within which species have evolved. Environmental fluctuation includes predictability, such as diel cycles of aquatic oxygen fluctuation driven by primary producers. Oxygen availability and fluctuation shape the physiological responses of aquatic animals to warming, so that, in theory, oxygen fluctuation could influence their thermal ecology. We describe annual oxygen variability in agricultural drainage channels and show that disruption of oxygen fluctuation through dredging of plants reduces the thermal tolerance of freshwater animals. We compared the temperature responses of snails, amphipods, leeches and mussels exposed to either natural oxygen fluctuation or constant oxygen in situ under different acclimation periods. Oxygen saturation in channel water ranged from c. 0 % saturation at night to >300 % during the day. Temperature showed normal seasonal variation and was almost synchronous with daily oxygen fluctuation. A dredging event in 2020 dramatically reduced dissolved oxygen variability and the correlation between oxygen and temperature was lost. The tolerance of invertebrates to thermal stress was significantly lower when natural fluctuation in oxygen availability was reduced and decoupled from temperature. This highlights the importance of natural cycles of variability and the need to include finer scale effects, including indirect biological effects, in modelling the ecosystem-level consequences of climate change. Furthermore, restoration and management of primary producers in aquatic habitats could be important to improve the thermal protection of aquatic invertebrates and their resistance to environmental variation imposed by climate change.

Protective interaction of human phagocytic APC subsets with Cryptococcus neoformans induces genes associated with metabolism and antigen presentation.

Cryptococcal meningitis is the most common cause of meningitis among HIV/AIDS patients in sub-Saharan Africa, and worldwide causes over 223,000 cases leading to more than 181,000 annual deaths. Usually, the fungus gets inhaled into the lungs where the initial interactions occur with pulmonary phagocytes such as dendritic cells and macrophages. Following phagocytosis, the pathogen can be killed or can replicate intracellularly. Previous studies in mice showed that different subsets of these innate immune cells can either be antifungal or permissive for intracellular fungal growth. Our studies tested phagocytic antigen-presenting cell (APC) subsets from the human lung against C. neoformans. Human bronchoalveolar lavage was processed for phagocytic APCs and incubated with C. neoformans for two hours to analyze the initial interactions and fate of the fungus, living or killed. Results showed all subsets (3 macrophage and 3 dendritic cell subsets) interacted with the fungus, and both living and killed morphologies were discernable within the subsets using imaging flow cytometry. Single cell RNA-seq identified several different clusters of cells which more closely related to interactions with C. neoformans and its protective capacity against the pathogen rather than discrete cellular subsets. Differential gene expression analyses identified several changes in the innate immune cell's transcriptome as it kills the fungus including increases of TNF-α (TNF) and the switch to using fatty acid metabolism by upregulation of the gene FABP4. Also, increases of TNF-α correlated to cryptococcal interactions and uptake. Together, these analyses implicated signaling networks that regulate expression of many different genes - both metabolic and immune - as certain clusters of cells mount a protective response and kill the pathogen. Future studies will examine these genes and networks to understand the exact mechanism(s) these phagocytic APC subsets use to kill C. neoformans in order to develop immunotherapeutic strategies to combat this deadly disease.

Early IFN-ß administration protects cigarette smoke exposed mice against lethal influenza virus infection without increasing lung inflammation.

During influenza A virus (IAV) infection, it is unclear whether type I interferons (IFNs) have defensive antiviral effects or contribute to immunopathology in smokers. We treated nonsmoking (NS) and cigarette smoke (CS)-exposed mice intranasally with early (prophylactic) or late (therapeutic) IFN-ß. We compared the mortality and innate immune responses of the treated mice following challenge with IAV. In NS mice, both early and late IFN-ß administration decreased the survival rate in mice infected with IAV, with late IFN-ß administration having the greatest effect on survival. In contrast, in CS-exposed mice, early IFN-ß administration significantly increased survival during IAV infection while late IFN-ß administration did not alter mortality. With regards to inflammation, in NS mice, IFN-ß administration, especially late administration, significantly increased IAV-induced inflammation and lung injury. Early IFN-ß administration to CS-exposed mice did not increase IAV-induced inflammation and lung injury as occurred in NS mice. Our results demonstrate, although IFN-ß administration worsens the susceptibility of NS mice to influenza infection with increased immunopathology, early IFN-ß administration to CS-exposed mice, which have suppression of the intrinsic IFN response, improved outcomes during influenza infection.

Diel oxygen fluctuation drives the thermal response and metabolic performance of coastal marine ectotherms.

Coastal marine systems are characterized by high levels of primary production that result in diel oxygen fluctuations from undersaturation to supersaturation. Constant normoxia, or 100% oxygen saturation, is therefore rare. Since the thermal sensitivity of invertebrates is directly linked to oxygen availability, we hypothesized that (i) the metabolic response of coastal marine invertebrates would be more sensitive to thermal stress when exposed to oxygen supersaturation rather than 100% oxygen saturation and (ii) natural diel fluctuation in oxygen availability rather than constant 100% oxygen saturation is a main driver of the thermal response. We tested the effects of oxygen regime on the metabolic rate, and haemocyanin and lactate levels, of velvet crabs (Necora puber) and blue mussels (Mytilus edulis), under rising temperatures (up to 24°C) in the laboratory. Oxygen supersaturation and photosynthetically induced diel oxygen fluctuation amplified animal metabolic thermal response significantly in both species, demonstrating that the natural variability of oxygen in coastal environments can provide considerable physiological benefits under ocean warming. Our study highlights the significance of integrating ecologically relevant oxygen variability into experimental assessments of animal physiology and thermal response, and predictions of metabolic performance under climate warming. Given the escalating intensity and frequency of climate anomalies, oxygen variation caused by coastal vegetation will likely become increasingly important in mitigating the effects of higher temperatures on coastal fauna.

The use of continuous electronic prescribing data to infer trends in antimicrobial consumption and estimate the impact of stewardship interventions in hospitalized children.

BACKGROUND: Understanding antimicrobial consumption is essential to mitigate the development of antimicrobial resistance, yet robust data in children are sparse and methodologically limited. Electronic prescribing systems provide an important opportunity to analyse and report antimicrobial consumption in detail. OBJECTIVES: We investigated the value of electronic prescribing data from a tertiary children's hospital to report temporal trends in antimicrobial consumption in hospitalized children and compare commonly used metrics of antimicrobial consumption. METHODS: Daily measures of antimicrobial consumption [days of therapy (DOT) and DDDs] were derived from the electronic prescribing system between 2010 and 2018. Autoregressive moving-average models were used to infer trends and the estimates were compared with simulated point prevalence surveys (PPSs). RESULTS: More than 1.3 million antimicrobial administrations were analysed. There was significant daily and seasonal variation in overall consumption, which reduced annually by 1.77% (95% CI 0.50% to 3.02%). Relative consumption of meropenem decreased by 6.6% annually (95% CI -3.5% to 15.8%) following the expansion of the hospital antimicrobial stewardship programme. DOT and DDDs exhibited similar trends for most antimicrobials, though inconsistencies were observed where changes to dosage guidelines altered consumption calculation by DDDs, but not DOT. PPS simulations resulted in estimates of change over time, which converged on the model estimates, but with much less precision. CONCLUSIONS: Electronic prescribing systems offer significant opportunities to better understand and report antimicrobial consumption in children. This approach to modelling administration data overcomes the limitations of using interval data and dispensary data. It provides substantially more detailed inferences on prescribing patterns and the potential impact of stewardship interventions.

Long-term cigarette smoke exposure dysregulates pulmonary T cell response and IFN-γ protection to influenza virus in mouse.

BACKGROUND: Influenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models. METHODS: C57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration. RESULTS: Although long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection. CONCLUSIONS: Our results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.

Synthetic Biology of Cannabinoids and Cannabinoid Glucosides in Nicotiana benthamiana and Saccharomyces cerevisiae.

Phytocannabinoids are a group of plant-derived metabolites that display a wide range of psychoactive as well as health-promoting effects. The production of pharmaceutically relevant cannabinoids relies on extraction and purification from cannabis (Cannabis sativa) plants yielding the major constituents, Δ9-tetrahydrocannabinol and cannabidiol. Heterologous biosynthesis of cannabinoids in Nicotiana benthamiana or Saccharomyces cerevisiae may provide cost-efficient and rapid future production platforms to acquire pure and high quantities of both the major and the rare cannabinoids as well as novel derivatives. Here, we used a meta-transcriptomic analysis of cannabis to identify genes for aromatic prenyltransferases of the UbiA superfamily and chalcone isomerase-like (CHIL) proteins. Among the aromatic prenyltransferases, CsaPT4 showed CBGAS activity in both N. benthamiana and S. cerevisiae. Coexpression of selected CsaPT pairs and of CHIL proteins encoding genes with CsaPT4 did not affect CBGAS catalytic efficiency. In a screen of different plant UDP-glycosyltransferases, Stevia rebaudiana SrUGT71E1 and Oryza sativa OsUGT5 were found to glucosylate olivetolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid. Metabolic engineering of N. benthamiana for production of cannabinoids revealed intrinsic glucosylation of olivetolic acid and cannabigerolic acid. S. cerevisiae was engineered to produce olivetolic acid glucoside and cannabigerolic acid glucoside.

Suboptimal sleep and incident cardiovascular disease among African Americans in the Jackson Heart Study (JHS).

BACKGROUND: Suboptimal sleep, including insufficient/long sleep duration and poor sleep quality, is a risk factor for cardiovascular disease (CVD) common but there is little information among African Americans, a group with a disproportionate CVD burden. The current study examined the association between suboptimal sleep and incident CVD among African Americans. METHODS: This study included 4,522 African Americans without CVD at baseline (2000-2004) of the Jackson Heart Study (JHS). Self-reported sleep duration was defined as very short (<6 h/night), short (6 h/night), recommended (7-8 h/night), and long (≥9 h/night). Participants' self-reported sleep quality was defined as "high" and "low" quality. Suboptimal sleep was defined by low quality sleep and/or insufficient/long sleep duration. Incident CVD was a composite of incident coronary heart disease and stroke. Associations between suboptimal sleep and incident CVD were examined using Cox proportional hazards models over 15 follow-up years with adjustment for predictors of CVD risk and obstructive sleep apnea. RESULTS: Sample mean age was 54 years (SD = 13), 64% female and 66% reported suboptimal sleep. Suboptimal sleep was not associated with incident CVD after covariate adjustment [HR(95% CI) = 1.18(0.97-1.46)]. Long [HR(95%CI) = 1.32(1.02-1.70)] and very short [HR(95% CI) = 1.56(1.06-2.30)] sleep duration were associated with incident CVD relative to recommended sleep duration. Low quality sleep was not associated with incident CVD (p = 0.413). CONCLUSIONS: Long and very short self-reported sleep duration but not self-reported sleep quality were associated with increased hazard of incident CVD.

Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes.

Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.

Reducing emergency department (ED) computed tomography (CT) utilization in women treated for gynecologic cancers.

OBJECTIVES: The objective of this quality improvement (QI) project was to decrease the rate of low-value computed tomography (CT) imaging in established gynecologic oncology patients presenting to the emergency department (ED). METHODS: This was a cohort study with a before and after design that evaluated implementation of a QI project designed to decrease CT utilization in established gynecologic oncology patients in the ED. The pre-intervention cohort included patients admitted through the ED from 4/1/17 to 5/31/18, while the post-intervention cohort was from 6/1/18 to 5/31/19. The intervention included gynecologic oncology consultation before CT on patients who had imaging within the prior 3 weeks. Details regarding CT, ED length of stay (LOS), and oncologic history were abstracted. The value of CT was determined by consensus from 2 reviewers. Prospective data monitoring evaluated for patient safety. RESULTS: Prior to intervention, there were 129 unique ED encounters in gynecologic oncology patients leading to admission. CT scans were performed in 101 (78.3%) encounters, 57.7% of which were deemed to be of low-value. Following implementation, the CT utilization rate decreased significantly from median monthly rate of 75.2% to 49.1% (p < 0.00001), and the ED LOS decreased from 8.1 to 6.9 h (p = 0.0102). The number of CT scans deemed to be low-value in the post-intervention group decreased to 2 (3.8%). CONCLUSIONS: Implementation of an early consultation policy and imaging guidelines led to a significant decrease in unnecessary CT utilization and shorter ED LOS in gynecologic oncology patients presenting to the ED.

ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes: protocol for the ELECTRIC randomised trial.

BACKGROUND: Urinary incontinence (UI) is highly prevalent in nursing and residential care homes (CHs) and profoundly impacts on residents' dignity and quality of life. CHs predominantly use absorbent pads to contain UI rather than actively treat the condition. Transcutaneous posterior tibial nerve stimulation (TPTNS) is a non-invasive, safe and low-cost intervention with demonstrated effectiveness for reducing UI in adults. However, the effectiveness of TPTNS to treat UI in older adults living in CHs is not known. The ELECTRIC trial aims to establish if a programme of TPTNS is a clinically effective treatment for UI in CH residents and investigate the associated costs and consequences. METHODS: This is a pragmatic, multicentre, placebo-controlled, randomised parallel-group trial comparing the effectiveness of TPTNS (target n = 250) with sham stimulation (target n = 250) in reducing volume of UI in CH residents. CH residents (men and women) with self- or staff-reported UI of more than once per week are eligible to take part, including those with cognitive impairment. Outcomes will be measured at 6, 12 and 18 weeks post randomisation using the following measures: 24-h Pad Weight Tests, post void residual urine (bladder scans), Patient Perception of Bladder Condition, Minnesota Toileting Skills Questionnaire and Dementia Quality of Life. Economic evaluation based on a bespoke Resource Use Questionnaire will assess the costs of providing a programme of TPTNS. A concurrent process evaluation will investigate fidelity to the intervention and influencing factors, and qualitative interviews will explore the experiences of TPTNS from the perspective of CH residents, family members, CH staff and managers. DISCUSSION: TPTNS is a non-invasive intervention that has demonstrated effectiveness in reducing UI in adults. The ELECTRIC trial will involve CH staff delivering TPTNS to residents and establish whether TPTNS is more effective than sham stimulation for reducing the volume of UI in CH residents. Should TPTNS be shown to be an effective and acceptable treatment for UI in older adults in CHs, it will provide a safe, low-cost and dignified alternative to the current standard approach of containment and medication. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03248362. Registered on 14 August 2017. ISRCTN, ISRCTN98415244. Registered on 25 April 2018. https://www.isrctn.com/.

Clinical impact of removing respiratory motion during liver SABR.

BACKGROUND: Liver tumors are subject to motion with respiration, which is typically accounted for by increasing the target volume. The prescription dose is often reduced to keep the mean liver dose under a threshold level to limit the probability of radiation induced liver toxicity. A retrospective planning study was performed to determine the potential clinical gains of removal of respiratory motion from liver SABR treatment volumes, which may be achieved with gating or tumor tracking. METHODS: Twenty consecutive liver SABR patients were analysed. The treated PTV included the GTV in all phases of respiration (ITV) with a 5 mm margin. The goal prescription was 50Gy/5# (BED 100 Gy10) but was reduced by 2.5 Gy increments to meet liver dose constraints. Elimination of motion was modelled by contouring the GTV in the expiration phase only, with a 5 mm PTV margin. All patients were replanned using the no-motion PTV and tumor dose was escalated to higher prescription levels where feasible given organ-at-risk constraints. For the cohort of patients with metastatic disease, BED gains were correlated to increases in tumour control probability (TCP). The effect of the gradient of the TCP curve on the magnitude of TCP increase was evaluated by repeating the study for an additional prescription structure, 54Gy/3# (BED 151 Gy10). RESULTS: Correlation between PTV size and prescribed dose exists; PTVs encompassing < 10% of the liver could receive the highest prescription level. A monotonically increasing correlation (Spearman's rho 0.771, p = 0.002) between the degree of PTV size reduction and motion vector magnitude was observed for GTV sizes <100cm3. For 11/13 patients initially planned to a decreased prescription, tumor dose escalation was possible (5.4Gy10-21.4Gy10 BED) using the no-motion PTV. Dose escalation in excess of 20 Gy10 increased the associated TCP by 5% or more. A comparison of TCP gains between the two fractionation schedules showed that, for the same patient geometry, the absolute increase in BED was the overarching factor rather than the gradient of the TCP curve. CONCLUSIONS: In liver SABR treatments unable to be prescribed optimal dose due to exceeding mean liver thresholds, eliminating respiratory motion allowed dose escalation in the majority of patients studied and substantially increased TCP.

Salivary Gland Cancers of the Nasopharynx: A Population-Based Analysis of 383 Cases.

OBJECTIVES/HYPOTHESIS: Salivary gland nasopharynx cancers (SGNPCs) are rare malignancies with few cases discussed in the literature. This study represents the largest cohort of SGNPC to date. STUDY DESIGN: Retrospective population-based analysis. METHODS: The Surveillance, Epidemiology, and End Results registry from 1973 to 2015 was utilized to extract 383 cases of SGNPC. Data were analyzed for demographic characteristics, incidence, clinicopathologic traits, and outcome prognosticators. RESULTS: White female patients aged >40 years were most commonly affected. The incidence was measured as 0.019 per 100,000 people. The majority of tumors presented at advanced stages (stage III/IV, 60.8%). Adenoid cystic carcinoma, adenocarcinoma, and mucoepidermoid carcinoma were the most commonly encountered histologies (43.1%, 31.6%, 13.3%, respectively). Cervical node involvement and distant metastasis were measured at 23% and 11.9%, respectively. Mucoepidermoid carcinomas presented with the best disease-specific survival at 5 and 10 years. Asian ethnicity, age <80 years, and earlier American Joint Committee on Cancer stages were positive prognostic factors. The inclusion of surgical therapy improved 5-year outcomes among the most common histologies, except for mucoepidermoid carcinoma. CONCLUSIONS: Salivary gland nasopharyngeal cancer represents a group of rare histologies with similar outcomes as squamous cell carcinomas. However, prognosis is primarily dependent on histologic subtype, race, age, and American Joint Committee on Cancer stage.

Basaloid nasopharyngeal carcinoma: A population-based analysis of a rare tumor.

OBJECTIVES: Basaloid nasopharyngeal carcinoma (BNPC) is an extremely rare malignancy with a paucity of cases reported in the literature. This analysis represents the largest cohort of BNPC to date. STUDY DESIGN: Retrospective population-based analysis. METHODS: The Surveillance, Epidemiology, and End Results registry from 2001 to 2015 was utilized to extract a total of 82 cases of BNPC. Data were analyzed for incidence trends, demographic, and tumor characteristics, as well as potential outcome prognosticators. RESULTS: White male patients between the ages of 40 to 79 years were most commonly affected. The incidence was measured at 0.06 per 100 thousand people. The majority of tumors were considered high grade (grade III/IV; 92.2%). At presentation, patients were most commonly advanced stage (American Joint Committee on Cancer [AJCC] stage IV) at 29.3%, followed by AJCC stages II and III (20.7%, respectively). T2 tumors were most common at 28.8%. Cervical node involvement and distant metastasis were measured at 53.7% and 10.4%, respectively. One-year, 5-year, and 10-year disease-specific survival was 87.7%, 60.7%, and 29.8%, respectively. No prognostic factors were identified in this study. CONCLUSION: Basaloid squamous cell carcinoma represents a histologic subtype of nasopharyngeal carcinoma with excellent short-term outcomes but poor survival at 10 years when compared to conventional squamous cell carcinomas. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2727-2732, 2019.

RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo.

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

Physico-chemical properties and optimization of the deformable FlexyDos3D radiation dosimeter.

Deformable 3D radiation dosimetry is receiving growing interest for the validation of image-guided radiotherapy treatments (IGRT) of moving and deformable targets. Previously, a proof-of-concept of a flexible anthropomorphic 3D dosimeter called 'FlexyDos3D' has been demonstrated. One of the concerns with respect to the FlexyDos3D dosimeter is its dose-response instability. The effect of different formulations of the dosimeter on its stability were investigated. A stable formulation for the dosimeter was found by optimising the ratios of curing agent and base of the silicone matrix between 3% and 4.5% [w/w] curing agent. The effects of elevated curing temperatures and times upon the dosimetric properties were also investigated and the dose-response was found to be independent of curing times for curing times over an hour at 120 °C. 1H NMR spectra of the dosimeter chemical constituents and the effect of radiation dose were determined. The evaporation and diffusion rates of chloroform in the dosimeter were determined and are the likely cause of the dosimeters depth-dose profile uncertainties. A composition for a stable silicone dosimeter which can be cured quickly at elevated temperatures was found, demonstrating the potential for 3D printing of patient-specific dosimeters. However, it is suggested that another radical initiator be used in future formulations of the dosimeter.