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Calcification by coral reef communities is estimated to account for half of all carbonate produced in shallow water environments and more than 25% of the total carbonate buried in marine sediments globally. Production of calcium carbonate by coral reefs is therefore an important component of the global carbon cycle; it is also threatened by future global warming and other global change pressures. Numerical models of reefal carbonate production are needed for understanding how carbonate deposition responds to environmental conditions including atmospheric CO2 concentrations in the past and into the future. However, before any projections can be made, the basic test is to establish model skill in recreating present-day calcification rates. Here we evaluate four published model descriptions of reef carbonate production in terms of their predictive power, at both local and global scales. We also compile available global data on reef calcification to produce an independent observation-based data set for the model evaluation of carbonate budget outputs. The four calcification models are based on functions sensitive to combinations of light availability, aragonite saturation (Ωa) and temperature and were implemented within a specifically developed global framework, the Global Reef Accretion Model (GRAM). No model was able to reproduce independent rate estimates of whole-reef calcification, and the output from the temperature-only based approach was the only model to significantly correlate with coral-calcification rate observations. The absence of any predictive power for whole reef systems, even when consistent at the scale of individual corals, points to the overriding importance of coral cover estimates in the calculations. Our work highlights the need for an ecosystem modelling approach, accounting for population dynamics in terms of mortality and recruitment and hence calcifier abundance, in estimating global reef carbonate budgets. In addition, validation of reef carbonate budgets is severely hampered by limited and inconsistent methodology in reef-scale observations.

INTRODUCTION: Inverted papillomas are relatively rare, benign epithelial tumours of the nasal cavity which generate considerable interest because they are locally aggressive, have a tendency to recur and are associated with malignancy. AIMS: To review our experience of the management of inverted papillomas, and to review the literature in order to evaluate recurrence rates, rates of synchronous and metachronous carcinoma, and outcomes of treatment, both endoscopic and conventional. METHODS: We retrospectively reviewed all cases of inverted papilloma that presented to our unit, a tertiary referral centre, over a 20-year period from 1985 to 2005. A Medline review of the literature was performed to identify published case series of inverted papillomas. We undertook a critical analysis of the literature. RESULTS: We treated 65 patients with inverted papilloma over the 20-year period, with a mean follow up of five years (range one to 20 years). Fifty-eight patients initially underwent nasal biopsy, often with polypectomy. Thirty-six had endoscopic surgery, with five (14 per cent) suffering recurrence, whilst 16 had a lateral rhinotomy and medial maxillectomy, of which four (25 per cent) suffered a recurrence. Seven septal inverted papillomas required local resection, with no subsequent recurrences. There were seven (11 per cent) synchronous and two metachronous malignancies.Sixty-three case series with adequate data were identified from the literature. There were 163 (7.1 per cent) cases of synchronous carcinoma, out of 2297 cases. Metachronous carcinomas were reported in 74 out of 2047 cases, representing a transformation rate of 3.6 per cent. However, the true population base for these figures is uncertain, given that many series were reported from tertiary centres, where recurrent and problematic cases are likely to be over-represented. The recurrence rates were 12.8 per cent for endoscopic procedures, 17.0 per cent for lateral rhinotomy with medial maxillectomy, and 34.2 per cent for limited resections such as nasal polypectomy and Caldwell-Luc approaches. No significant association between atypia or dysplasia and recurrence or malignant transformation was found. The mean time taken to develop a metachronous carcinoma was 52 months (range six to 180 months). The estimated malignant potential for recurrent disease was up to 11 per cent. CONCLUSION: Patients with inverted papilloma should undergo thorough surgery to remove all mucosal disease, most probably by the endoscopic, endonasal route when complete resection is possible. Cases demonstrating atypia or dysplasia may be treated by the endoscopic route. Recurrent disease and metachronous carcinoma can develop after a prolonged period of time. Long-term follow up is recommended to detect recurrence, as disease can become quite extensive before it becomes symptomatic. [ABSTRACT FROM AUTHOR]

We undertook a prospective observational study of 108 consecutive patients with endoscopic paranasal mucopurulent secretions. Only 31 patients (29 per cent) had facial pain. In 20 (65 per cent), the endoscopic site of purulent secretions corresponded to the site of pain. In those with facial pain, 74 per cent had nasal obstruction, 68 per cent had objective hyposmia and 84 per cent had mucopurulent rhinorrhoea. In the 31 patients with facial pain, 19 (61 per cent) became symptom free following medical treatment. The remaining 12 patients underwent surgery and their symptoms resolved, except for one patient with a tension-type headache and another with pain of unknown cause.Most patients with purulent secretions from the paranasal sinuses do not have facial pain; therefore, chronic rhinosinusitis is not synonymous with pain.Patients with sinogenic facial pain usually have endoscopic findings that correlate with the site of pain, and the majority also have other nasal symptoms. Chronic infective rhinosinusitis usually responds to medical therapy, and the remainder resolve with surgery. [ABSTRACT FROM AUTHOR]

Chronic throat clearing or a feeling of 'something' at the back of the oropharynx or nasopharynx is a common cause for referral to otorhinolaryngology services. While treatment of an underlying causative condition might be expected to improve these symptoms, in many cases a clear underlying cause is not found. Currently, there is no recognized treatment which is effective against these troublesome symptoms. This observational study investigated the effectiveness of a regime of sipping ice cold carbonated water to try to break the vicious cycle of throat clearing. Seventy-two patients with these symptoms who had previously been advised to use the regime were contacted with a postal questionnaire. Sixty-three per cent of patients documented an improvement in their symptom severity score. The most severely and most frequently affected patients had the greatest benefit. We conclude that the suggested regime can be effective in breaking the vicious cycle of persistent throat-clearing. [ABSTRACT FROM AUTHOR]

Rhinocerebral mucormycosis is a devastating, rapidly progressive and often fatal opportunistic fungal infection predominantly affecting individuals with underlying metabolic and/or immunological compromise. Intracranial extension of the disease has invariably been associated with mortality.We present a review of optimum management of rhinocerebral mucormycosis and a case report of sinonasal mucormycosis with intracranial and orbital extension which was treated successfully with a combination of systemic liposomal amphotericin B therapy and wide surgical debridement. [ABSTRACT FROM AUTHOR]

Objectives: To establish the etiology of facial pain in individuals attending the nasal clinic of the Department of Otorhinolaryngology, University Hospital, Nottingham, U.K., with normal nasal endoscopy and computed tomography of the paranasal sinuses. Study Design: A retrospective analysis of a cohort of 973 patients consecutively presenting to the nasal clinic with symptoms of rhinosinusitis and/or facial pain. Methods: We reviewed the case notes of 973 consecutive patients who presented to the nasal clinic with either symptoms of rhinosinusitis or facial pain, and in particular 101 who had facial pain without any objective evidence of nasal disease as detected by nasal endoscopy or computed tomography. The diagnosis was based on the outcome and response to treatment after a mean of 2 years 2 months. Results: One hundred one patients had pain as a predominant symptom with normal nasal endoscopy and computed tomography of the paranasal sinuses. None of these patients responded to either medical or surgical treatment for what some workers have hypothesized could be "occult" sinonasal disease. A neurological diagnosis was made in 99 patients. Eighty patients received successful medical treatment for "neurological" diagnoses, 8 patients experienced spontaneous resolution of their symptoms, 7 failed to respond to any treatment modality, 2 were lost to follow-up, and 2 refused any treatment. Conclusion: The majority of patients presenting to a rhinologic clinic with facial pain and no objective evidence of sinus disease, as detected by endoscopy and computed tomography, responded well to neurological treatment and surgical intervention was unnecessary. These patients should receive a trial of medical therapy, such as low-dose amitriptyline for 6 weeks in the first instance, before any surgical intervention is considered. [ABSTRACT FROM AUTHOR]

Objectives: A review of the presenting features, management, and outcome of extranodal non-Hodgkin's lymphoma (NHL) of the sinonasal tract during a 10-year period in Nottingham, UK. Study Design: Twenty-four patients received a diagnosis of extranodal NHL of the nasal cavity, paranasal sinuses, or both, from 1987 to 1996. The patients' data were collected prospectively in the Nottinghamshire Lymphoma Registry. Methods: All patients' records and their histology were reviewed along with data entered into the Nottinghamshire Lymphoma Registry, noting the patient's age, sex, presenting symptoms and signs, staging, computed tomography findings, histology, treatment, complications, and outcome. Results: The 24 patients with extranodal NHL of the sinonasal tract represent 1.63% of the 1,457 patients with NHL seen in the 10-year period of this study in Nottinghamshire. The median age was 72 years (range, 42-96 y), with a male dominance (male-to-female ratio: 15:9). Most patients presented with nonspecific nasal symptoms such as nasal obstruction and epistaxis. Only one patient had a relapse involving the central nervous system after treatment. All the histology was reviewed and showed a predominance of large B-cell subtype (21 patients). The overall 5-year survival was 40% (95% CI, 19%-61%) and 33% for 10-year (95% CI, 12%-54%). The cause-specific survival at 5 years and 10 years was 62% (95% CI, 39%-86%). Conclusions: A high degree of suspicion and appropriate use of computed tomography scans and surgical biopsy are the keys to the management of NHL. [ABSTRACT FROM AUTHOR]

Objective: To report the results of endoscopic laser-assisted dacryocystorhinostomy in anticoagulated patients. Study Design: A retrospective study of 16 consecutive anticoagulated patients with distal nasolacrimal duct obstruction treated by endoscopic laser-assisted dacryocystorhinostomy. Methods: A case note review was made of all patients treated with endoscopic laser-assisted dacryocystorhinostomy who were taking coumadin in two centers between 1993 and 2000. The parameters of age, gender, indications for surgery, surgical findings, complications, and outcome were analyzed. The mean follow-up time was 14 months (range, 9-26 mo). Results: Fifteen of the 16 patients who were treated had an eventual successful outcome, but 6 patients required revision surgery. The patient whose symptoms were not improved was shown to have functional epiphora. No patient had a problem with primary or secondary epistaxis, and no patient required admission. A major benefit was the lack of disruption of anticoagulant therapy. Conclusions: Endoscopic laser-assisted dacryocystorhinostomy is a safe, efficient technique for the relief of distal nasolacrimal duct obstruction in anticoagulated patients. Not only does it avoid any disruption to their anticoagulant therapy, but it also can be performed as an outpatient procedure. [ABSTRACT FROM AUTHOR]

Intracranial foreign bodies are typically removed via a craniotomy, which carries significant peri-operative risks. Nasal endoscopy for removal of intracranial foreign bodies is rare and has been attempted only a few times. Here, we describe a case in which nasal endoscopy was employed to successfully remove an air rifle pellet from the anterior cranial fossa, with subsequent repair of the associated cerebrospinal fistula. We thus advocate nasal endoscopy as an alternate line of management for the removal of foreign bodies from the anterior cranial fossa when possible, due to its significantly lower associated morbidity, provided adequate neurosurgical backup is available if required. [ABSTRACT FROM AUTHOR]

Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract., Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid., Results: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline., Conclusions: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy., (© 2024 Genentech and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: Obesity is the top modifiable risk factor for Alzheimer's disease. We hypothesized that high fat diet (HFD)-induced obesity alters brain transcriptomics in APOE-genotype and sex dependent manners. Here, we investigated interactions between HFD, APOE, and sex, using a knock-in mouse model of the human APOE3 and APOE4 alleles., Methods: Six-month-old APOE3-TR and APOE4-TR mice were treated with either HFD or control chow. After 4 months, total RNA was extracted from the cerebral cortices and analyzed by poly-A enriched RNA sequencing on the Illumina platform., Results: Female mice demonstrated profound HFD-induced transcriptomic changes while there was little to no effect in males. In females, APOE3 brains demonstrated about five times more HFD-induced transcriptomic changes (399 up-regulated and 107 down-regulated genes) compared to APOE4 brains (30 up-regulated and 60 down-regulated). Unsupervised clustering analysis revealed two gene sets that responded to HFD in APOE3 mice but not in APOE4 mice. Pathway analysis demonstrated that HFD in APOE3 mice affected cortical pathways related to feeding behavior, blood circulation, circadian rhythms, extracellular matrix, and cell adhesion., Conclusions: Female mice and APOE3 mice have the strongest cortical transcriptomic responses to HFD related to feeding behavior and extracellular matrix remodeling. The relative lack of response of the APOE4 brain to stress associated with obesity may leave it more susceptible to additional stresses that occur with aging and in AD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: Acute knee injuries are commonly encountered in both the clinical and sideline setting and may be treated operatively or non-operatively. This article describes an evidence-based approach to non-operative acute knee injury. This includes history, physical exam, imaging, and initial management. In addition, the non-operative management of three such injuries-ligament injury, meniscus injury, and patellar dislocation injury-will be discussed via a case-based practical approach., Recent Findings: Aside from grade III ACL tears, most acute knee ligament injuries, especially in the absence of other concurrent injuries, can be treated non-operatively. There is new evidence that acute traumatic meniscus tears in those younger than 40 can be successfully treated non-operatively and can do equally, as well as those that undergo surgery, at 1 year out from injury. Based on the current literature, a short period of knee bracing in extension with progression to weightbearing to tolerance is recommended after initial patellar dislocation. Many of the most common acute knee injuries, including MCL tears, meniscus tears, and patellar dislocations, can be managed non-operatively. A detailed systemic approach to initial evaluation, including pertinent history, physical exam, and appropriate imaging, is essential and complementary to the subsequent non-operative treatment algorithm., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Receptor-interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)-α, Toll-like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1-mediated inflammation and cell death. GDC-8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo-controlled, double-blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single- (5-225 mg) and multiple- (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC-8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC-8264. All adverse events in GDC-8264-treated subjects in both stages were mild. GDC-8264 exhibited dose-proportional increases in systemic exposure; the mean terminal half-life ranged from 10-13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC-8264 had minimal renal excretion at all doses. A high-fat meal had no significant effect on the PKs of GDC-8264. In an ex vivo stimulation assay of whole blood, GDC-8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK-PD modeling, the GDC-8264 half-maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC-8264 support its further development for treatment of RIP1-driven diseases., (© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias., Methods: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry., Results: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα])., Discussion: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Serious infections are an important concern for patients with autoimmune conditions. We sought to estimate serious infection rates among patients with select autoimmune conditions relative to the general population in Taiwan and the USA., Methods: This retrospective cohort study estimated setting-specific standardized serious infection incidence rates and ratios among patients with systemic lupus erythematosus, including extra-renal lupus and lupus nephritis, rheumatoid arthritis and primary membranous nephropathy, compared with the general population using insurance claims for hospitalizations between 2000 and 2013. Multivariable Cox proportional hazard models were used to estimate adjusted hazard ratios for serious infections, adjusting for age, sex, index year, prior serious infection, comorbidities and medications., Results: In Taiwan, serious infection rates were 22.7, 28.7, 70.6, 43.4 and 215.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. In the USA, serious infection rates were 2.6, 9.0, 15.6, 21.0 and 63.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. Patients had significantly higher serious infection rates than the general population in both settings, largely driven by bacterial, respiratory, urinary tract and opportunistic infections. Patients with lupus nephritis had the highest burden of serious infections relative to the general population, with 7- to 25-fold higher adjusted hazard ratios in Taiwan and the USA, respectively., Conclusion: This study identified a significant excess serious infection burden among patients with targeted autoimmune conditions compared with the general populations in Taiwan and the USA., (© 2022. The Author(s).)

The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.

Background: High-school sports participation in the United States has increased over the years with a corresponding increase in the number of injuries. Leading medical and sports organizations nationwide advocate for an increase in proper medical supervision of athletes., Objectives: To analyze athletic medical coverage in Illinois high schools and compare differences between public and private Illinois high school., Methods: A survey addressing various components of sports medical coverage was distributed in 2018 to all 810 Illinois High School Association (IHSA) high schools to be completed electronically., Results: The response rate was 50% (407/810 schools). Of the responding schools, 14% were private high schools and 86% public high schools. An orthopedic surgeon, family doctor, pediatrician, or another type of physician were present on sidelines in 9.2% of private high schools and 8.5% of public high schools. Athletic trainers (ATs) were present on sidelines in 91% of private high schools and in 79% of public high schools. There was 68% of private high schools reporting coaches trained in CPR versus 85% in public high schools. Both private and public high schools had high rates of having written emergency action plans (89% vs 91%), AED on site (100% vs 99%), written concussion management protocols (96% vs 97%)., Conclusion: Our study found similar rates of high school medical coverage as compared to national studies, with some significant differences found between private and public high schools. Most Illinois high schools had high rates of having written EAPs, concussion management protocols and AEDs on site. Overall, an increase of medical supervision and emergency preparedness is needed, which should come in the form of increasing AT and physician presence alongside community and school engagement for improved implementation of coverage.

Objective: Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study., Methods: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48., Results: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo., Conclusion: While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition., (© 2021, American College of Rheumatology.)