A new look at the use of improper priors in Bayes factors for model comparison is presented. As is well known, in such a case, the Bayes factor is only defined up to an arbitrary constant. Most ...current methods overcome the problem by using part of the sample to train the Bayes factor (Fractional Bayes Factor) or to transform the improper prior in to a proper distribution (Intrinsic Bayes Factors) and use the remainder of the sample for the model comparison. It is provided an alternative approach which relies on matching divergences between density functions so as to establish a value for the constant appearing in the Bayes factor. These are the Kullback–Leibler divergence and the Fisher information divergence; the latter being crucial as it does not depend on an unknown normalizing constant. Demonstrations of the performance of the proposed method are provided through numerous illustrations and comparisons, showing that the main advantage over existing ones is that it does not require any input from the experimenter; it is fully automated.
Oral mucositis is a frequent and devastating toxicity secondary to cancer treatment, which may affect 20-40% of patients receiving conventional chemotherapy and 60-85% of patients undergoing ...hematopoietic stem cell transplantation. The pathobiology of mucositis includes a complex cascade of biologic events in which pro-inflammatory cytokines, ROS, second messengers, and the oral microbiome contribute to tissue damage of the oral mucosa. Management strategies to oral mucositis secondary to chemotherapy include preventative measures and therapeutic approaches.
A literature search of published animal and clinical studies was perform to review the epidemiology, pathophysiology and treatment options for cancer regimen-induced mucositis. We also discuss new data coming from recent pertinent clinical trials.
Mucositis is one of the most common debilitating toxicities secondary to cancer treatment and can adversely affect patients' quality of life. Epidemiological data for mucositis are often under-reported. Research efforts have shown that genetics plays a major role in the development of this toxicity. Although few therapeutic agents are available, several promising drugs are under investigations.
Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity. Traditionally, the ...condition has been described as a noninflammatory disease; however, more recently it has been associated with ocular inflammation. Keratoconus normally develops in the second and third decades of life and progresses until the fourth decade. The condition affects all ethnicities and both sexes. The prevalence and incidence rates of keratoconus have been estimated to be between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 cases per 100,000 persons/year, respectively, with highest rates typically occurring in 20- to 30-year-olds and Middle Eastern and Asian ethnicities. Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings. A family history of keratoconus, eye rubbing, eczema, asthma, and allergy are risk factors for developing keratoconus. Detecting keratoconus in its earliest stages remains a challenge. Corneal topography is the primary diagnostic tool for keratoconus detection. In incipient cases, however, the use of a single parameter to diagnose keratoconus is insufficient, and in addition to corneal topography, corneal pachymetry and higher order aberration data are now commonly used. Keratoconus severity and progression may be classified based on morphological features and disease evolution, ocular signs, and index-based systems. Keratoconus treatment varies depending on disease severity and progression. Mild cases are typically treated with spectacles, moderate cases with contact lenses, while severe cases that cannot be managed with scleral contact lenses may require corneal surgery. Mild to moderate cases of progressive keratoconus may also be treated surgically, most commonly with corneal cross-linking. This article provides an updated review on the definition, epidemiology, histopathology, aetiology and pathogenesis, clinical features, detection, classification, and management and treatment strategies for keratoconus.
It has been 24 years since rapamycin (sirolimus) was approved to mitigate solid organ transplant rejection and 16 years since mTOR (mammalian/mechanistic target of rapamycin) inhibitors reached ...patients as a cancer therapy. While the clinical benefits of mTOR inhibitors (mTORi) are robust, so too are their toxicities. Among the most common issues is the development of ulcers of the oral mucosa (mTOR-inhibitor associated stomatitis; mIAS). These lesions are distinct from those of other anti-cancer agents, occur with regularity, and impact patient outcomes. mIAS' pathogenesis has been the subject of speculation, and its similar presentation to recurrent aphthous stomatitis (RAS) has led to the hypothesis that it might serve as a surrogate to better understand RAS. Based on a review of the literature, the current manuscript provides a hypothesis regarding the mechanisms by which mTORis uniquely initiate mucosal injury and an explanation for the observation that steroids (also an immunosuppressive) are effective in its treatment through a non-immunologic mechanism. Unexplained unique features of mIAS are discussed in this review in the context of future investigation.
To compare recovery in a rat model of sciatic nerve injury using a novel polyglycolic acid (PGA) conduit, which contains collagen fibers within the tube, as compared with both a hollow collagen ...conduit and nerve autograft. We hypothesize that a conduit with a scaffold will provide improved nerve regeneration over hollow conduits and demonstrate no significant differences when compared with autograft.
A total of 72 Sprague-Dawley rats were randomized into 3 experimental groups, in which a unilateral 10-mm sciatic defect was repaired using either nerve autograft, a hollow collagen conduit, or a PGA collagen–filled conduit. Outcomes were measured at 12 and 16 weeks after surgery, and included bilateral tibialis anterior muscle weight, voltage and force maximal contractility, assessment of ankle contracture, and nerve histology.
In all groups, outcomes improved between 12 and 16 weeks. On average, the autograft group outperformed both conduit groups, and the hollow conduit demonstrated improved outcomes when compared with the PGA collagen–filled conduit. Differences in contractile force, however, were significant only at 12 weeks (autograft > hollow collagen conduit > PGA collagen–filled conduit). At 16 weeks, contractile force demonstrated no significant difference but corroborated the same absolute results (autograft > hollow collagen conduit > PGA collagen–filled conduit).
Nerve repair using autograft provided superior motor nerve recovery over the 2 conduits for a 10-mm nerve gap in a murine acute transection injury model. The hollow collagen conduit demonstrated superior results when compared with the PGA collagen–filled conduit.
The use of a hollow collagen conduit provides superior motor nerve recovery as compared with a PGA collagen–filled conduit.
Methane flux from freshwater mineral-soil (FWMS) wetlands and its variability among sites is largely modulated by plant-mediated transport. However, plant-mediated transport processes are rarely ...resolved in land surface models and are poorly parametrized for plants commonly found in FWMS wetlands. Here, relationships between methane flux and CO₂ uptake, as well as plant conductance of methane were evaluated for three plant species and two characteristic functional types: emergent (narrow-leaved cattail) and floating-leaved (American lotus and water lily). We found significant but contrasting correlations between methane flux and CO₂ uptake in cattails (r² = 0.51, slope = −0.16, during morning) and water lily (r² = 0.32, slope = 0.064, after midday). This relationship was not significant in American lotus, showing that stomata regulation of methane fluxes is species-specific and not generalizable across the floating-leaved plant functional type. Conductance of methane per leaf area showed distinct seasonal dynamics across species. Conductance was similar among the floating-leaved species (6.2 × 10−3 m d−1 in lotus and 7.2 × 10−3 m d−1 in water lily) and higher than conductance in the emergent species (2.7 × 10−3 m d−1). Our results provide direct observations of plant conductance rates and identify the vegetation parameters (leaf area, stomatal conductance) that modify them. Our results further suggest that models of methane emissions from FWMS should parameterize plant-mediated transport in different plant functional types, scaled by leaf area and with variable seasonal phenological dynamics, and consider possible species-specific mechanisms that control methane transport through plants.
Background
Immune checkpoint inhibitors (ICIs) are increasingly accepted as a treatment option for several cancers. Although various systemic immune‐related adverse events (irAEs) have been ...characterized, the effect of ICIs on the oral cavity and contiguous structures is still poorly understood.
Methods
Electronic medical records of 4683 patients in the Mass General Brigham Registered Patient Data Registry who received ICI therapy (ICIT) between December 2011 and September 2019 were reviewed. Reports of oral conditions were categorized into oral mucosal disorders, xerostomia, and dysgeusia. After applying exclusion criteria, demographic characteristics and clinical features were summarized for the patients who had oral irAEs.
Results
In total, 317 patients developed oral conditions that were associated with ICIT (incidence, 6.8%; 317 of 4683 patients). These conditions included xerostomia (68.5%), oral mucosal disorders (33.4%), and dysgeusia (24.0%). In patients with oral irAEs, respiratory cancer (28.4%) was the most common primary cancer, followed by melanoma (26.2%), and head and neck cancer (14.8%). Oral mucosal disorders developed after the initiation of ICIT between 2 and 851 days (between 1 and 1332 days in patients with xerostomia and between 1 and 1455 days in patients with dysgeusia). Of all oral irAEs, 50.9% developed within 3 months, and 85.5% developed within 12 months.
Conclusions
Oral side effects appear to be more common among patients who receive ICIT than has been previously reported. Concomitant cytotoxic regimens may exacerbate the risk of oral adverse events, perhaps representing the sum of the effects of different, but simultaneous or sequential, pathogenic mechanisms. Additional studies are warranted to better characterize oral irAEs and their biologic basis.
The incidence rate of oral immune‐related adverse events in patients who receive immune‐checkpoint inhibitor therapy is 6.8%. In these patients, 50.9% of oral immune‐related adverse events develop in 3 months, and 85.5% develop in 12 months.
Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common ...clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non–portal hypertensive–related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration.
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