Search

Chronic kidney disease is linked to impaired cognitive function and increased neurovascular disease risk even after correction for classical risk factors. The mechanism(s) underlying these links are unclear but may involve interactions of uraemic toxins with the blood-brain barrier (BBB). Here, we studied how the major uraemic toxinp-cresol sulfate (pCS) could affect BBB integrity. Exposure of human hCMEC/D3 endothelial cells to pCS dose-dependently increased paracellular permeability and disrupted intercellular tight junctions, a permeabilising effect mirrored in mice. Whole brain RNAseq analysis identified pCS-mediated suppression of neuronal activity, transcription and mitochondrial respiration pathways.In vitrostudies identified pCS binding to the epidermal growth factor receptor (EGFR), leadingviaannexin A1 and STAT3 signalling to mobilisation of matrix metalloproteinase (MMP)-2/9. Confirming this pathwayin vivo, the BBB damaging effects of pCS were prevented by pre-treatment with the EGFR antagonist erlotinib or the MMP2/9 inhibitor SB-3CT. Finally, hCMEC/D3 cells exposed to haemodialysis patient serum, but not to that of healthy donors, showed an erlotinib-sensitive increase in paracellular permeability that closely correlated in size to the total serum pCS content. Overall, we define a pathway linking the uraemic toxin pCS with BBB damage suggesting that targeting the EGFR may be useful in mitigating against cerebrovascular damage in chronic kidney disease.Translational StatementPatients with chronic kidney disease (CKD) have increased risk of cognitive impairment and stroke, pathologies associated cerebromicrovascular disease, but it is not clear why. Here, we show that the uraemic toxin p-cresol sulfate impairs BBB functionin vitroandin vivothrough EGFR-dependent MMP mobilisation. Importantly, serum from haemodialysis patients can also impair permeability of anin vitroBBB model, an effect prevented by EGFR inhibition, and proportional in magnitude to serum pCS content. Our data suggest that existing EGFR inhibitory drugs might have utility in preventing cerebral small vessel disease in CKD patients.

Teleconnections from the Madden–Julian Oscillation (MJO) are a key source of predictability of weather on the extended timescale of about 10–40 d. The MJO teleconnection is sensitive to a number of factors, including the mean dry static stability, the mean flow, and the propagation and intensity characteristics of the MJO, which are traditionally difficult to separate across models. Each of these factors may evolve in response to increasing greenhouse gas emissions, which will impact MJO teleconnections and potentially impact predictability on extended timescales. Current state-of-the-art climate models do not agree on how MJO teleconnections over central and eastern North America will change in a future climate. Here, we use results from the Coupled Model Intercomparison Project Phase 6 (CMIP6) historical and SSP585 experiments in concert with a linear baroclinic model (LBM) to separate and investigate alternate mechanisms explaining why and how boreal winter (January) MJO teleconnections over the North Pacific and North America may change in a future climate and to identify key sources of inter-model uncertainty. LBM simulations suggest that a weakening teleconnection due to increases in tropical dry static stability alone is robust across CMIP6 models and that uncertainty in mean state winds is a key driver of uncertainty in future MJO teleconnections. Uncertainty in future changes to the MJO's intensity, eastward propagation speed, zonal wavenumber, and eastward propagation extent are other important sources of uncertainty in future MJO teleconnections. We find no systematic relationship between future changes in the Rossby wave source and the MJO teleconnection or between changes to the zonal wind or stationary Rossby wave number and the MJO teleconnection over the North Pacific and North America. LBM simulations suggest a reduction of the boreal winter MJO teleconnection over the North Pacific and an uncertain change over North America, with large spread over both regions that lends to weak confidence in the overall outlook. While quantitatively determining the relative importance of MJO versus mean state uncertainties in determining future teleconnections remains a challenge, the LBM simulations suggest that uncertainty in the mean state winds is a larger contributor to the uncertainty in future projections of the MJO teleconnection than the MJO.

Primary care, urgent care, and emergency department providers periodically treat epistaxis, either as recurrent nosebleed or an acute persistent episode. Silver nitrate application to the decongested and anesthetized nasal mucosa addresses the former in most cases. The plethora of commercial nasal packing devices testifies to the discomfort, technical difficulty, and frustration associated with traditional gauze-packing methods. Inflatable anterior nasal balloon packs reliably control most nosebleeds. Addition of a Foley catheter nasopharyngeal balloon pack manages most posterior epistaxis. Cautery and the two packing techniques mentioned above should treat most cases not requiring otolaryngology consultation or interventional radiology. Appropriate anesthetic and analgesics lessen the unpleasantness for both the patient and the provider. Topical moisturizing facilitates mucosal healing. Oxymetazoline 0.05% nasal spray provides the patient means to address rebleeding after discharge from treatment.

Familiarity with common oral conditions allows clinicians to observe and treat patients in the primary care setting or refer to a dentist, oral surgeon, otolaryngologist, or other specialist. Recurrent aphthous stomatitis (canker sores) is the most common ulcerative condition of the oral cavity. Recurrent herpes simplex labialis and stomatitis also commonly cause oral ulcers. Corticosteroids, immunocompromise, antibiotics, and dentures can predispose patients to oral candidiasis. Benign migratory glossitis (geographic tongue) occurs in up to 3% of the population but generally lacks symptoms, although some people experience food sensitivity or a burning sensation. Hairy tongue is associated with a low fiber diet, tobacco and alcohol use, and poor oral hygiene in older male patients. Generally, hairy tongue is asymptomatic except for an unattractive appearance or halitosis. Tobacco and alcohol use can cause mucosal changes resulting in leukoplakia and erythroplakia. These can represent precancerous changes and increase the risk of squamous cell carcinoma. Mandibular and maxillary tori are common bony cortical outgrowths that require no treatment in the absence of repeat trauma from chewing or interference with dentures. Oral lichen planus occurs in up to 2% of individuals and can present as lacy reticulations or oral erosions and ulcerations. Traumatic buccal mucosal fibromas and labial mucoceles from biting can be excised.

This paper reviews current indications for otolaryngology consultation for tonsillectomy and adenoidectomy (TA). Despite often being performed concurrently, these procedures should be considered separate surgeries done for different indications. The American Academy of Otolaryngology - Head and Neck Surgery published tonsillectomy guidelines for children in 2019. These recommendations are often extrapolated to adults in clinical practice despite less robust literature support for this age group. TA should be recommended for pediatric obstructive sleep apnea. Specific frequencies of tonsillitis have been identified that indicate benefit from tonsillectomy in normal children; certain modifying health factors warrant consideration of surgery with fewer infections. The guidelines include consideration of tonsillectomy for poorly validated indications such as halitosis, febrile seizure, dental malocclusion, dysphagia, dysphonia, and psoriasis.

It seems strange to suggest that moving to a neutral position on assisted suicide and euthanasia reflects active engagement with the matter.1 Quite the opposite would seem to be the case. Historically, the medical …

The intertropical convergence zone (ITCZ) exports energy and imports moisture in a way that has been well-understood for decades. By analyzing a set of uniform, non-rotating aquaplanet simulations ...

USDOE Office of Science (SC), Biological and Environmental Research (BER) U.S. Department of Energy, DOE/SC-ARM-18-005

The response of the Madden-Julian oscillation (MJO) to ocean feedbacks is studied with coupled and uncoupled simulations of four general circulation models (GCMs). Monthly mean SST from each coupled model is prescribed to its respective uncoupled simulation, to ensure identical SST mean state and low-frequency variability between simulation pairs. Consistent with previous studies, coupling improves each model's ability to propagation MJO convection beyond the Maritime Continent. Analysis of the MJO moist static energy budget reveals that improved MJO eastward propagation in all four coupled models arises from enhanced meridional advection of column water vapor (CWV). Despite the identical mean state SST in each coupled and uncoupled simulation pair, coupling increases mean-state CWV near the Equator, sharpening equatorial moisture gradients and enhancing meridional moisture advection and MJO propagation. CWV composites during MJO and non-MJO periods demonstrate that the MJO itself does not cause enhanced moisture gradients. Instead, analysis of low-level subgrid-scale moistening conditioned by rainfall rate (R) and SST anomaly reveals that coupling enhances low-level convective moistening for R > 5 mm/day; this enhancement is most prominent near the Equator. The low-level moistening process varies among the four models, which we interpret in terms of their ocean model configurations, cumulus parameterizations, and the sensitivity of convection to column relative humidity.

We have investigated the predictability of precipitation using a new configuration of the superparameterized Community Atmosphere Model, SP-CAM. The new configuration, called the multiple-instance superparameterized-CAM, or MP-CAM, uses the average heating and drying rates from 10 independent two-dimensional cloud-permitting models (CPMs) in each grid column of the global model, instead of a single CPM. The 10 CPMs start from slightly different initial conditions, and simulate alternative realizations of the convective cloud systems. By analyzing the ensemble of possible realizations, we can study the predictability of the cloud systems, and identify the weather regimes and physical mechanisms associated with chaotic convection. We explore alternative methods for quantifying the predictability of precipitation. Our results show that unpredictable precipitation occurs when the simulated atmospheric state is close to critical points as defined by Peters and Neelin (2006, https://doi.org/10.1038/nphys314). The predictability of precipitation is also influenced by the convective available potential energy (CAPE) and the degree of mesoscale organization. It is strongly controlled by the large-scale circulation. A companion paper compares the global atmospheric circulations simulated by SP-CAM and MP-CAM.

Tropical South America plays a central role in global climate. Bowen ratio teleconnects to circulation and precipitation processes far afield, and the global CO2 growth rate is strongly influenced by carbon cycle processes in South America. However, quantification of basin‐wide seasonality of flux partitioning between latent and sensible heat, the response to anomalies around climatic norms, and understanding of the processes and mechanisms that control the carbon cycle remains elusive. Here, we investigate simulated surface‐atmosphere interaction at a single site in Brazil, using models with different representations of precipitation and cloud processes, as well as differences in scale of coupling between the surface and atmosphere. We find that the model with parameterized clouds/precipitation has a tendency toward unrealistic perpetual light precipitation, while models with explicit treatment of clouds produce more intense and less frequent rain. Models that couple the surface to the atmosphere on the scale of kilometers, as opposed to tens or hundreds of kilometers, produce even more realistic distributions of rainfall. Rainfall intensity has direct consequences for the “fate of water,” or the pathway that a hydrometeor follows once it interacts with the surface. We find that the model with explicit treatment of cloud processes, coupled to the surface at small scales, is the most realistic when compared to observations. These results have implications for simulations of global climate, as the use of models with explicit (as opposed to parameterized) cloud representations becomes more widespread., Key Points Ecophysiological function during seasonal drought is dependent upon storage and availability of rainfall that falls during the wet seasonThe scale of coupling between land and atmosphere strongly influences this “fate of water” in simulationsSimulations tend toward “water limitation” or “light limitation” depending on this scale of coupling

A 3‐D cloud‐resolving model has been used to investigate the domain size dependence of simulations of convective self‐aggregation (CSA) in radiative‐convective equilibrium. We investigate how large a domain is needed to allow multiple convective clusters and also how the properties equilibrated CSA depend on domain size. We used doubly periodic square domains of widths 768, 1,536, 3,072, and 6,144 km, over 350 simulated days. In the 768‐, 1,536‐, and 3,072‐km domains, the simulations produced circular convective clusters surrounded by broader regions of dry, subsiding air. In the 6,144‐km domain, the convection ultimately forms two semiconnected bands. As the domain size increases, equilibrated CSA moistens in two ways. First, as the circulation widens, this leads to stronger boundary layer winds and a more humid boundary layer. Second, the stronger inflow into the convective region boundary layer is associated with a warmer convective region boundary layer, which leads to intensified deep convection, more melting and freezing near the freezing level, enhanced midlevel stability, increased congestus activity, and detrainment of moist air into the dry region. In the larger domains, the deep convection and congestus slowly oscillate out of phase with each other with a time period of about 25 to 30 days. We hypothesize that other important domain size sensitivities, including a decrease in net moist static energy export from the convective region, are fundamentally linked to the increasing relationship between domain size and boundary layer wind speed. Our results suggest that the statistics of CSA converge only for domains wider than about 3,000 km.