Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins͞epithelial sodium channel (DEG͞ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50°C), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate-to high-intensity pain sensation. C ation channels of the degenerin͞epithelial sodium channel family (DEG͞ENaC) have been proposed as transducers of somatosensory stimuli in several species (1). The structural hallmarks of these proteins are two hydrophobic transmembrane domains, with short N and C termini and a large extracellular loop. In vertebrates, the DEG͞ENaC family includes several related subunits of Na ϩ -selective (P NA ͞P K , 8-40) acid-sensing ion channels (ASIC1a, ASIC1b, ASIC2a, ASC2b, ASIC3, and ASIC4; previously named ASIC-␣͞BNC2, ASIC-␤, MDEG1͞ BNC1, MDEG2, DRASIC, and SPASIC, respectively) (2-4). ASIC proteins associate as homo-or heteromultimers to form functional receptors. Because these receptors are gated by protons, it has been suggested that they might be involved in the perception of pain during tissue acidosis (5). However, there is evidence also that they are involved in mechanosensation; many DEG͞ENaC proteins are localized to mechanosensitive cells in Caenorhabditis elegans, Drosophila melanogaster, rat, and mouse (1, 6, 7). In C. elegans, mutations in DEG͞ENaC proteins such as MEC-4 and MEC-10 lead to impaired touch responses (8,9), and the targeted deletion of ASIC2 in mice resulted in a reduced sensitivity of low-threshold mechanoreceptors (7).One member of the ASIC family, ASIC3, seems to be a particularly good candidate for the transduction of proton and mechanical stimuli, because ASIC3 is expressed predominantly in dorsal root ganglia neurons (10) including large-diameter mechanoreceptors and unmyelinated small-diameter peptidergic nociceptors (3, 6, 11). In addition, ASIC3 protein was found to be present in sensory nerve terminals in Meissner corpuscles lanceolate fibers, which correspond to rapidly adapting lowthreshold mechanoreceptors, as well as in free nerve endings, which may correspond to nociceptors (6).Previous studies have shown that ASIC3 can be activated by protons and generate biphasic inward currents when it was expressed in heterologous cells (12). A transient inward current can be induced when extracellular pH falls to 7.0, which is...

BackgroundThe prevalence of type 2 diabetes is rising, and most of these patients also have hypertension, substantially increasing the risk of cardiovascular morbidity and mortality. The majority of these patients do not reach target blood pressure levels for a wide variety of reasons. When a literature review provided no clear focus for action when patients are not at target, we initiated a study to identify characteristics of patients and providers associated with achieving target BP levels in community-based practice.MethodsWe conducted a practice- based, cross-sectional observational and mailed survey study. The setting was the practices of 27 family physicians and nurse practitioners in 3 eastern provinces in Canada. The participants were all patients with type 2 diabetes who could understand English, were able to give consent, and would be available for follow-up for more than one year. Data were collected from each patient's medical record and from each patient and physician/nurse practitioner by mailed survey. Our main outcome measures were overall blood pressure at target (< 130/80), systolic blood pressure at target, and diastolic blood pressure at target. Analysis included initial descriptive statistics, logistic regression models, and multivariate regression using hierarchical nonlinear modeling (HNLM).ResultsFifty-four percent were at target for both systolic and diastolic pressures. Sixty-two percent were at systolic target, and 79% were at diastolic target. Patients who reported eating food low in salt had higher odds of reaching target blood pressure. Similarly, patients reporting low adherence to their medication regimen had lower odds of reaching target blood pressure.ConclusionsWhen primary care health professionals are dealing with blood pressures above target in a patient with type 2 diabetes, they should pay particular attention to two factors. They should inquire about dietary salt intake, strongly emphasize the importance of reduction, and refer for detailed counseling if necessary. Similarly, they should inquire about adherence to the medication regimen, and employ a variety of patient-oriented strategies to improve adherence.

Aim: This study assessed the work productivity and financial impact of advanced gastroesophageal adenocarcinomas, comprising gastric, esophageal and gastroesophageal junction cancers, on patients of working age and their caregivers. Patients & methods: A multicenter medical chart review and surveys of patients with advanced gastroesophageal adenocarcinoma and their caregivers was conducted in France, Germany, the UK, China, Japan and the USA. Results: Across differing regions, the study highlighted the impact of cancer on patients’ ability to work, to function normally and on their wellbeing, as well as the economic burden placed on patients and their caregivers. Conclusion: Advanced gastroesophageal adenocarcinomas have a significant impact on patients’ and caregivers’ well-being and are associated with reduced work productivity, and income loss.

Aim: Assessing treatment patterns, outcomes and clinical characteristics in advanced renal cell carcinoma clinical practice. Materials & methods: A US cross-sectional physician survey conducted February–September 2019. Results: Surveyed physicians reported first-line treatment of 445 patients involving tyrosine kinase inhibitor monotherapy (51.0%), immuno-oncology (IO/IO combination) therapy (25.8%) or other regimens (23.1%). A total of 60.9% had physician-assessed IMDC risk. Of these 61.9, 50.9 and 27.6% of patients with favorable, intermediate and poor risk, respectively, received tyrosine kinase inhibitor monotherapy. A total of 16.7, 26.9 and 34.5% of patients with favorable, intermediate or poor risk received IO/IO combination therapy. Complete/partial responses (∼35% patients) remained comparable across first-line treatments. Conclusion: Guideline-recommended therapies are not widely prescribed. Many patients experienced poor clinical outcomes highlighting a need for more effective treatments.

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platinum choice, chemotherapy cycles and PCI or thoracic radiotherapy use. PD-L1 (atezolizumab or durvalumab) plus chemotherapy showed an improvement in median rwPFS. Further analysis in overall survival is still needed to explore the benefit and characteristic factors that may influence the PD-L1 use in Chinese ES-SCLC patients.Legal entity responsible for the study: The authors.

Aim: To assess symptoms, healthcare resource utilization and health-related quality of life in advanced renal cell carcinoma (aRCC) clinical practice. Materials & methods: The USA point-in-time survey of physicians and patients was conducted between February and September 2019. Results: Data were available for 227 patients. Mean (standard deviation) number of symptoms was 3.4 (3.2); differences were observed across International Metastatic RCC Database Consortium risk categories (p < 0.001), with fewer symptoms in favorable-risk patients. Disease burden, measured by greater healthcare resource utilization and worse health-related quality of life, was high, particularly in International Metastatic RCC Database Consortium intermediate- or poor- versus favorable-risk patients. In total, 45 patients (21.6%) were hospitalized due to aRCC within a 6-month period, 35 (16.8%) had one hospitalization and ten (4.8%) experienced ≥2 hospitalizations due to aRCC. Mean (standard deviation) 19-Item Functional Assessment of Cancer Therapy Kidney Symptom Index score was 53.6 (13.2) for this population, significantly lower than the reference value (59.8; p < 0.001). Conclusion: A clear need exists for improved disease management in patients with aRCC.

analyzed. Completion rates across EORTC-QLQ-C30 items were high (92.2%-94.6% overall rate of non-missing values). Large variation across countries have been observed in mean scores on functional scores as well as symptom scales. Eastern vs Western Europe contrasted sharply, with Serbia and Poland reporting lower functional and much higher symptom scores for fatigue, nausea and vomiting, pain and insomnia. Mean mapped utility scores and standard deviations (SD) were 0.72 (0.17) for Eastern Europe, with 0.72 (0.20), 0.81 (0.13), 0.73 (0.16) and 0.66 (0.17) for CY/H/ P/RS respectively and 0.77 (SD=0.17) for Western Europe countries with 0.76 (0.17), 0.83 (0.12), 0.78 (0.17) and 0.78 (0.19) for BE/ES/NL/UK respectively. Conclusions: mCRC has important detrimental effect on HRQoL, and even more so among real-world mCRC patients than those participating in clinical trials. Variations across countries and compared to trials require further analysis.