Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension.

Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

The human bitter taste receptor TAS2R7 facilitates the detection of bitter salts.

The human sense of taste is devoted to the analysis of the chemical composition of food prior to ingestion. Among the five basic taste qualities bitter taste perception is believed to avoid ingestion of potentially toxic substances. The receptors facilitating the detection of hundreds of chemically different bitter compounds belong to the taste 2 receptor (TAS2R) family, which are part of the G protein-coupled superfamily. Although the chemical classes of bitter compounds that have been identified as agonists of one of the 25 potentially functional human bitter taste receptors cover an enormous chemical space, one distinct group of bitter compounds, the bitter salts have not been assigned to any bitter taste receptor. To close this gap, we screened the entire human bitter taste receptor repertoire by functional calcium mobilization assays with the most famous bitter salt, magnesium sulfate, also known as Epsom salt. Although the profound pharmacological activity and the bitter taste of spring water containing magnesium sulfate has been known since 1697, the molecular basis for its taste has not been elucidated until now. Our screening resulted in the identification of a single receptor, the TAS2R7, responding to magnesium sulfate at concentrations humans perceive this salt as bitter. Subsequently, TAS2R7 was stimulated with other salts and it was found that this receptor also responds to manganese2+ and iron2+ ions, but not to potassium ions. Magnesium sulfate is known to exert a number of beneficial effects on the human body and thus, has been used as medicine against premature uterine contractions, as anti-arrhythmic drug and as laxative, however, magnesium sulfate overdosage can result in cardiac arrest and thus have fatal consequences. Therefore, it appears reasonable that nature placed TAS2R7 as sentinel for high concentrations of bitter salts on our tongues.

Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart.

G-protein-coupled receptors (GPCRs) are key mediators in cardiovascular physiology, yet frontline therapies for heart disease target only a small fraction of the cardiac GPCR repertoire. Moreover, there is emerging evidence that GPCRs implicated in taste (Tas1r and Tas2rs) have specific functions beyond the oral cavity. Our recent description of these receptors in heart tissue foreshadows a potential novel role in cardiac cells. In this study, we identified novel agonist ligands for cardiac-Tas2rs to enable the functional investigation of these receptors in heart tissue. Five Tas2rs cloned from heart tissue were screened against a panel of 102 natural or synthetic bitter compounds in a heterologous expression system. We identified agonists for Tas2r108, Tas2r137, and Tas2r143 that were then tested in Langendorff-perfused mouse hearts (from 8-wk-old male C57BL/6 mice). All Tas2r agonists tested exhibited concentration-dependent effects, with agonists for Tas2r108 and Tas2r137, leading to a ∼40% decrease in left ventricular developed pressure and an increase in aortic pressure, respectively. These responses were abrogated in the presence of Gαi and Gßγ inhibitors (pertussis toxin and gallein). This study represents the first demonstration of profound Tas2r agonist-induced, G protein-dependent effects on mouse heart function.

Participant Experience with Protocol Research Kidney Biopsies in the Kidney Precision Medicine Project.

BACKGROUND: Kidney biopsies are procedures commonly performed in clinical nephrology and are increasingly used in research. In this study we aimed to evaluate the experiences of participants who underwent research kidney biopsies in the Kidney Precision Medicine Project (KPMP). METHODS: KPMP research participants with acute kidney injury (AKI) or chronic kidney disease (CKD) were enrolled at nine recruitment sites in the United States between September 2019 to January 2023. At 28 days post-biopsy, participants were invited to complete a survey to share their experiences, including: motivation to participate in research; comprehension of informed consent; pain and anxiety during and after the biopsy procedure; overall satisfaction with KPMP participation; and impact of the study on their lives. The survey was developed in collaboration with the KPMP Community Engagement Committee and the Institute of Translational Health Sciences at the University of Washington. RESULTS: 111 participants completed the survey, 23 enrolled for AKI and 88 for CKD. Median age was 61 (IQR 48-67) years, 43% were women, 28% were Black, and 18% were of Hispanic ethnicity. Survey respondents most commonly joined KPMP to help future patients (59%). The consent form was understood by 99% and 97% recognized their important role in the study. Pain during the biopsy was reported by 50%, at a median level of 1 (IQR 0-3) on a 0-10 scale. Anxiety during the biopsy was described by 64% at a median level of 3 (IQR 1-5) on a 0-10 scale. More than half conveyed that KPMP participation impacted their diet, physical activity, and how they think about kidney disease. CONCLUSIONS: KPMP survey respondents were most commonly motivated to participate in research protocol kidney biopsies by altruism, with excellent understanding of the informed consent process.

Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications.

BACKGROUND AND OBJECTIVES: Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman-Tukey double-arcsine transformations were used to stabilize variance as complications were rare. RESULTS: A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location. CONCLUSIONS: Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.

Blends of Non-caloric Sweeteners Saccharin and Cyclamate Show Reduced Off-Taste due to TAS2R Bitter Receptor Inhibition.

Non-caloric sweeteners are widely used for the formulation of calorie-reduced beverages for health-conscious consumers. However, disadvantages such as undesired off-tastes limit the use of non-nutritive sweeteners. Therefore, the food industry is constantly searching for novel sweeteners and frequently resorts to using blends combining non-caloric sweeteners in a single formulation. The earliest blend allowing higher sweetness levels with reduced bitter off-taste combined saccharin with cyclamate. However, the mechanism by which sweetener blends become superior to single compounds remained obscure. By functional expression of human bitter taste receptors, we found the explanation for the phenomenon observed ∼60 years ago. We demonstrate that cyclamate potently blocks the receptors responsible for saccharin's bitter off-taste. This effect occurs at concentrations where cyclamate itself does not elicit a side taste. Intriguingly, also saccharin inhibits cyclamate-activated bitter receptors. Our experiments demonstrate that heterologous assays are useful for understanding perceptual phenomena and the development of novel tastant formulations.

Risk Factors for Heat-Related Illness in Washington Crop Workers.

Crop workers are at high risk of heat-related illness (HRI) from internal heat generated by heavy physical work, particularly when laboring in hot and humid conditions. The aim of this study was to identify risk factors for HRI symptoms in Washington crop workers using an audio computer-assisted self-interview (A-CASI) instrument that has undergone reliability and validity evaluation. A cross-sectional A-CASI survey of 97 crop workers in Washington State was conducted during the summer of 2013. Potential HRI risk factors in demographic, training, work, hydration, clothing, health, and environmental domains were selected a priori for evaluation. Mixed-effects logistic regression was used to identify risk factors for self-reported symptoms associated with heat strain and HRI (dizziness/light-headedness or heavy sweating) experienced at work in hot conditions. An increase in age was associated with a lower odds of HRI symptoms (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.87-0.98). Piece rate compared with hourly payment (OR = 6.20; 95% CI = 1.11-34.54) and needing to walk for more than 3 minutes to get to the toilet, compared with less than 3 minutes (OR = 4.86; 95% CI = 1.18-20.06), were associated with a higher odds of HRI symptoms. In this descriptive study of risk factors for HRI symptoms in Washington crop workers, decreased age (and less work experience), piece rate pay, and longer distance to the toilet were associated with self-reported HRI symptoms. Modifiable workplace factors should be considered in HRI prevention efforts that are evaluated using objective measures in representative working populations.