Background In the context of clinical research, investigators have historically selected the outcomes that they consider to be important, but these are often discordant with patients’ priorities. ...Efforts to define and report patient-centered outcomes are gaining momentum, though little work has been done in nephrology. We aimed to identify patient and caregiver priorities for outcomes in hemodialysis. Study Design Nominal group technique. Setting & Participants Patients on hemodialysis therapy and their caregivers were purposively sampled from 4 dialysis units in Australia (Sydney and Melbourne) and 7 dialysis units in Canada (Calgary). Methodology Identification and ranking of outcomes. Analytical Approach Mean rank score (of 10) for top 10 outcomes and thematic analysis. Results 82 participants (58 patients, 24 caregivers) aged 24 to 87 (mean, 58.4) years in 12 nominal groups identified 68 outcomes. The 10 top-ranked outcomes were fatigue/energy (mean rank score, 4.5), survival (defined by patients as resilience and coping; 3.7), ability to travel (3.6), dialysis-free time (3.3), impact on family (3.2), ability to work (2.5), sleep (2.3), anxiety/stress (2.1), decrease in blood pressure (2.0), and lack of appetite/taste (1.9). Mortality ranked only 14th and was not regarded as the complement of survival. Caregivers ranked mortality, anxiety, and depression higher than patients, whereas patients ranked ability to work higher. Four themes underpinned their rankings: living well, ability to control outcomes, tangible and experiential relevance, and severity and intrusiveness. Limitations Only English-speaking participants were eligible. Conclusions Although trials in hemodialysis have typically focused on outcomes such as death, adverse events, and biological markers, patients tend to prioritize outcomes that are more relevant to their daily living and well-being. Researchers need to consider interventions that are likely to improve these outcomes and measure and report patient-relevant outcomes in trials, and clinicians may become more patient-orientated by using these outcomes in their clinical encounters.
Background Survival and quality of life for patients on hemodialysis therapy remain poor despite substantial research efforts. Existing trials often report surrogate outcomes that may not be relevant ...to patients and clinicians. The aim of this project was to generate a consensus-based prioritized list of core outcomes for trials in hemodialysis. Study Design In a Delphi survey, participants rated the importance of outcomes using a 9-point Likert scale in round 1 and then re-rated outcomes in rounds 2 and 3 after reviewing other respondents’ scores. For each outcome, the median, mean, and proportion rating as 7 to 9 (critically important) were calculated. Setting & Participants 1,181 participants (202 17% patients/caregivers, 979 health professionals) from 73 countries completed round 1, with 838 (71%) completing round 3. Outcomes & Measurements Outcomes included in the potential core outcome set met the following criteria for both patients/caregivers and health professionals: median score ≥ 8, mean score ≥ 7.5, proportion rating the outcome as critically important ≥ 75%, and median score in the forced ranking question < 10. Results Patients/caregivers rated 4 outcomes higher than health professionals: ability to travel, dialysis-free time, dialysis adequacy, and washed out after dialysis (mean differences of 0.9, 0.5, 0.3, and 0.2, respectively). Health professionals gave a higher rating for mortality, hospitalization, decrease in blood pressure, vascular access complications, depression, cardiovascular disease, target weight, infection, and potassium (mean differences of 1.0, 1.0, 1.0, 0.9, 0.9, 0.8, 0.7, 0.4, and 0.4, respectively). Limitations The Delphi survey was conducted online in English and excludes participants without access to a computer and internet connection. Conclusions Patients/caregivers gave higher priority to lifestyle-related outcomes than health professionals. The prioritized outcomes for both groups were vascular access problems, dialysis adequacy, fatigue, cardiovascular disease, and mortality. This process will inform a core outcome set that in turn will improve the relevance, efficiency, and comparability of trial evidence to facilitate treatment decisions.
Breathlessness that persists despite treatment for the underlying conditions is debilitating. Identifying this discrete entity as a clinical syndrome should raise awareness amongst patients, ...clinicians, service providers, researchers and research funders.Using the Delphi method, questions and statements were generated
expert group consultations and one-to-one interviews (n=17). These were subsequently circulated in three survey rounds (n=34, n=25, n=31) to an extended international group from various settings (clinical and laboratory; hospital, hospice and community) and working within the basic sciences and clinical specialties. The
target agreement for each question was 70%. Findings were discussed at a multinational workshop.The agreed term, chronic breathlessness syndrome, was defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology and that results in disability. A stated duration was not needed for "chronic". Key terms for French and German translation were also discussed and the need for further consensus recognised, especially with regard to cultural and linguistic interpretation.We propose criteria for chronic breathlessness syndrome. Recognition is an important first step to address the therapeutic nihilism that has pervaded this neglected symptom and could empower patients and caregivers, improve clinical care, focus research, and encourage wider uptake of available and emerging evidence-based interventions.
The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.
We randomly assigned 9361 persons with a ...systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval CI, 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.
Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.).
Much of the present-day volume of Earth's continental crust had formed by the end of the Archean Eon, 2.5 billion years ago, through the conversion of basaltic (mafic) crust into sodic granite of ...tonalite, trondhjemite and granodiorite (TTG) composition. Distinctive chemical signatures in a small proportion of these rocks, the so-called high-pressure TTG, are interpreted to indicate partial melting of hydrated crust at pressures above 1.5 GPa (>50 km depth), pressures typically not reached in post-Archean continental crust. These interpretations significantly influence views on early crustal evolution and the onset of plate tectonics. Here we show that high-pressure TTG did not form through melting of crust, but through fractionation of melts derived from metasomatically enriched lithospheric mantle. Although the remaining, and dominant, group of Archean TTG did form through melting of hydrated mafic crust, there is no evidence that this occurred at depths significantly greater than the ~40 km average thickness of modern continental crust.
Background:
High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes, including coronary heart disease, stroke, ...decompensated heart failure, chronic kidney disease, and decline in cognitive function. Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg. Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease. However, the optimal systolic blood pressure to reduce blood pressure–related adverse outcomes is unclear, and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large, definitive clinical trial.
Purpose:
To describe the design considerations of the Systolic Blood Pressure Intervention Trial (SPRINT) and the baseline characteristics of trial participants.
Methods:
The Systolic Blood Pressure Intervention Trial is a multicenter, randomized, controlled trial that compares two strategies for treating systolic blood pressure: one targets the standard target of <140 mm Hg, and the other targets a more intensive target of <120 mm Hg. Enrollment focused on volunteers of age ≥50 years (no upper limit) with an average baseline systolic blood pressure ≥130 mm Hg and evidence of cardiovascular disease, chronic kidney disease, 10-year Framingham cardiovascular disease risk score ≥15%, or age ≥75 years. The Systolic Blood Pressure Intervention Trial recruitment also targeted three pre-specified subgroups: participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2), participants with a history of cardiovascular disease, and participants 75 years of age or older. The primary outcome is first the occurrence of a myocardial infarction (MI), acute coronary syndrome, stroke, heart failure, or cardiovascular disease death. Secondary outcomes include all-cause mortality, decline in kidney function or development of end-stage renal disease, incident dementia, decline in cognitive function, and small-vessel cerebral ischemic disease.
Results:
Between 8 November 2010 and 15 March 2013, Systolic Blood Pressure Intervention Trial recruited and randomized 9361 people at 102 clinics, including 3331 women, 2648 with chronic kidney disease, 1877 with a history of cardiovascular disease, 3962 minorities, and 2636 ≥75 years of age.
Limitations:
Although the overall recruitment target was met, the numbers recruited in the high-risk subgroups were lower than planned.
Conclusions:
The Systolic Blood Pressure Intervention Trial will provide important information on the risks and benefits of intensive blood pressure treatment targets in a diverse sample of high-risk participants, including those with prior cardiovascular disease, chronic kidney disease, and those aged ≥75 years.
Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy ...and limitations in detecting individual CaP foci to optimize management.
To determine the per-lesion detection rate for CaP foci by mpMRI and identify predictors of tumor detection.
We carried out a retrospective analysis of a prospectively managed database correlating lesion-specific results from mpMRI co-registered with whole-mount pathology (WMP) prostatectomy specimens from June 2010 to February 2018. Participants include 588 consecutive patients with biopsy-proven CaP undergoing 3-T mpMRI before radical prostatectomy at a single tertiary institution.
We measured mpMRI sensitivity in detecting individual CaP and clinically significant (any Gleason score ≥7) CaP foci and predictors of tumor detection using multivariate analysis.
The final analysis included 1213 pathologically confirmed tumor foci in 588 patients with primarily intermediate- (75%) or high-risk (12%) CaP. mpMRI detected 45% of all lesions (95% confidence interval CI 42–47%), including 65% of clinically significant lesions (95% CI 61–69%) and nearly 80% of high-grade tumors. Some 74% and 31% of missed solitary and multifocal tumors, respectively, were clinically significant. The majority of missed lesions were small (61.1% ≤1cm); 28.3% were between 1 and 2cm, and 10.4% were >2cm. mpMRI missed at least one clinically significant focus in 34% of patients overall, and in 45% of men with multifocal lesions. On multivariate analysis, smaller, low-grade, multifocal, nonindex tumors with lower prostate-specific antigen density were more likely to be missed. Limitations include selection bias in a prostatectomy cohort, lack of specificity data, an imperfect co-registration process, and uncertain clinical significance for undetected lesions.
mpMRI detects less than half of all and less than two-thirds of clinically significant CaP foci. The moderate per-lesion sensitivity and significant proportion of men with undetected tumor foci demonstrate the current limitations of mpMRI.
Magnetic resonance imaging of the prostate before surgical removal for prostate cancer finds less than half of all individual prostate cancer tumors. Large, solitary, aggressive tumors are more likely to be visualized on imaging.
In this retrospective review of robotic radical prostatectomy specimens for prostate cancer processed using whole-mount pathology, 3-T multiparametric magnetic resonance imaging detected 45% of all individual prostate cancers and 65% of clinically significant tumors. Smaller, low-risk, nonindex, and multifocal tumors were more likely to be missed.
There is a significant drive to identify alternative materials that exhibit room temperature phosphorescence for technologies including bio-imaging, photodynamic therapy and organic light-emitting ...diodes. Ideally, these materials should be non-toxic and cheap, and it will be possible to control their photoluminescent properties. This was achieved here by embedding carbon nanodots within crystalline particles of alkaline earth carbonates, sulphates and oxalates. The resultant nanocomposites are luminescent and exhibit a bright, sub-second lifetime afterglow. Importantly, the excited state lifetimes, and steady-state and afterglow colours can all be systematically controlled by varying the cations and anions in the host inorganic phase, due to the influence of the cation size and material density on emissive and non-emissive electronic transitions. This simple strategy provides a flexible route for generating materials with specific, phosphorescent properties and is an exciting alternative to approaches relying on the synthesis of custom-made luminescent organic molecules.
In clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early ...initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease.
We randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m2 of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause.
Between July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval CI, 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis).
In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Funded by the National Health and Medical Research Council of Australia and others; Australian New Zealand Clinical Trials Registry number, 12609000266268.)
Human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal ...lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.
•An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.•The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.
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