Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. METHODS: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. RESULTS: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. CONCLUSIONS: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Twice-Weekly Hemodialysis With Adjuvant Pharmacotherapy and Transition to Thrice-Weekly Hemodialysis: A Pilot Study.

RATIONALE & OBJECTIVE: Thrice-weekly hemodialysis (HD) is the most common treatment modality for kidney failure in the United States. We conducted a pilot study to assess the feasibility and safety of incremental-start HD in patients beginning maintenance HD. STUDY DESIGN: Pilot study. SETTING & PARTICIPANTS: Adults with estimated glomerular filtration rate (eGFR) ≥5 mL/min/1.73 m2 and urine volume ≥500 mL/d beginning maintenance HD at 14 outpatient dialysis units. EXPOSURE: Randomized allocation (1:1 ratio) to twice-weekly HD and adjuvant pharmacologic therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or thrice-weekly HD (conventional HD group). OUTCOME: The primary outcome was feasibility. Secondary outcomes included changes in urine volume and solute clearance. RESULTS: Of 77 patients invited to participate, 51 consented to do so, representing 66% of eligible patients. We randomized 23 patients to the incremental HD group and 25 patients to the conventional HD group. Protocol-based loop diuretics, sodium bicarbonate, and patiromer were prescribed to 100%, 39%, and 17% of patients on twice-weekly HD, respectively. At a mean follow-up of 281.9 days, participant adherence was 96% to the HD schedule (22 of 23 and 24 of 25 in the incremental and conventional groups, respectively) and 100% in both groups to serial timed urine collection. The incidence rate ratio for all-cause hospitalization was 0.31 (95% CI, 0.08-1.17); and 7 deaths were recorded (1 in the incremental and 6 in the conventional group). At week 24, the incremental HD group had lower declines in urine volume (a difference of 51.0 [95% CI, -0.7 to 102.8] percentage points) and in the averaged urea and creatinine clearances (a difference of 57.9 [95% CI, -22.6 to 138.4] percentage points). LIMITATIONS: Small sample size, time-limited twice-weekly HD. CONCLUSIONS: It is feasible to enroll patients beginning maintenance HD into a randomized study of incremental-start HD with adjuvant pharmacotherapy who adhere to the study protocol during follow-up. Larger multicenter clinical trials are indicated to determine the efficacy and safety of incremental HD with longer twice-weekly HD periods. FUNDING: Funding was provided by Vifor Inc. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, identifier NCT03740048.

Design details for overdose education and take-home naloxone kits: Codesign with family medicine, emergency department, addictions medicine and community.

INTRODUCTION: Overdose education and naloxone distribution (OEND) programmes equip and train people who are likely to witness an opioid overdose to respond with effective first aid interventions. Despite OEND expansion across North America, overdose rates are increasing, raising questions about how to improve OEND programmes. We conducted an iterative series of codesign stakeholder workshops to develop a prototype for take-home naloxone (THN)-kit (i.e., two doses of intranasal naloxone and training on how to administer it). METHODS: We recruited people who use opioids, frontline healthcare providers and public health representatives to participate in codesign workshops covering questions related to THN-kit prototypes, training on how to use it, and implementation, including refinement of design artefacts using personas and journey maps. Completed over 9 months, the workshops were audio-recorded and transcribed with visible results of the workshops (i.e., sticky notes, sketches) archived. We used thematic analyses of these materials to identify design requirements for THN-kits and training. RESULTS: We facilitated 13 codesign workshops to identify and address gaps in existing opioid overdose education training and THN-kits and emphasize timely response and stigma in future THN-kit design. Using an iterative process, we created 15 prototypes, 3 candidate prototypes and a final prototype THN-kit from the synthesis of the codesign workshops. CONCLUSION: The final prototype is available for a variety of implementation and evaluation processes. The THN-kit offers an integrated solution combining ultra-brief training animation and physical packaging of nasal naloxone to be distributed in family practice clinics, emergency departments, addiction medicine clinics and community settings. PATIENT OR PUBLIC CONTRIBUTION: The codesign process was deliberately structured to involve community members (the public), with multiple opportunities for public contribution. In addition, patient/public participation was a principle for the management and structuring of the research team.

Left atrial 4D flow cardiovascular magnetic resonance: a reproducibility study in sinus rhythm and atrial fibrillation.

BACKGROUND: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows sophisticated quantification of left atrial (LA) blood flow, and could yield novel biomarkers of propensity for intra-cardiac thrombus formation and embolic stroke. As reproducibility is critically important to diagnostic performance, we systematically investigated technical and temporal variation of LA 4D flow in atrial fibrillation (AF) and sinus rhythm (SR). METHODS: Eighty-six subjects (SR, n = 64; AF, n = 22) with wide-ranging stroke risk (CHA2DS2VASc 0-6) underwent LA 4D flow assessment of peak and mean velocity, vorticity, vortex volume, and stasis. Eighty-five (99%) underwent a second acquisition within the same session, and 74 (86%) also returned at 30 (27-35) days for an interval scan. We assessed variability attributable to manual contouring (intra- and inter-observer), and subject repositioning and reacquisition of data, both within the same session (same-day scan-rescan), and over time (interval scan). Within-subject coefficients of variation (CV) and bootstrapped 95% CIs were calculated and compared. RESULTS: Same-day scan-rescan CVs were 6% for peak velocity, 5% for mean velocity, 7% for vorticity, 9% for vortex volume, and 10% for stasis, and were similar between SR and AF subjects (all p > 0.05). Interval-scan variability was similar to same-day scan-rescan variability for peak velocity, vorticity, and vortex volume (all p > 0.05), and higher for stasis and mean velocity (interval scan CVs of 14% and 8%, respectively, both p < 0.05). Longitudinal changes in heart rate and blood pressure at the interval scan in the same subjects were associated with significantly higher variability for LA stasis (p = 0.024), but not for the remaining flow parameters (all p > 0.05). SR subjects showed significantly greater interval-scan variability than AF patients for mean velocity, vortex volume, and stasis (all p < 0.05), but not peak velocity or vorticity (both p > 0.05). CONCLUSIONS: LA peak velocity and vorticity are the most reproducible and temporally stable novel LA 4D flow biomarkers, and are robust to changes in heart rate, blood pressure, and differences in heart rhythm.

Temporal trends in fluid management with incremental hemodialysis
.

BACKGROUND: Incremental hemodialysis (HD) is seldom prescribed in the United States. This study describes longitudinal changes in volume management in patients with incident end-stage kidney disease (ESKD) initiated on bi-weekly (twice a week) HD, later converted to thrice-weekly HD. MATERIALS AND METHODS: 23 patients (mean age 65.6 years, 48% male, and 30% black) were included. Repeated measurement analysis of regression was used to test for differences in interdialytic weight gain (IDWG) and ultrafiltration rate (UFR) over three dialysis periods: the first 3 months of bi-weekly HD, the last 3 months of bi-weekly HD, and the first 3 months of thrice-weekly HD. RESULTS: The mean transition time to thrice-weekly HD was 332.9 days. Compared to the first 3 months of HD, the IDWG and UFR increased by 0.6 kg and 2.2 mL/kg/h in the last 3 months of bi-weekly HD (p = 0.02 and 0.009, respectively) and by 0.7 kg and 2.1 mL/kg/h in the first 3 months of thrice-weekly HD (p = 0.002). The average proportion of patients with IDWG > 5.7% of the dry weight was 0% in the first 3 months of bi-weekly HD, 12% in the last 3 months of bi-weekly HD, and 4% in the first 3 months of thrice-weekly HD; while the average proportion of patients with UFR > 10 mL/kg/h was 16%, 39%, and 25%, respectively. CONCLUSION: Fluid management in incident-ESKD patients receiving bi-weekly HD deteriorates prior to conversion to thrice-weekly HD. Further studies are needed to optimize the prescription of incremental HD.

Acute kidney injury is common with intravenous abuse of extended-release oral oxymorphone and delayed renal recovery rates are associated with increased KDIGO staging.

AIM: Prescription opioid abuse poses a serious problem in the United States, representing 615 per 100 000 deaths annually. Extended-release oxymorphone (Opana-ER) is an oral opioid pain medication that has recently been found to cause thrombotic microangiopathy when intravenously abused. In this retrospective study, we attempted to determine the prevalence and outcomes of acute kidney injury (AKI) among patients intravenously abusing extended-release oral oxymorphone. METHODS: A query of electronic medical records for 'drug abuse' at an academic medical centre during January 2012 to December 2015 was performed and yielded 2350 patients. Patients were further identified by documented intravenous abuse of extended-release oxymorphone. Patients were stratified based on multiple renal indices and outcomes. Potential confounders were also identified. RESULTS: One hundred and sixty-five patients were found to have a documented history of intravenous abuse of extended-release oral oxymorphone. Prevalence of AKI in this population was a 47.8%. KDIGO stage-I patients consisted of 17.8% of patients with AKI, 40.5% were classified as KDIGO stage-II AKI, and 41.8% were classified as KDIGO stage-III AKI. Among patients with AKI, average age was found to be 37.5 years, 59.4% experienced renal recovery, 56.9% required intensive care unit admission, 13.9% progressed to end-stage renal disease (ESRD), and 7.6% expired during admission. CONCLUSION: Clinicians should be educated to help recognize intravenous abuse of extended-release oral oxymorphone and its associated effects. Our data suggests AKI is common in these patients; higher KDIGO staging appears to be associated with slower rates of renal recovery, increased comorbidities and progression to both CKD and ESRD.

Early discharge and rehabilitation in paediatric acquired brain and neurological injury: a transferable model.

Children and young people who require rehabilitation following sustaining an acquired brain injury often experience long lengths of stay (LOS) and potentially poorer recovery outcomes due to limited access to therapy and little proactive discharge planning. After stakeholder enquiry we launched a new team and pathway with a primary aim to reduce LOS. The secondary aims were to pilot an outreach model, reduce cost and improve patient and family satisfaction. We achieved a significantly improved change in quality care with a financial gain and increased patient and family satisfaction.

Computed tomography myocardial perfusion vs 15O-water positron emission tomography and fractional flow reserve.

OBJECTIVES: Computed tomography (CT) can perform comprehensive cardiac imaging. We compared CT coronary angiography (CTCA) and CT myocardial perfusion (CTP) with 15O-water positron emission tomography (PET) and invasive coronary angiography (ICA) with fractional flow reserve (FFR). METHODS: 51 patients (63 (61-65) years, 80 % male) with known/suspected coronary artery disease (CAD) underwent 320-multidetector CTCA followed by "snapshot" adenosine stress CTP. Of these 22 underwent PET and 47 ICA/FFR. Obstructive CAD was defined as CTCA stenosis >50 % and CTP hypoperfusion, ICA stenosis >70 % or FFR <0.80. RESULTS: PET hyperaemic myocardial blood flow (MBF) was lower in obstructive than non-obstructive territories defined by ICA/FFR (1.76 (1.32-2.20) vs 3.11 (2.44-3.79) mL/(g/min), P < 0.001) and CTCA/CTP (1.76 (1.32-2.20) vs 3.12 (2.44-3.79) mL/(g/min), P < 0.001). Baseline and hyperaemic CT attenuation density was lower in obstructive than non-obstructive territories (73 (71-76) vs 86 (84-88) HU, P < 0.001 and 101 (96-106) vs 111 (107-114) HU, P 0.001). PET hyperaemic MBF corrected for rate pressure product correlated with CT attenuation density (r = 0.579, P < 0.001). There was excellent per-patient sensitivity (96 %), specificity (85 %), negative predictive value (90 %) and positive predictive value (94 %) for CTCA/CTP vs ICA/FFR. CONCLUSION: CT myocardial attenuation density correlates with 15O-water PET MBF. CTCA and CTP can accurately identify obstructive CAD. KEY POINTS: •CT myocardial perfusion can aid the assessment of suspected coronary artery disease. • CT attenuation density from "snapshot" imaging is a marker of myocardial perfusion. • CT myocardial attenuation density correlates with 15 O-water PET myocardial blood flow. • CT attenuation density is lower in obstructive territories defined by invasive angiography. • Diagnostic accuracy of CTCA+CTP is comparable to invasive angiography + fractional flow reserve.

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.

BACKGROUND: The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). METHODS: In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. FINDINGS: In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). INTERPRETATION: (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. FUNDING: Chief Scientist Office Scotland and British Heart Foundation.

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

RATIONALE: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial).

BACKGROUND: Most patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients. METHODS: An unblinded, parallel-group, randomized controlled trial will be conducted across diverse healthcare systems and dialysis organizations in the USA. Adult patients initiating chronic hemodialysis (HD) at participating centers will be screened. Eligibility criteria include receipt of fewer than 18 treatments of HD and residual kidney function defined as kidney urea clearance ≥3.5 mL/min/1.73 m2 and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients' all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients). DISCUSSION: Our proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers. TRIAL REGISTRATION: Clinicaltrials.gov NCT05828823. Registered on 25 April 2023.

Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.

BACKGROUND: The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. METHODS AND RESULTS: Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001). CONCLUSIONS: Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Perceptions regarding genetic testing in populations at risk for nephropathy.

BACKGROUND: Population ancestry-based differences exist in genetic risk for many kidney diseases. Substantial debate remains regarding returning genetic test results to participants. African-Americans (AAs) and European-Americans (EAs) at risk for end-stage kidney disease were queried for views on the value and use of genetic testing in research. METHODS: A standardized survey regarding attitudes toward genetic testing was administered to 130 individuals (64 AA, 66 EA) with first-degree relatives on dialysis. Fisher's exact test was used to assess differences in participant attitudes between population groups. RESULTS: Mean (SD) age of surveyed AAs and EAs was 45.5 (12.8) and 50.5 (14.4) years, respectively (p = 0.04), with similar familial relationships (p = 0.22). AAs and EAs wished to know their test results if risk could be: (1) reduced by diet or exercise (100 and 98%, p = 0.99); (2) reduced by medical treatment (100 and 98%, p = 0.99), or (3) if no treatments were available (90 and 82%, p = 0.21). If informed they lacked a disease susceptibility variant, 87% of AAs and 88% of EAs would be extremely or pretty likely to inform family members (p = 0.84). If informed they had a disease susceptibility variant, 92% of AAs and 89% of EAs would be extremely or pretty likely to inform their family (p = 0.43). CONCLUSIONS: Attitudes toward obtaining and using genetic test results for disease in research contexts were similar in AAs and EAs at risk for end-stage kidney disease. A substantial majority would want information regardless of available treatments and would share the information with the family. These results have important implications for patient care, study design and the informed consent process.

Ethnicity, medical insurance, and living kidney donation.

BACKGROUND: Relationships between race/ethnicity, recipient medical insurance, and living donor kidney transplantation (LKT) are incompletely described. METHODS: Associations between medical insurance and LKT were assessed in 447 recipients at a southeastern US transplant center. Primary and secondary payers were included in the analyses. RESULTS: A total of 387 deceased donor transplantations and 60 LKTs were performed in 246 (55%) European American (EA), 175 (39.2%) African American (AA), 15 (3.4%) Asian, and 11 (2.5%) Hispanic recipients. Among recipients, 182 (40.8%) were privately insured, 125 (28%) had Medicaid, and the remainder had Medicare, Medicare supplements, or Medicare replacement policies. A higher proportion of patients with private insurance, relative to those without private insurance, received LKT (22% vs. 7.6%, p < 0.0001). Among ethnic groups, LKT with, vs. without, private insurance was 27.5% vs. 12.4% in EAs (p = 0.0028) and 14.3% vs. 0.9% in AAs (p = 0.0005). Medicaid recipients (n = 125) were less likely to receive LKT than those without Medicaid (4.8% vs. 16.8%, p = 0.0003). Among the 69 AA recipients with Medicaid, none received LKT (0 Medicaid vs. 9.5% without Medicaid, p = 0.0065). CONCLUSIONS: Recipient insurance status is associated with LKT, positively with private insurance and negatively with Medicaid. AAs were impacted to a greater extent, potentially contributing to lower rates of LKT.

Acute changes in myocardial tissue characteristics during hospitalization in patients with COVID-19.

Background: Patients with a history of COVID-19 infection are reported to have cardiac abnormalities on cardiovascular magnetic resonance (CMR) during convalescence. However, it is unclear whether these abnormalities were present during the acute COVID-19 illness and how they may evolve over time. Methods: We prospectively recruited unvaccinated patients hospitalized with acute COVID-19 (n = 23), and compared them with matched outpatient controls without COVID-19 (n = 19) between May 2020 and May 2021. Only those without a past history of cardiac disease were recruited. We performed in-hospital CMR at a median of 3 days (IQR 1-7 days) after admission, and assessed cardiac function, edema and necrosis/fibrosis, using left and right ventricular ejection fraction (LVEF, RVEF), T1-mapping, T2 signal intensity ratio (T2SI), late gadolinium enhancement (LGE) and extracellular volume (ECV). Acute COVID-19 patients were invited for follow-up CMR and blood tests at 6 months. Results: The two cohorts were well matched in baseline clinical characteristics. Both had normal LVEF (62 ± 7 vs. 65 ± 6%), RVEF (60 ± 6 vs. 58 ± 6%), ECV (31 ± 3 vs. 31 ± 4%), and similar frequency of LGE abnormalities (16 vs. 14%; all p > 0.05). However, measures of acute myocardial edema (T1 and T2SI) were significantly higher in patients with acute COVID-19 when compared to controls (T1 = 1,217 ± 41 ms vs. 1,183 ± 22 ms; p = 0.002; T2SI = 1.48 ± 0.36 vs. 1.13 ± 0.09; p < 0.001). All COVID-19 patients who returned for follow up (n = 12) at 6 months had normal biventricular function, T1 and T2SI. Conclusion: Unvaccinated patients hospitalized for acute COVID-19 demonstrated CMR imaging evidence of acute myocardial edema, which normalized at 6 months, while biventricular function and scar burden were similar when compared to controls. Acute COVID-19 appears to induce acute myocardial edema in some patients, which resolves in convalescence, without significant impact on biventricular structure and function in the acute and short-term. Further studies with larger numbers are needed to confirm these findings.

The serotonin transporter sustains human brown adipose tissue thermogenesis.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

Coronary Atherosclerotic Plaque Activity and Future Coronary Events.

Importance: Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease activity have the potential to identify individuals at greatest risk. Objective: To assess whether coronary atherosclerotic plaque activity as assessed by noninvasive imaging is associated with recurrent coronary events in patients with myocardial infarction. Design, Setting, and Participants: This prospective, longitudinal, international multicenter cohort study recruited participants aged 50 years or older with multivessel coronary artery disease and recent (within 21 days) myocardial infarction between September 2015 and February 2020, with a minimum 2 years' follow-up. Intervention: Coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography. Main Outcomes and Measures: Total coronary atherosclerotic plaque activity was assessed by 18F-sodium fluoride uptake. The primary end point was cardiac death or nonfatal myocardial infarction but was expanded during study conduct to include unscheduled coronary revascularization due to lower than anticipated primary event rates. Results: Among 2684 patients screened, 995 were eligible, 712 attended for imaging, and 704 completed an interpretable scan and comprised the study population. The mean (SD) age of participants was 63.8 (8.2) years, and most were male (601 [85%]). Total coronary atherosclerotic plaque activity was identified in 421 participants (60%). After a median follow-up of 4 years (IQR, 3-5 years), 141 participants (20%) experienced the primary end point: 9 had cardiac death, 49 had nonfatal myocardial infarction, and 83 had unscheduled coronary revascularizations. Increased coronary plaque activity was not associated with the primary end point (hazard ratio [HR], 1.25; 95% CI, 0.89-1.76; P = .20) or unscheduled revascularization (HR, 0.98; 95% CI, 0.64-1.49; P = .91) but was associated with the secondary end point of cardiac death or nonfatal myocardial infarction (47 of 421 patients with high plaque activity [11.2%] vs 19 of 283 with low plaque activity [6.7%]; HR, 1.82; 95% CI, 1.07-3.10; P = .03) and all-cause mortality (30 of 421 patients with high plaque activity [7.1%] vs 9 of 283 with low plaque activity [3.2%]; HR, 2.43; 95% CI, 1.15-5.12; P = .02). After adjustment for differences in baseline clinical characteristics, coronary angiography findings, and Global Registry of Acute Coronary Events score, high coronary plaque activity was associated with cardiac death or nonfatal myocardial infarction (HR, 1.76; 95% CI, 1.00-3.10; P = .05) but not with all-cause mortality (HR, 2.01; 95% CI, 0.90-4.49; P = .09). Conclusions and Relevance: In this cohort study of patients with recent myocardial infarction, coronary atherosclerotic plaque activity was not associated with the primary composite end point. The findings suggest that risk of cardiovascular death or myocardial infarction in patients with elevated plaque activity warrants further research to explore its incremental prognostic implications.

Guidance on medical physics expert support for nuclear medicine.

The Ionising Radiation (Medical Exposure) Regulations require employers to appoint suitable medical physics experts (MPE) for nuclear medicine services, and they also define the areas where MPEs are required to provide advice and specify matters that they must contribute towards. Applications for employer licences under IR(ME)R require employers to specify the level of MPE support available and if this is provided by onsite MPEs or remotely. Assessment of these applications by the Administration of Radioactive Substances Advisory Committee (ARSAC) has highlighted variability in the levels of MPE support being provided for similar services across the UK. A working party including representatives from IPEM, ARSAC, BIR and BNMS was formed and has produced these recommendations on MPE support. Nuclear medicine services were divided into seven broad categories and MPE support for each category has been considered. However, some services that differ from the scenarios provided in this guidance may require different levels of MPE support. Positron emission tomography (PET)/CT and gamma camera imaging have been considered separately here, although it is recognised that both PET/CT and gamma cameras are often sited within the same department in many centres. The separation has been done for pragmatic purposes, as there are felt to be sufficient differences in the MPE role requirements. This guidance sets out recommendations for MPE support, and broader physics support, to run a safe nuclear medicine service and defines the responsibilities of these staff for a range of clinical nuclear medicine services. The recommendations on MPE support made are advice, but will assist employers in meeting regulatory requirements.

Quantifying sodium [18F]fluoride uptake in abdominal aortic aneurysms.

BACKGROUND: Aortic microcalcification activity is a recently described method of measuring aortic sodium [18F]fluoride uptake in the thoracic aorta on positron emission tomography. In this study, we aimed to compare and to modify this method for use within the infrarenal aorta of patients with abdominal aortic aneurysms. METHODS: Twenty-five patients with abdominal aortic aneurysms underwent an sodium [18F]fluoride positron emission tomography and computed tomography scan. Maximum and mean tissue-to-background ratios (TBR) and abdominal aortic microcalcification activity were determined following application of a thresholding and variable radius method to correct for vertebral sodium [18F]fluoride signal spill-over and the nonlinear changes in aortic diameter, respectively. Agreement between the methods, and repeatability of these approaches were assessed. RESULTS: The aortic microcalcification activity method was much quicker to perform than the TBR method (14 versus 40 min, p < 0.001). There was moderate-to-good agreement between TBR and aortic microcalcification activity measurements for maximum (interclass correlation co-efficient, 0.67) and mean (interclass correlation co-efficient, 0.88) values. These correlations sequentially improved with the application of thresholding (intraclass correlation coefficient 0.93, 95% confidence interval 0.89-0.95) and variable diameter (intraclass correlation coefficient 0.97, 95% confidence interval 0.94-0.99) techniques. The optimised method had good intra-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.36 and limits of agreement - 0.43 to 0.43) and inter-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.47 and limits of agreement - 0.53 to 0.53) repeatability. CONCLUSIONS: Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of sodium [18F]fluoride uptake that are comparable to established methods.

Renal replacement treatment initiation with twice-weekly versus thrice-weekly haemodialysis in patients with incident dialysis-dependent kidney disease: rationale and design of the TWOPLUS pilot clinical trial.

INTRODUCTION: The optimal haemodialysis (HD) prescription-frequency and dose-for patients with incident dialysis-dependent kidney disease (DDKD) and substantial residual kidney function (RKF)-that is, renal urea clearance ≥2 mL/min/1.73 m2 and urine volume ≥500 mL/day-is not known. The aim of the present study is to test the feasibility and safety of a simple, reliable prescription of incremental HD in patients with incident DDKD and RKF. METHODS AND ANALYSIS: This parallel-group, open-label randomised pilot trial will enrol 50 patients from 14 outpatient dialysis units. Participants will be randomised (1:1) to receive twice-weekly HD with adjuvant pharmacological therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or outright thrice-weekly HD (standard HD group). Age ≥18 years, chronic kidney disease progressing to DDKD and urine output ≥500 mL/day are key inclusion criteria; patients with left ventricular ejection fraction <30% and acute kidney injury requiring dialysis will be excluded. Adjuvant pharmacological therapy (ie, effective diuretic regimen, patiromer and sodium bicarbonate) will complement twice-weekly HD. The primary feasibility end points are recruitment rate, adherence to the assigned HD regimen, adherence to serial timed urine collections and treatment contamination. Incidence rate of clinically significant volume overload and metabolic imbalances in the first 3 months after randomisation will be used to assess intervention safety. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Institutional Review Board of Wake Forest School of Medicine in North Carolina, USA. Patient recruitment began on 14 June 2019, was paused between 13 March 2020 and 31 May 2020 due to COVID-19 pandemic, resumed on 01 June 2020 and will last until the required sample size has been attained. Participants will be followed in usual care fashion for a minimum of 6 months from last individual enrolled. All regulations and measures of ethics and confidentiality are handled in accordance with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT03740048; Pre-results.