Summary Background Results of previous studies support the hypothesis that implantable haemodynamic monitoring systems might reduce rates of hospitalisation in patients with heart failure. We ...undertook a single-blind trial to assess this approach. Methods Patients with New York Heart Association (NYHA) class III heart failure, irrespective of the left ventricular ejection fraction, and a previous hospital admission for heart failure were enrolled in 64 centres in the USA. They were randomly assigned by use of a centralised electronic system to management with a wireless implantable haemodynamic monitoring (W-IHM) system (treatment group) or to a control group for at least 6 months. Only patients were masked to their assignment group. In the treatment group, clinicians used daily measurement of pulmonary artery pressures in addition to standard of care versus standard of care alone in the control group. The primary efficacy endpoint was the rate of heart-failure-related hospitalisations at 6 months. The safety endpoints assessed at 6 months were freedom from device-related or system-related complications (DSRC) and freedom from pressure-sensor failures. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00531661. Findings In 6 months, 84 heart-failure-related hospitalisations were reported in the treatment group (n=270) compared with 120 in the control group (n=280; rate 0·32 vs 0·44, hazard ratio HR 0·72, 95% CI 0·60–0·85, p=0·0002). During the entire follow-up (mean 15 months SD 7), the treatment group had a 37% reduction in heart-failure-related hospitalisation compared with the control group (158 vs 254, HR 0·63, 95% CI 0·52–0·77; p<0·0001). Eight patients had DSRC and overall freedom from DSRC was 98·6% (97·3–99·4) compared with a prespecified performance criterion of 80% (p<0·0001); and overall freedom from pressure-sensor failures was 100% (99·3–100·0). Interpretation Our results are consistent with, and extend, previous findings by definitively showing a significant and large reduction in hospitalisation for patients with NYHA class III heart failure who were managed with a wireless implantable haemodynamic monitoring system. The addition of information about pulmonary artery pressure to clinical signs and symptoms allows for improved heart failure management. Funding CardioMEMS.
Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors ...directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.
Seeking More Time with Synchrony Stevenson, Lynne Warner; Montgomery, Jay A
The New England journal of medicine,
2024-Jan-18, Volume:
390, Issue:
3
Journal Article
Twelve pumpkin cultivars (Cucurbita maxima D.), cultivated in Iowa, were studied for their seed oil content, fatty acid composition, and tocopherol content. Oil content ranged from 10.9 to 30.9%. ...Total unsaturated fatty acid content ranged from 73.1 to 80.5%. The predominant fatty acids present were linoleic, oleic, palmitic, and stearic. Significant differences were observed among the cultivars for stearic, oleic, linoleic, and gadoleic acid content of oil. Low linolenic acid levels were observed (<1%). The tocopherol content of the oils ranged from 27.1 to 75.1 micrograms/g of oil for α-tocopherol, from 74.9 to 492.8 micrograms/g for gamma-tocopherol, and from 35.3 to 1109.7 micrograms/g for delta-tocopherol. The study showed potential for pumpkin seed oil from all 12 cultivars to have high oxidative stability that would be suitable for food and industrial applications, as well as high unsaturation and tocopherol content that could potentially improve the nutrition of human diets.
Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the ...knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.
Abstract Background Decompensated heart failure (HF) is associated with unacceptable morbidity and mortality risks. Recent implantable technology advancements allow frequent filling pressure ...monitoring and provide insight into HF pathophysiology and a new tool for HF management. Methods The CHAMPION trial is a prospective, multicenter, randomized, single-blind clinical trial testing the hypothesis that HF management guided by frequently assessed pulmonary artery pressures is superior to traditional methods. A total of 550 subjects with New York Heart Association (NYHA) functional class III HF were enrolled at 64 sites in the United States. All subjects received the CardioMEMS HF sensor as a permanent pulmonary artery implant and were randomized to the treatment or the control group before discharge. The treatment group received traditional HF management guided by hemodynamic information from the sensor. The control group received traditional HF disease management. Safety endpoints include freedom from device/system-related complications and freedom from HF sensor failure at 6 months. The efficacy endpoint is a reduction in the rate of HF-related hospitalizations in the treatment group versus the control group at 6 months. Conclusions The CHAMPION trial will investigate the safety and clinical efficacy of the CardioMEMS hemodynamic monitoring system and may establish this management strategy as a new paradigm for the medical management of patients with symptomatic HF.
Abstract
In the negative feedback loop driving the Neurospora circadian oscillator, the negative element, FREQUENCY (FRQ), inhibits its own expression by promoting phosphorylation of its ...heterodimeric transcriptional activators, White Collar-1 (WC-1) and WC-2. FRQ itself also undergoes extensive time-of-day-specific phosphorylation with over 100 phosphosites previously documented. Although disrupting individual or certain clusters of phosphorylation sites has been shown to alter circadian period lengths to some extent, it is still elusive how all the phosphorylations on FRQ control its activity. In this study, we systematically investigated the role in period determination of all 110 reported FRQ phosphorylation sites, using mutagenesis and luciferase reporter assays. Surprisingly, robust FRQ phosphorylation is still detected even when 84 phosphosites were eliminated altogether; further mutating another 26 phosphoresidues completely abolished FRQ phosphorylation. To identify phosphoresidue(s) on FRQ impacting circadian period length, a series of clustered frq phosphomutants covering all the 110 phosphosites were generated and examined for period changes. When phosphosites in the N-terminal and middle regions of FRQ were eliminated, longer periods were typically seen while removal of phosphorylation in the C-terminal tail resulted in extremely short periods, among the shortest reported. Interestingly, abolishing the 11 phosphosites in the C-terminal tail of FRQ not only results in an extremely short period, but also impacts temperature compensation (TC), yielding an overcompensated circadian oscillator. In addition, the few phosphosites in the middle of FRQ are also found to be crucial for TC. When different groups of FRQ phosphomutations were combined intramolecularly, expected additive effects were generally observed except for one novel case of intramolecular epistasis, where arrhythmicity resulting from one cluster of phosphorylation site mutants was restored by eliminating phosphorylation at another group of sites.
Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due ...to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation.
Pulmonary function and high-resolution CT (HRCT) were assessed in 28 non-smokers, 61 healthy smokers and 49 COPD smokers; 17 healthy smokers and 18 COPD smokers quit smoking for 12 months following the baseline visit. Total EMP (CD42b
CD31
), pulmonary capillary EMP (CD42b
CD31
ACE
) and apoptotic EMP (CD42b
CD62E
/CD42b
CD31
) levels were quantified by flow cytometry.
Compared with non-smokers, healthy smokers and COPD smokers had elevated levels of circulating EMPs due to active pulmonary capillary endothelial apoptosis. Levels remained elevated over 12 months in healthy smokers and COPD smokers who continued smoking, but returned to non-smoker levels in healthy smokers who quit. In contrast, levels remained significantly abnormal in COPD smokers who quit.
Pulmonary capillary apoptosis is reversible in healthy smokers who quit, but continues to play a role in COPD pathogenesis in smokers who progressed to airflow obstruction despite smoking cessation.
NCT00974064; NCT01776398.
Abstract
Background
Alzheimer’s disease pathophysiology may affect sound processing (central auditory function) in the brain. This study aims to investigate the link between tests of central auditory ...function, such as dichotic digits, and brain pathology in older adults at high risk for developing dementia.
Method
28 individuals (13 cognitively unimpaired (CU) and 15 mild cognitively impaired (MCI)) were enrolled (Table 1). Amyloid deposition was assessed with
18
F AZD4694 PET and tau accumulation was assessed with
18
FMK6240 PET. Standard uptake value ratios (SUVR) were determined using the cerebellar and the inferior cerebellar cortex as reference region for amyloid and tau PET, respectively. Hearing assessments were conducted using a custom audiological testing system from Creare LLC. Voxel‐based regression models evaluated the association between dichotic digit scores and amyloid and tau deposition as assessed by PET, adjusting for Pure Tone Average (PTA) and a control condition for speech in noise (Triple digits score). Random field theory (RFT) was used to correct for multiple comparisons.
Result
In the voxel‐wise analysis, negative associations between dichotic digits scores and amyloid‐PET were found in the temporal, occipital and parietal areas. Negative associations between dichotic digits scores and tau‐PET were present in the temporal area, with higher t‐values in the primary and secondary somatosensory cortices
(Figure 1, panel A)
. Negative correlations were found between dichotic digits scores and both amyloid (p<0.001) and tau (p<0.05) SUVRs
(Figure 1, panel B)
. In addition, dichotic digits scores were significantly lower in MCI individuals (p<0.001)
(Figure 1, panel C)
.
Conclusion
This study is the first to assess associations between central auditory hearing in CU and MCI individuals using PET biomarkers. These findings highlight the link between central auditory deficits and AD hallmarks in auditory processing‐related brain regions. This suggests a potential decreased capacity for interhemispheric transfer in mildly cognitively impaired individuals.
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