Objectives We evaluated the prognostic value of myocardial flow reserve (MFR) using rubidium-82 (82 Rb) positron emission tomography (PET) in patients assessed for ischemia. Background The clinical ...value of MFR quantification using82 Rb PET beyond relative myocardial perfusion imaging remains uncertain. Methods We prospectively enrolled 704 consecutive patients; 677 (96%) completed follow-up (median 387 days interquartile range: 375 to 416 days). Patients were divided into 4 groups: I, normal summed stress score (SSS) (<4) and normal myocardial flow reserve (MFR) (>2); II, normal SSS and MFR <2; III, SSS ≥4 and MFR ≥2; IV, SSS ≥4 and MFR <2. Results For patients with a normal SSS and those with an abnormal SSS, there were significant differences in outcomes for hard events (cardiac death and myocardial infarction) between patients with MFR ≥2 and those with MFR <2 (I: 1.3% vs. II: 2% p = 0.029; III: 1.1% vs. IV: 11.4% p = 0.05) and for major adverse cardiac events (MACE) (p = 0.003 and p < 0.001, respectively). In the adjusted Cox model, MFR was an independent predictor of hard events (hazard ratio: 3.3; 95% confidence interval: 1.1 to 9.5; p = 0.029) and MACE (hazard ratio: 2.4, 95% confidence interval: 1.4 to 4.4, p = 0.003). The incremental prognostic value of the MFR over the SSS was demonstrated by comparing the adjusted SSS model with and without the MFR for hard events (p = 0.0197) and MACE (p = 0.002). Conclusions MFR quantified using82 Rb PET predicts hard cardiac events and MACE independent of the SSS and other parameters. Routine assessment of82 Rb PET–quantified MFR could improve risk stratification for patients being investigated for ischemia.
Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; ...however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.
The introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case ...incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia.
Following pilot releases in 2015-2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niterói, Brazil during 2017-2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone. Three years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niterói, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40-70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika.
We demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika.
Trace metals are required for numerous processes in phytoplankton and can influence the growth and structure of natural phytoplankton communities. The metal contents of phytoplankton reflect ...biochemical demands as well as environmental availability and influence the distribution of metals in the ocean. Metal quotas of natural populations can be assessed from analyses of individual cells or bulk particle assemblages or inferred from ratios of dissolved metals and macronutrients in the water column. Here, we review the available data from these approaches for temperate, equatorial, and Antarctic waters in the Pacific and Atlantic Oceans. The data show a generalized metal abundance ranking of Fe≈Zn>Mn≈Ni≈Cu≫Co≈Cd; however, there are notable differences between taxa and regions that inform our understanding of ocean metal biogeochemistry. Differences in the quotas estimated by the various techniques also provide information on metal behavior. Therefore, valuable information is lost when a single metal stoichiometry is assumed for all phytoplankton.
Background
Relative myocardial perfusion imaging (MPI) is the standard imaging approach for the diagnosis and prognostic work-up of coronary artery disease (CAD). However, this technique may ...underestimate the extent of disease in patients with 3-vessel CAD. Positron emission tomography (PET) is also able to quantify myocardial blood flow. Rubidium-82 (
82
Rb) is a valid PET tracer alternative in centers that lack a cyclotron. The aim of this study was to assess whether assessment of myocardial flow reserve (MFR) measured with
82
Rb PET is an independent predictor of severe obstructive 3-vessel CAD.
Methods
We enrolled a cohort of 120 consecutive patients referred to a dipyridamole
82
Rb PET MPI for evaluation of ischemia neither with prior coronary artery bypass graft nor with recent percutaneous coronary intervention that also underwent coronary angiogram within 6 months of the PET study. Patients with and without 3-vessel CAD were compared.
Results
Among patients with severe 3-vessel CAD, MFR was globally reduced (<2) in 88% (22/25). On the adjusted logistic Cox model, MFR was an independent predictor of 3-vessel CAD .5 unit decrease, HR: 2.1, 95% CI (1.2-3.8);
P
= .015. The incremental value of
82
Rb MFR over the SSS was also shown by comparing the adjusted SSS models with and without
82
Rb MFR (
P
= .005).
Conclusion
82
Rb MFR is an independent predictor of 3-vessel CAD and provided added value to relative MPI. Clinical integration of this approach should be considered to enhance detection and risk assessment of patients with known or suspected CAD.
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the
FMR1 gene that encodes ...the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated
Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
Abstract
Ponds are often identified by their small size and shallow depths, but the lack of a universal evidence-based definition hampers science and weakens legal protection. Here, we compile ...existing pond definitions, compare ecosystem metrics (e.g., metabolism, nutrient concentrations, and gas fluxes) among ponds, wetlands, and lakes, and propose an evidence-based pond definition. Compiled definitions often mentioned surface area and depth, but were largely qualitative and variable. Government legislation rarely defined ponds, despite commonly using the term. Ponds, as defined in published studies, varied in origin and hydroperiod and were often distinct from lakes and wetlands in water chemistry. We also compared how ecosystem metrics related to three variables often seen in waterbody definitions: waterbody size, maximum depth, and emergent vegetation cover. Most ecosystem metrics (e.g., water chemistry, gas fluxes, and metabolism) exhibited nonlinear relationships with these variables, with average threshold changes at 3.7 ± 1.8 ha (median: 1.5 ha) in surface area, 5.8 ± 2.5 m (median: 5.2 m) in depth, and 13.4 ± 6.3% (median: 8.2%) emergent vegetation cover. We use this evidence and prior definitions to define ponds as waterbodies that are small (< 5 ha), shallow (< 5 m), with < 30% emergent vegetation and we highlight areas for further study near these boundaries. This definition will inform the science, policy, and management of globally abundant and ecologically significant pond ecosystems.
The role of telemedical monitoring in diabetic foot ulcer care is still uncertain. Our aim was to compare telemedical and standard outpatient monitoring in the care of patients with diabetic foot ...ulcers in a randomized controlled trial.
Of the 736 screened individuals with diabetic foot ulcers, 401 met the eligibility criteria and were randomized between October 2010 and November 2014. The per-protocol telemedical monitoring consisted of two consultations in the patient's own home and one consultation at the outpatient clinic. Standard practice consisted of three outpatient clinic visits. The three-visit cycle was repeated until study end point. The study end points were defined as complete ulcer healing, amputation, or death.
One hundred ninety-three individuals were randomized to telemedical monitoring and 181 to standard care. Demographics were similar in both groups. A cause-specific Cox proportional hazards model showed no difference in individuals monitored through telemedicine regarding wound healing (hazard ratio 1.11 95% CI 0.87, 1.42, P = 0.42) or amputation (0.87 0.54, 1.42, P = 0.59). We found a higher mortality incidence in the telemedical monitoring group compared with the standard outpatient monitoring group (8.68 6.93, 10.88, P = 0.0001).
The findings of no significant difference regarding amputation and healing between telemedical and standard outpatient monitoring seem promising; however, for telemedical monitoring, a higher mortality throws into question the role of telemedicine in monitoring diabetic foot ulcers. Further studies are needed to investigate effects of telemedicine on mortality and other clinical outcomes and to identify patient subgroups that may have a poorer outcome through telemedical monitoring.
Technology has greatly influenced and radically changed human life, from communication to creativity and from productivity to entertainment. The authors, starting from considerations concerning the ...implementation of new technologies with a strong impact on people’s everyday lives, take up Collingridge’s dilemma and relate it to the application of AI in healthcare. Collingridge’s dilemma is an ethical and epistemological problem concerning the relationship between technology and society which involves two approaches. The proactive approach and socio-technological experimentation taken into account in the dilemma are discussed, the former taking health technology assessment (HTA) processes as a reference and the latter the AI studies conducted so far. As a possible prevention of the critical issues raised, the use of the medico-legal method is proposed, which classically lies between the prevention of possible adverse events and the reconstruction of how these occurred.
The authors believe that this methodology, adopted as a European guideline in the medico-legal field for the assessment of medical liability, can be adapted to AI applied to the healthcare scenario and used for the assessment of liability issues. The topic deserves further investigation and will certainly be taken into consideration as a possible key to future scenarios.
What is the Prognostic Value of Myocardial Perfusion Imaging Using Rubidium-82 Positron Emission Tomography?
Keiichiro Yoshinaga, Benjamin J. W. Chow, Kathryn Williams, Li Chen, Robert A. deKemp, ...Linda Garrard, Alexander Lok-Tin Szeto, May Aung, Ross A. Davies, Terrence D. Ruddy, Rob S. B. Beanlands
The prognostic value of dipyridamole stress rubidium-82 positron emission tomography (PET) was determined in 367 patients followed up for 3.1 ± 0.9 years. Rubidium-82 PET showed a significant prognostic value for predicting cardiac events, including death and nonfatal myocardial infarction. Normal PET myocardial perfusion imaging (MPI) indicated a low risk. Among patients referred for PET MPI after an equivocal single-photon-emission computed tomography study, patients with an abnormal PET MPI had higher event rates compared with patients with a normal PET MPI. In a subset of patients with obesity, rubidium-82 PET also seemed to have prognostic value. The prognostic value of PET MPI supports its use in the risk stratification of cardiac patients.
The objective was to determine the prognostic value of rubidium-82 (82Rb) positron emission tomography (PET) myocardial perfusion imaging (MPI).
82Rb PET MPI accurately diagnoses coronary artery disease (CAD). However, there are limited data evaluating its prognostic value.
Follow-up (3.1 ± 0.9 years) was obtained in 367 patients who underwent dipyridamole 82Rb PET MPI. Patients were divided into groups based on their summed stress score (SSS): group I, normal (<4); group II, mild (4 to 7); and group III, moderate (8 to 11) to severe (≥12).
There were significant differences among patients in the 3 SSS groups for hard events (cardiac death and myocardial infarction MI) (p < 0.001) and total cardiac events (hard events, revascularization and hospitalization) (p < 0.001). The annual hard events rates were 0.4%, 2.3%, and 7.0% in the normal, mild, and moderate-severe groups, respectively. In adjusted survival models, 82Rb PET SSS was the strongest predictor of total cardiac events and a significant predictor of hard events. Among patients referred for PET after 99mTc single-photon emission computed tomography, the annual total event rate was higher with abnormal versus normal SSS on PET (15.2% vs. 1.3%, p < 0.001). In patients with obesity, the annual total event rate was 11.1% with an abnormal scan and 1.5% with a normal scan (p < 0.001).
This study shows that 82Rb PET MPI has significant prognostic value for predicting cardiac events, including death and MI. It also seems to have prognostic value in patients whose diagnosis remains uncertain after single-photon emission computed tomography MPI and in obese patients. The prognostic value of PET MPI may improve the management of cardiac patients.
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