Improved delivery of rate-adaptive pacing using an impedance-derived contractility sensor in high-intensity exercise: A case report.

Effective rate-adaptive pacing may be difficult in the presence of atrial fibrillation (AF), and is important during high-intensity exercise. This case presents a 74-year-old elite cyclist with AF and a biventricular pacemaker after atrioventricular (AV) node ablation. He reported sudden breathlessness due to heart rate drops, caused by breaching the artefact threshold on the minute-ventilation sensor. He was exchanged to a generator with an impedance-derived contractility sensor (closed-loop stimulation), resulting in resolution of symptoms, and no further rate drops. This is the first description of the utility of closed-loop stimulation in high-intensity exercise.

Variations in bacterial community structure and antimicrobial resistance gene abundance in cattle manure and poultry litter.

Cattle manure and poultry litter are widely used as fertilizers as they are excellent sources of nutrients; however, potential adverse environmental effects exist during land applications, due to the release of zoonotic bacteria and antimicrobial resistance (AMR) genes. This study was conducted to understand linkages between physiochemical composition, bacterial diversity, and AMR gene presence of cattle manure and poultry litter using quantitative polymerase chain reaction to enumerate four AMR genes (ermB, sulI, intlI, and blactx-m-32), Illumina sequencing of the 16 S region, and analysis of physical and chemical properties. Principal coordinate analysis of Bray-Curtis distance revealed distinct bacterial community structures between the two manure sources. Greater alpha diversity occurred in cattle manure compared to poultry litter (P < 0.05). Redundancy analysis showed a strong relationship between manure physiochemical and composition and bacterial abundance, with positive relationships occurring among electrical conductivity and carbon/nitrogen, and negative associations for total solids and soluble fractions of heavy metals. Cattle manure exhibited greater abundance of macrolide (ermB) and sulfonamide (sulI) resistant genes. Consequently, fresh cattle manure applications may result in greater potential spread of AMR genes to the soil-water environment (relative to poultry litter) and novel best management strategies (such as composting) may reduce the release of AMR genes to the soil-water environment.

Hydrogen Sulfide and the Immune System.

Hydrogen sulfide (H2S) is the "third gasotransmitter" recognized alongside nitric oxide (NO) and carbon monoxide (CO). H2S exhibits an array of biological effects in mammalian cells as revealed by studies showing important roles in the cardiovascular system, in cell signalling processes, post-translational modifications and in the immune system. Regarding the latter, using pharmacological and genetic approaches scientists have shown this molecule to have both pro- and anti-inflammatory effects in mammalian systems. The anti-inflammatory effects of H2S appeared to be due to its inhibitory action on the nuclear factor kappa beta signalling pathway; NF-kB representing a transcription factor involved in the regulation pro-inflammatory mediators like nitric oxide, prostaglandins, and cytokines. In contrast, results from several animal model describe a more complicated picture and report on pro-inflammatory effects linked to exposure to this molecule; linked to dosage used and point of administration of this molecule. Overall, roles for H2S in several inflammatory diseases spanning arthritis, atherosclerosis, sepsis, and asthma have been described by researchers. In light this work fascinating research, this chapter will cover H2S biology and its many roles in the immune system.

Hierarchical Pooling in Graph Neural Networks to Enhance Classification Performance in Large Datasets.

Deep learning methods predicated on convolutional neural networks and graph neural networks have enabled significant improvement in node classification and prediction when applied to graph representation with learning node embedding to effectively represent the hierarchical properties of graphs. An interesting approach (DiffPool) utilises a differentiable graph pooling technique which learns 'differentiable soft cluster assignment' for nodes at each layer of a deep graph neural network with nodes mapped on sets of clusters. However, effective control of the learning process is difficult given the inherent complexity in an 'end-to-end' model with the potential for a large number parameters (including the potential for redundant parameters). In this paper, we propose an approach termed FPool, which is a development of the basic method adopted in DiffPool (where pooling is applied directly to node representations). Techniques designed to enhance data classification have been created and evaluated using a number of popular and publicly available sensor datasets. Experimental results for FPool demonstrate improved classification and prediction performance when compared to alternative methods considered. Moreover, FPool shows a significant reduction in the training time over the basic DiffPool framework.

Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome.

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non-verbal and visuo-spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.

Hydrogen Sulfide Treatment Improves Post-Infarct Remodeling and Long-Term Cardiac Function in CSE Knockout and Wild-Type Mice.

Hydrogen sulfide (H2S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H2S up-regulation has been shown to reduce ischemic injury, and H2S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H2S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE-/-). The slow-release H2S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE-/- with wild-type (WT) mice (n = 5-10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE-/- mice were observed, except CSE-/- mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H2S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.

Protective Smell of Hydrogen Sulfide and Polysulfide in Cisplatin-Induced Nephrotoxicity.

Though historically known as a toxic gas, hydrogen sulfide (H2S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential of H2S in cisplatin-induced nephrotoxicity. Specifically, reduction of H2S by cystathionine γ-lyase (CSE) downregulation upon cisplatin treatment may contribute to cisplatin-induced renal cell injury, possibly by augmentation of endogenous reactive oxygen species (ROS) production, while H2S donation may prevent subsequent renal dysfunction by inhibiting NADPH oxidase activation. Intriguingly, H2S slow-releasing compound GYY4137 seems to increase the anticancer activity of cisplatin, at least in several cancer cell lines, and this is probably due to its own anticancer effect. However, the efficacy of H2S donors in tumor-bearing animals remains to be tested in terms of renal protection and cancer inhibition after receiving cisplatin. Furthermore, accumulative evidence regarding usage of polysulfide, a novel H2S derived molecule, in the therapy of cisplatin-induced nephrotoxicity, was also summarized.

An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic.

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S-alkenyl-l-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S-allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds.

Identifying determinants of Mozambican men's willingness to use a male contraceptive pill.

Objective: Given the possibility of a male contraceptive pill in the near future, understanding men's attitudes towards this contraceptive method is crucial, especially in high-risk populations with limited access to education. This research was conducted to identify the determinants of Mozambican men's willingness to use a contraceptive pill when it is made available. Methods: A sample of 412 Mozambican men was presented with 36 vignettes comprising four within-subject factors (cost of pills, pill efficacy, side effects and context). Each vignette presented a scenario in which a man is asked by his partner to use the contraceptive pill, and participants indicated their own willingness to use the pill under each circumstance. Results: Cluster analysis revealed that participants took one of four different positions regarding their willingness to use a contraceptive pill: never (11%); depends on side effects alone (25%); depends on side effects and costs (11%); depends on side effects and context (46%). These positions were associated with participants' sociodemographic characteristics. Conclusion: Among the Mozambican men in this study, a minority appeared to believe that the responsibility for contraception should be shared between sexual partners. Men's willingness to use a contraceptive pill was, however, more pronounced in the case of serious medical risk to their partner. Overall, only about one-fifth of participants were either reluctant or unwilling to consider using a male contraceptive pill.

Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function.

PurposeKlinefelter syndrome (KS) is associated with lower socioeconomic status and greater morbidity. However, relatively little is known about the quality of life for men with KS, or how KS and other factors combine to determine it.MethodsA total of 132 men with KS were recruited in clinics, and 313 matched controls were identified by Statistics Denmark. Demographics, socioeconomic status, health problems and behaviors, sexual function, medical follow-up, and mental and physical quality of life (MQoL and PQoL, respectively) were assessed for all participants through surveys.ResultsMen with KS reported significantly lower education attainment levels, income, physical activity, and both PQoL and MQoL, as well as more illness, medication, and sexual dysfunction. KS status was associated directly with lower PQoL, as well as indirectly through reduced income, physical activity, and sexual function, and increased body mass index. KS status and younger age were associated directly with lower MQoL, as well as indirectly through reduced income, physical activity, and partner status (for KS status), or through partner status (for age).ConclusionKS status is associated with lower PQoL and MQoL through both direct and indirect paths. These results suggest the need for more comprehensive research and clinical approaches to addressing quality of life for men with KS.

Characterizing the phosphorus forms extracted from soil by the Mehlich III soil test.

Phosphorus (P) can limit crop production in many soils, and soil testing is used to guide fertilizer recommendations. The Mehlich III (M3) soil test is widely used in North America, followed by colorimetric analysis for P, or by inductively coupled plasma-based spectrometry (ICP) for P and cations. However, differences have been observed in M3 P concentrations measured by these methods. Using 31P nuclear magnetic resonance (P-NMR) and mass spectrometry (MS), we characterized P forms in M3 extracts. In addition to the orthophosphate that would be detected during colorimetric analysis, several organic P forms were present in M3 extracts that would be unreactive colorimetrically but measured by ICP (molybdate unreactive P, MUP). Extraction of these P forms by M3 was confirmed by P-NMR and MS in NaOH-ethylenediaminetetraacetic acid extracts of whole soils and residues after M3 extraction. The most abundant P form in M3 extracts was myo-inositol hexaphosphate (myo-IHP, phytate), a compound that may not contribute to plant-available P if tightly sorbed in soil. Concentrations of myo-IHP and other organic P forms varied among soils, and even among treatment plots on the same soil. Extraction of myo-IHP in M3 appeared to be linked to cations, with substantially more myo-IHP extracted from soils fertilized with alum-treated poultry litter than untreated litter. These results suggest that ICP analysis may substantially over-estimate plant-available P in samples with high MUP concentrations, but there is no way at present to determine MUP concentrations without analysis by both colorimetry and ICP. This study also tested procedures that will improve future soil P-NMR studies, such as treatment of acid extracts, and demonstrated that techniques such as P-NMR and MS are complimentary, each yielding additional information that analysis by a single technique may not provide.

H2S biosynthesis and catabolism: new insights from molecular studies.

Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissues.

Effects of Land-Applied Ammonia Scrubber Solutions on Yield, Nitrogen Uptake, Soil Test Phosphorus, and Phosphorus Runoff.

Ammonia (NH) scrubbers reduce amounts of NH and dust released from animal rearing facilities while generating nitrogen (N)-rich solutions, which may be used as fertilizers. The objective of this study was to determine the effects of various NH scrubber solutions on forage yields, N uptake, soil-test phosphorus (P), and P runoff. A small plot study was conducted using six treatments: (i) an unfertilized control, (ii) potassium bisulfate (KHSO) scrubber solution, (iii) aluminum sulfate [Al(SO) ⋅14HO, alum] scrubber solution, (iv) sodium bisulfate (NaHSO) scrubber solution, (v) sulfuric acid (HSO) scrubber solution, and (vi) ammonium nitrate (NHNO) fertilizer. The scrubber solutions were obtained from ARS Air Scrubbers attached to commercial broiler houses. All N sources were applied at a rate of 112 kg N ha. Plots were harvested approximately every 4 wk and soil-test P measurements were made, then a rainfall simulation study was conducted. Cumulative forage yields were greater ( < 0.05) for KHSO (7.6 Mg ha) and NaHSO (7.5 Mg ha) scrubber solutions than for alum (6.7 Mg ha) or HSO (6.5 Mg ha) scrubber solutions or for NHNO (6.9 Mg ha). All N sources resulted in higher yields than the control (5.1 Mg ha). The additional potassium in the KHSO treatment likely resulted in higher yields. Although Mehlich-III-extractable P was not affected, water-extractable P in soil was lowered by the alum-based scrubber solution, which also resulted in lower P runoff. This study demonstrates that N captured using NH scrubbers is a viable N fertilizer.

Water-Extractable Phosphorus in Animal Manure and Manure Compost: Quantities, Characteristics, and Temporal Changes.

Water-extractable P (WEP) in manure and manure compost is widely used as an indicator of P release to runoff from manure and compost that are land applied. A survey of 600 manures and composts was conducted to assess trends in WEP (dry weight equivalent) related to manure and compost types from sources in the Mid-Atlantic region. Manure and compost WEP ranged from 0.2 to 20.8 g kg. Mean WEP was highest in turkey and swine manures (manure: 4.1-5.6 g kg; no composts tested), followed by layer and broiler chicken manures (manure: 3.0-3.5 g kg; compost: 4.6-5.1 g kg), cattle manure (dairy and beef manure: 2.1-2.8 g kg; compost: 1.1-2.7 g kg), and horse manure (manure: 2.7 g kg; compost: 1.9 g kg). Across all manures and composts, WEP was negatively correlated with manure dry matter content ( = 0.42, < 0.001). Moreover, WEP was strongly correlated ( = 0.66, < 0.001) to degree of P saturation expressed as a molar ratio of total P to total metals (Ca, Mg, Fe, Al, and Mn). Although WEP levels of beef, broiler chicken, and turkey manures from this survey are similar to those from a decade ago, WEP is now significantly lower for dairy (30%, < 0.001), swine (46%, < 0.001), and layer chickens (39%, < 0.05). Lower WEP resulted from decreasing total P and/or increasing P sorption capacity, combined with increasing dry matter content. Results highlight the potential to use degree of P saturation to predict WEP and suggest an opportunity to reduce WEP by managing manure handling, storage, and chemistry.

Phosphorus Leaching from Soil Cores from a Twenty-Year Study Evaluating Alum Treatment of Poultry Litter.

Adding alum to poultry litter is a best management practice used to stabilize P in less soluble forms, reducing nonpoint-source P runoff. However, little research has been conducted on how alum additions to litter affect subsequent leaching of P from soil. The objective of this study was to evaluate the effects of alum-treated versus untreated poultry litter on P leaching from soil cores receiving long-term poultry litter applications. Two intact soil cores were taken from each of 52 plots in a long-term study with 13 treatments: a control, four rates each of untreated and alum-treated litter (2.24, 4.49, 6.72, and 8.96 Mg ha), and four rates of ammonium nitrate (65, 130, 195, and 260 kg N ha). One core from each plot received the same fertilizer as for the previous 20 yr, whereas the other was unfertilized in the study year, resulting in a total of 25 treatments. Cores were exposed to natural rainfall, and P leaching was measured for 1 yr. The average soluble reactive P concentrations in the leachate varied from 0.16 to 0.44 mg P L in fertilized alum-treated cores, whereas leachate from cores fertilized with untreated litter ranged from 0.40 to 2.64 mg P L. At the highest litter rate (8.96 Mg ha), alum reduced total dissolved P and total P concentrations in leachate by 83 and 80%, respectively, compared with untreated litter. These results indicate that alum additions to poultry litter significantly reduced soluble and total P fractions in leachate.

A simple mathematical method to estimate ammonia emission from in-house windrowing of poultry litter.

In-house windrowing between flocks is an emerging sanitary management practice to partially disinfect the built-up litter in broiler houses. However, this practice may also increase ammonia (NH3) emission from the litter due to the increase in litter temperature. The objectives of this study were to develop mathematical models to estimate NH3 emission rates from broiler houses practicing in-house windrowing between flocks. Equations to estimate mass-transfer areas form different shapes windrowed litter (triangular, rectangular, and semi-cylindrical prisms) were developed. Using these equations, the heights of windrows yielding the smallest mass-transfer area were estimated. Smaller mass-transfer area is preferred as it reduces both emission rates and heat loss. The heights yielding the minimum mass-transfer area were 0.8 and 0.5 m for triangular and rectangular windrows, respectively. Only one height (0.6 m) was theoretically possible for semi-cylindrical windrows because the base and the height were not independent. Mass-transfer areas were integrated with published process-based mathematical models to estimate the total house NH3 emission rates during in-house windrowing of poultry litter. The NH3 emission rate change calculated from the integrated model compared well with the observed values except for the very high NH3 initial emission rate from mechanically disturbing the litter to form the windrows. This approach can be used to conveniently estimate broiler house NH3 emission rates during in-house windrowing between flocks by simply measuring litter temperatures.

Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO).

BACKGROUND: Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement. METHODS AND FINDINGS: We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus current standard of care without routine salvage use (control) in cesarean section among women at risk of haemorrhage. Randomisation was stratified, using random permuted blocks of variable sizes. In an intention-to-treat analysis, we used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage ≥2 ml in RhD-negative women with RhD-positive babies (a secondary outcome) between groups. Among 3,028 women randomised (2,990 analysed), 95.6% of 1,498 assigned to intervention had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) versus 3.9% of 1,492 assigned to control. Donor blood transfusion rate was 3.5% in the control group versus 2.5% in the intervention group (adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01, p = 0.056; adjusted risk difference -1.03, 95% CI -2.13 to 0.06). In a planned subgroup analysis, the transfusion rate was 4.6% in women assigned to control versus 3.0% in the intervention group among emergency cesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 2.2% versus 1.8% among elective cesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46). No case of amniotic fluid embolism was observed. The rate of fetomaternal haemorrhage was higher with the intervention (10.5% in the control group versus 25.6% in the intervention group, adjusted OR 5.63, 95% CI 1.43 to 22.14, p = 0.013). We are unable to comment on long-term antibody sensitisation effects. CONCLUSIONS: The overall reduction observed in donor blood transfusion associated with the routine use of cell salvage during cesarean section was not statistically significant. TRIAL REGISTRATION: This trial was prospectively registered on ISRCTN as trial number 66118656 and can be viewed on http://www.isrctn.com/ISRCTN66118656.

Identification of a previously undetected metabolic defect in the Complex II Caenorhabditis elegans mev-1 mutant strain using respiratory control analysis.

Hypometabolism may play an important role in the pathogenesis of ageing and ageing-related diseases. The nematode Caenorhabditis elegans offers the opportunity to study "living mitochondria" in a small (~1 mm) animal replete with a highly stereotypical, yet complex, anatomy and physiology. Basal oxygen consumption rate is often employed as a proxy for energy metabolism in this context. This parameter is traditionally measured using single-chamber Clark electrodes without the addition of metabolic modulators. Recently, multi-well oxygen electrodes, facilitating addition of metabolic modulators and hence study of respiratory control during different mitochondrial respiration states, have been developed. However, only limited official protocols exist for C. elegans, and key limitations of these techniques are therefore unclear. Following modification and testing of some of the existing protocols, we used these methods to explore mitochondrial bioenergetics in live nematodes of an electron transfer chain Complex II mutant strain, mev-1, and identified a previously undetected metabolic defect. We find that mev-1 mutants cannot respond adequately to increased energy demands, suggesting that oxidative phosphorylation is more severely impaired in these animals than has previously been appreciated.

Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents.

Hydrogen sulfide (H2S) has been investigated for its potential in therapy. Recently, we reported novel H2S donor molecules based on a thiophosphorus core, which slowly release H2S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H2S donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic H2S donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line. A seven membered ring compound, 17, was found to be the most potent with sub-micromolar IC50s in breast (0.76µM) and ovarian (0.76µM) cancer cell lines. No significant H2S release was detected in aqueous solution for this compound. However, confocal imaging showed that H2S was released from 17 inside cells at a similar level to the widely studied H2S donor GYY4137, which was shown to release 10µM H2S after 12h at a concentration of 400µM. Comparison of 17 with its non-sulfur oxygen analogue, 26, provided evidence that the sulfur atom is important for its potency. However, the significant potency observed for 26 (5.94-11.0µM) indicates that the high potency of 17 is not entirely due to release of H2S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H2S in cancer with potent thiophosphorus agents.

Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

AIMS: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. METHODS AND RESULTS: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. CONCLUSIONS: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. CLINICAL TRIAL REGISTRATION: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov.