Left Ventricular Assist Device Flow Pattern Analysis Using a Novel Model Incorporating Left Ventricular Pulsatility

Our current understanding of flow through the circuit of left ventricular assist device (LVAD), left ventricle and ascending aorta remains incompletely understood. Computational fluid dynamics, which allow for analysis of flow in the cardiovascular system, have been used for this purpose, although current simulation models have failed to fully incorporate the interplay between the pulsatile left ventricle and continuous-flow generated by the LVAD. Flow-through the LVAD is dependent on the interaction between device and patient-specific factors with suboptimal flow patterns evoking increased risk of LVAD-related complications. Computational fluid dynamics can be used to analyze how different pump and patient factors affect flow patterns in the left ventricle and the aorta. Computational fluid dynamics simulations were carried out on a patient with a HeartMate II. Simulations were also conducted for theoretical scenarios substituting HeartWare HVAD, HeartMate 3 (HM3) in continuous mode and HM3 with Artificial Pulse. An anatomical model of the patient was reconstructed from computed tomography (CT) images, and the LVAD outflow was used as the inflow boundary condition. The LVAD outflow was calculated separately using a lumped-parameter-model of the systemic circulation, which was calibrated to the patient based on the patient-specific ventricular volume change reconstructed from 4 dimensional computed tomography and pulmonary capillary wedge pressure tracings. The LVADs were implemented in the lumped-parameter-model via published pressure head versus flow (H-Q) curves. To quantify the flushing effect, virtual contrast agent was released in the ascending aorta and its flushing over the cycles was quantified. Shear stress acting on the aortic endothelium and shear rate in the bloodstream were also quantified as indicators of normal/abnormal blood flow, especially the latter being a biomarker of platelet activation and hemolysis. LVAD speeds for the HVAD and HM3 were selected to match flow rates for the patient’s HMII (9,000 RPM for HMII, 5,500 RPM for HM3, and 2,200 RPM for HVAD), the cardiac outputs were 5.81 L/min, 5.83 L/min, and 5.92 L/min, respectively. The velocity of blood flow in the outflow cannula was higher in the HVAD than in the two HeartMate pumps with a cycle average (range) of 0.92 m/s (0.78–1.19 m/s), 0.91 m/s (0.86–1.00 m/s), and 1.74 m/s (1.40–2.24 m/s) for HMII, HM3, and HVAD, respectively. Artificial pulse increased the peak flow rate to 9.84 L/min for the HM3 but the overall cardiac output was 5.96 L/min, which was similar to the continuous mode. Artificial pulse markedly decreased blood stagnation in the ascending aorta; after six cardiac cycles, 48% of the blood was flushed out from the ascending aorta under the continuous operation mode while 60% was flushed under artificial pulse. Shear stress and shear rate in the aortic arch were higher with the HVAD compared to the HMII and HM3, respectively (shear stress: 1.76 vs. 1.33 vs. 1.33 Pa, shear rate: 136 vs. 91.5 vs. 89.4 s–1). Pump-specific factors such as LVAD type and programmed flow algorithms lead to unique flow patterns which influence blood stagnation, shear stress, and platelet activation. The pump-patient interaction can be studied using a novel computational fluid dynamics model to better understand and potentially mitigate the risk of downstream LVAD complications

Pharmacy practice research - A call to action.

Pharmacists have a societal duty of care. How to best provide that type of care requires scientific study. Pharmacy practice is a scientific discipline that studies the different aspects of the practice of pharmacy, and its impact on health care systems, medicine use, and patient care. Its scope has expanded globally to encompass clinical, behavioural, economic, and humanistic implications of the practice of pharmacy, as well as practice change and implementation in routine practice of innovations such as health interventions and patient-care services. The development, impact evaluation, implementation, and sustainability of health interventions and patient-care services represents a key research area for pharmacy practice. An approach for conducting these is provided. There is evidence that collaborative national and international research in this area is growing, showing an increased contribution to global health research. The role of universities and pharmacy professional associations in supporting the advancement of pharmacy through pharmacy practice research is also discussed. Finally, a call to action for pharmacy practice research, education, and practice is made

Pharmacy practice research priorities during the COVID-19 pandemic: Recommendations of a panel of experts convened by FIP Pharmacy Practice Research Special Interest Group

Across the globe, pharmacists on the frontline continue to fight COVID-19 and its continuously evolving physical, mental, and economic consequences armed by their knowledge, professionalism, and dedication. Their need for credible scientific evidence to inform their practice has never been more urgent. Despite the exponentially increasing number of publications since the start of the pandemic, questions remain unanswered, and more are created, than have been resolved by the increasing number of publications. A panel of leading journal editors was convened by the International Pharmaceutical Federation (FIP) Pharmacy Practice Research Special Interest Group to discuss the current status of COVID-19 related research, provide their recommendations, and identify focal points for pharmacy practice, social pharmacy, and education research moving forward. Key priorities identified spanned a wide range of topics, reflecting the need for good quality research to inform practice and education. The panel insisted that a foundation in theory and use of rigorous methods should continue forming the basis of inquiry and its resultant papers, regardless of topic area. From assessing the clinical and cost effectiveness of COVID-19 therapies and vaccines to assessing different models of pharmaceutical services and education delivery, these priorities will ensure that our practice is informed by the best quality scientific evidence at this very challenging time

Three-dimensional reconstruction of coronary arteries and plaque morphology using CT angiography - comparison and registration with IVUS

BACKGROUND: The aim of this study is to present a new methodology for three-dimensional (3D) reconstruction of coronary arteries and plaque morphology using Computed Tomography Angiography (CTA). METHODS: The methodology is summarized in six stages: 1) pre-processing of the initial raw images, 2) rough estimation of the lumen and outer vessel wall borders and approximation of the vessel’s centerline, 3) manual adaptation of plaque parameters, 4) accurate extraction of the luminal centerline, 5) detection of the lumen - outer vessel wall borders and calcium plaque region, and 6) finally 3D surface construction. RESULTS: The methodology was compared to the estimations of a recently presented Intravascular Ultrasound (IVUS) plaque characterization method. The correlation coefficients for calcium volume, surface area, length and angle vessel were 0.79, 0.86, 0.95 and 0.88, respectively. Additionally, when comparing the inner and outer vessel wall volumes of the reconstructed arteries produced by IVUS and CTA the observed correlation was 0.87 and 0.83, respectively. CONCLUSIONS: The results indicated that the proposed methodology is fast and accurate and thus it is likely in the future to have applications in research and clinical arena

Epidemiological and transmissibility analysis of influenza A(H1N1)v in a southern hemisphere setting: Peru

We present a preliminary analysis of 1,771 confirmed cases of influenza A(H1N1)v reported in Peru by 17 July including the frequency of the clinical characteristics, the spatial and age distribution of the cases and the estimate of the transmission potential. Age-specific frequency of cases was highest among school age children and young adults, with the lowest frequency of cases among seniors, a pattern that is consistent with reports from other countries. Estimates of the reproduction number lie in the range of 1.2 to 1.7, which is broadly consistent with previous estimates for this pandemic in other regions. Validation of these estimates will be possible as additional data become available

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

International audienceIt is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP , result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip -knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP -mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP -related tumours

Polymorphisms of two histamine-metabolizing enzymes genes and childhood allergic asthma: a case control study

<p>Abstract</p> <p>Background</p> <p>Histamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation. Genetic variants of <it>HNMT </it>and <it>ABP1 </it>genes were found to be associated with altered enzyme activity. We hypothesized that alleles leading to decreased enzyme activity and, therefore, decreased inactivation of histamine may be responsible for altered susceptibility to asthma.</p> <p>Methods</p> <p>The aim of this study was to analyze polymorphisms within the <it>HNMT </it>and <it>ABP1 </it>genes in the group of 149 asthmatic children and in the group of 156 healthy children. The genetic analysis involved four polymorphisms of the <it>HNMT </it>gene: rs2071048 (-1637T/C), rs11569723 (-411C/T), rs1801105 (Thr105Ile = 314C/T) and rs1050891 (1097A/T) and rs1049793 (His645Asp) polymorphism for <it>ABP1 </it>gene. Genotyping was performed with use of PCR-RFLP. Statistical analysis was performed using Statistica software; linkage disequilibrium analysis was done with use of Haploview software.</p> <p>Results</p> <p>We found an association of TT genotype and T allele of Thr105Ile polymorphism of <it>HNMT </it>gene with asthma. For other polymorphisms for <it>HNMT </it>and <it>ABP1 </it>genes, we have not observed relationship with asthma although the statistical power for some SNPs might not have been sufficient to detect an association. In linkage disequilibrium analysis, moderate linkage was found between -1637C/T and -411C/T polymorphisms of <it>HNMT </it>gene. However, no significant differences in haplotype frequencies were found between the group of the patients and the control group.</p> <p>Conclusions</p> <p>Our results indicate modifying influence of histamine N-methyltransferase functional polymorphism on the risk of asthma. The other HNMT polymorphisms and ABP1 functional polymorphism seem unlikely to affect the risk of asthma.</p

D-brane Instantons as Gauge Instantons in Orientifolds of Chiral Quiver Theories

Systems of D3-branes at orientifold singularities can receive non-perturbative D-brane instanton corrections, inducing field theory operators in the 4d effective theory. In certain non-chiral examples, these systems have been realized as the infrared endpoint of a Seiberg duality cascade, in which the D-brane instanton effects arise from strong gauge theory dynamics. We present the first UV duality cascade completion of chiral D3-brane theories, in which the D-brane instantons arise from gauge theory dynamics. Chiral examples are interesting because the instanton fermion zero mode sector is topologically protected, and therefore lead to more robust setups. As an application of our results, we provide a UV completion of certain D-brane orientifold systems recently claimed to produce conformal field theories with conformal invariance broken only by D-brane instantons.Comment: 50 pages, 32 figures. v2: version published in JHEP with references adde

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved