A survey on patient preferences towards CIED implantation

BackgroundCardiac implantable electronic device (CIED) implantation is increasingly performed worldwide with improving safety. Outpatient CIED implantation has similar complication rates compared to those implants which are hospitalized. Here, we analyze patient preferences on discharge timing after CIED implantation.ObjectiveTo identify and understand the factors contributing to patient preferences towards same-day or next-day discharge after CIED implantation.MethodsOne hundred and two patients undergoing new CIED implants were included in the study at two separate hospitals in CT (CT group) and FL (FL group) from 2018-2019. A 7-question survey was administered to the patients after the procedure. Survey responses and demographic data were statistically analyzed.ResultsSeventy-four percent of CT group and 58% of the FL group responded with a 10 score (0-10) that they were ready to be discharged home the same day (p=0.09). Both groups reported a low number of patients feeling safer by having a remote monitor provided at the time of discharge (44% CT group, 28% FL group; p=0.123). The mean distance of patients living from the hospital in CT group (21.6 miles) was significantly lower than that for the FL group (35.5 miles); p=0.01. Hypertension (86% vs 52%; p=0.0002) and Diabetes mellitus (44% vs 21%; p=0.013) were more prevalent in the FL group compared to the CT group.ConclusionDespite the influence of local practices, the majority of patients preferred same-day discharge after CIED implantation. Improved patient education regarding the ability of remote monitors to provide real-time response to acute events is needed.     

Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket

Ligand‐regulated pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a central role in xenobiotic metabolism. Despite its critical role in drug metabolism, PXR activation can lead to adverse drug‐drug interactions and early stage metabolism of drugs. Activated PXR can induce cancer drug resistance and enhance the onset of malignancy. Since promiscuity in ligand binding makes it difficult to develop competitive inhibitors targeting PXR ligand binding pocket (LBP), it is essential to identify allosteric sites for effective PXR antagonism. Here, molecular dynamics (MD) simulation studies unravelled the existence of two different conformational states, namely “expanded” and “contracted”, in apo PXR ligand binding domain (LBD). Ligand binding events shifted this conformational equilibrium and locked the LBD in a single “ligand‐adaptable” conformational state. Ensemble‐based computational solvent mapping identified a transiently open potential small molecule binding pocket between α5 and α8 helices, named “α8 pocket”, whose opening‐closing mechanism directly correlated with the conformational shift in LBD. A virtual hit identified through structure‐based virtual screening against α8 pocket locks the pocket in its open conformation. MD simulations further revealed that the presence of small molecule at allosteric site disrupts the LBD dynamics and locks the LBD in a “tightly‐contracted” conformation. The molecular details provided here could guide new structural studies to understand PXR activation and antagonism.     

A neural network approach for the prediction of in vitro culture parameters for maximum biomass yields in hairy root cultures

The present study deals with ANN based prediction of culture parameters in terms of inoculum density, pH and volume of growth medium per culture vessel and sucrose content of the growth medium for Glycyrrhiza hairy root cultures. This kind of study could be a model system in exploitation of hairy root cultures for commercial production of pharmaceutical compounds using large bioreactors. The study is aimed to evaluate the efficiency of regression neural network and back propagation neural network for the prediction of optimal culture conditions for maximum hairy root biomass yield. The training data for regression and back propagation networks were primed on the basis of function approximation, where final biomass fresh weight (f_wt) was considered as a function of culture parameters. On this basis the variables in culture conditions were described in the form of equations which are for inoculum density: y=0.02x+0.04, for pH of growth medium: y=x+2.8, for sucrose content in medium: y=9.9464x+(−9.7143) and for culture medium per culture vessel: y=10x. The fresh weight values obtained from training data were considered as target values and further compared with predicted fresh weight values. The empirical data were used as testing data and further compared with values predicted from trained networks. Standard MATLAB inbuilt generalized regression network with radial basis function radbas as transfer function in layer one and purelin in layer two and back propagation having purelin as transfer function in output layer and logsig in hidden layer were used. Although in comparative assessment both the networks were found efficient for prediction of optimal culture conditions for high biomass production, more accuracy in results was seen with regression network.     

Enhanced sensitivity of aged fibrotic hearts to angiotensin II- and hypokalemia-induced early afterdepolarization-mediated ventricular arrhythmias

Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24-26 mo) and young (3-4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 μM) or ionic stress with hypokalemia (2.7 mM). ANG II caused EAD-mediated VF in 16 of 19 aged hearts (83%) after 32 ± 7 min but in 0 of 9 young hearts (0%). ANG II-mediated VF was suppressed with KN-93 (Ca(2+)/calmodulin-dependent kinase inhibitor) and the reducing agent N-acetylcysteine. Hypokalemia caused EAD-mediated VF in 11 of 11 aged hearts (100%) after 7.4 ± 0.4 min. In 14 young hearts, however, VF did not occur in 6 hearts (43%) or was delayed in onset (31 ± 22 min, P < 0.05) in 8 hearts (57%). In patch-clamped myocytes, ANG II and hypokalemia (n = 6) induced EADs and triggered activity in both age groups (P = not significant) at a cycle length of >0.5 s. When myocytes of either age group were coupled to a virtual fibroblast using the dynamic patch-clamp technique, EADs arose in both groups at a cycle length of <0.5 s. Aged ventricles had significantly greater fibrosis and reduced connexin43 gap junction density compared with young hearts. The lack of differential age-related sensitivity at the single cell level in EAD susceptibility indicates that increased ventricular fibrosis in the aged heart plays a key role in increasing vulnerability to VF induced by oxidative and ionic stress.     

Relationships between fish size and otolith size of four bathydemersal fish species from the south eastern Arabian Sea,India

The objective of this study was to estimate a prey body size from the hard parts (e.g. otoliths) of a fish species frequently found in the guts of predators. Length–weight relationships between otolith size (length, height, weight and aspect ratio) and fish size (total length and weight) were determined for four fish species captured in the Arabian Sea by bottom trawl (2015 survey on‐board FORV Sagar Sampada, 200–300 m depth), off the west coast of India: Psenopsis cyanea, Pterygotrigla hemisticta, Bembrops caudimacula and Hoplostethus rubellopterus. No significant differences were noted between the size of the left and right otoliths (t test) in any of the four species. The length–weight relationship of the otolith in all four species showed a negative allometric growth pattern (t test, p < .05). The data fitted well to the regression model for otolith length (OL), otolith height (OH) and otolith weight (OW) to total length (TL) and total weight (TW). Results showed that these relationships are a helpful tool in predicting fish size from the otoliths and in calculating the biomass of these less‐studied fish species during feeding studies and palaentology.     

Photochemical synthesis of substituted indan-1-ones related to donepezil.

A photoenolization reaction is shown to be the key reaction step in the preparation of substituted indan-1-ones as convenient precursors for the synthesis of donepezil, a well-known acetylcholinesterase inhibitor. Model 2,5-dialkylphenacyl chlorides, differently substituted in the alpha-carbon position, were found to produce indan-1-ones upon irradiation in non-nucleophilic solvents in high chemical yields via hydrogen chloride release. While direct excitation of 4,5-dimethoxy-2-methylphenacyl chloride led to a complex mixture of photoproducts, photolysis of the corresponding benzoate was found to form 5,6-dimethoxyindan-1-one in 62-72% chemical yields and a relatively low quantum efficiency (Phi approximately 0.02). This compound can then be easily converted to donepezil by standard synthetic steps described in the literature. Isotopic exchange and quenching experiments revealed that the product is obtained by the photoenolization process via the triplet excited state, while minor side-photoproducts originate from the singlet excited state. Irradiation of the reactant in neat acetone, used both as a triplet sensitizer and solvent at the same time, was found to form 5,6-dimethoxyindan-1-one exclusively in high (90%) chemical yield.     

Diagonally Aligned Squared Metal Nano-pillar with Increased Hotspot Density as a Highly Reproducible SERS Substrate

Metal nanostructure on dielectric substrate with increased hotspot density has drawn considerable research interest in recent years toward the study of surface-enhanced Raman spectroscopy (SERS). In this paper, we report the fabrication of a diagonally aligned squared metal nano-pillar (SMNP) on a dielectric substrate and revealed it as an efficient SERS substrate with increased hotspot density for sensing of Raman active materials. Due to dipolar coupling and lightening rod effect between the neighboring nano-pillars, the localized surface plasmon resonance (LSPR) field intensity increased significantly in the space between two neighboring SMNP which would lead to the enhancement of SERS signal. The SMNP has been fabricated using electron beam lithographic (EBL) technique with hotspot density of 2.45 × 10⁷/mm². With the designed SERS substrate an average enhancement factor (EF) of 3.27 × 10⁸ has been observed with relative standard deviation of ～13 %.     

Longitudinal monitoring of cell metabolism in biopharmaceutical production using label-free fluorescence lifetime imaging microscopy

Chinese hamster ovary (CHO) cells are routinely used in the biopharmaceutical industry for production of therapeutic monoclonal antibodies (mAbs). Although multiple offline and time-consuming measurements of spent media composition and cell viability assays are used to monitor the status of culture in biopharmaceutical manufacturing, the day-to-day changes in the cellular microenvironment need further in-depth characterization. In this study, two-photon fluorescence lifetime imaging microscopy (2P-FLIM) was used as a tool to directly probe into the health of CHO cells from a bioreactor, exploiting the autofluorescence of intracellular nicotinamide adenine dinucleotide phosphate (NAD(P)H), an enzymatic cofactor that determines the redox state of the cells. A custom-built multimodal microscope with two-photon FLIM capability was utilized to monitor changes in NAD(P)H fluorescence for longitudinal characterization of a changing environment during cell culture processes. Three different cell lines were cultured in 0.5 L shake flasks and 3 L bioreactors. The resulting FLIM data revealed differences in the fluorescence lifetime parameters, which were an indicator of alterations in metabolic activity. In addition, a simple principal component analysis (PCA) of these optical parameters was able to identify differences in metabolic progression of two cell lines cultured in bioreactors. Improved understanding of cell health during antibody production processes can result in better streamlining of process development, thereby improving product titer and verification of scale-up. To our knowledge, this is the first study to use FLIM as a label-free measure of cellular metabolism in a biopharmaceutically relevant and clinically important CHO cell line.     

High-frequency<Emphasis Type="Italic">in vitro</Emphasis> flowering in six species of<Emphasis Type="Italic">ceropegia</Emphasis>

High-frequencyin vitro flowering is reported here fromin vitro regenerated shoots ofin vitro-raised seedlings of rare and endemicCeropegia lawii, Ceropegia maccannii, Ceropegia oculata, andCeropegia sahyadrica, as well as the widely distributedCeropegia bulbosa var.bulbosa andCeropegia hirsuta. In our first set of experiments, the MS medium contained 87 mM sucrose and was supplemented with varying concentrations of BAP (4.4 to 26.6 μM). For the second set of trials, varying concentrations of sucrose (87 to 233 mM) were tested in MS media containing a constant 4.4 p.M BAP. Sub-cultured apical as well as axillary buds flowered with similar frequencies after 30 d of incubation. For all six species, the highest percentage of flowering shoots was obtained with either 26.6 μM BAP or 175 mM sucrose. Although smaller in size, theirin vitro flowers were morphologically comparable within wVo-derived flowers. Variations among species were noted for the number of flower buds per shoot and the percentage of flower formation. Because all six species showed similar responses in both experiments, we can suggest that this protocol is applicable across the wide range ofCeropegia species.