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The multiple light scattering in biological tissues limits the measurement depth for traditional wavefront sensor. The attenuated ballistic light and the background noise caused by the diffuse light give low signal to noise ratio for wavefront measurement. To overcome this issue, we introduced a wavefront estimation method based on a ray tracing algorithm to overcome this issue. With the knowledge of the refractive index of the medium, the wavefront is estimated by calculating optical path length of rays from the target inside of the samples. This method can provide not only the information of spherical aberration from the refractive-index mismatch between the medium and biological sample but also other aberrations caused by the irregular interface between them. Simulations based on different configurations are demonstrated in this paper.

Background: The leadless Micra transcatheter-pacing system (Micra-TPS) is implanted via a femoral approach using a 27-French introducer sheath. The Micra Transcutaneous Pacing Study excluded patients with inferior vena cava (IVC) filters., Objective: To examine the feasibility and safety of Micra-TPS implantation through an IVC filter., Methods: This multicenter retrospective study included patients with an IVC filter who underwent a Micra-TPS implantation. Data for clinical and IVC filter characteristics, preprocedure imaging, and procedural interventions were collected. The primary outcome was a successful leadless pacemaker (LP) implantation via a femoral approach in the presence of an IVC filter. Periprocedural and delayed clinical complications were also evaluated., Results: Of the 1528 Micra-TPS implants attempted, 23 patients (1.5%) had IVC filters. The majority (69.6%) of IVC filters were permanent. Six (26.1%) patients underwent preprocedural imaging to assess for filter patency. One patient's filter was retrieved before LP implantation. The primary outcome was achieved in 21 of 22 patients (95.5%) with an existing IVC filter. An occluded IVC precluded LP implantation in one patient. Difficulty advancing the stiff guidewire or the 27-Fr sheath was encountered in five patients. These cases required repositioning of the wire (n = 2), gradual sheath upsizing (n = 2), or balloon dilation of the filter (n = 1). Postprocedure fluoroscopy revealed intact filters in all cases. During a median 6-month follow-up, there were no clinical complications related to the filter or the Micra-TPS., Conclusion: This multicenter experience demonstrates the feasibility and safety of Micra-TPS implantation via an IVC filter without acute procedural or delayed clinical complications., (© 2020 Wiley Periodicals LLC.)

Background: Cellular metabolism generates reactive oxygen species. The oxidation and deamination of the deoxynucleoside triphosphate (dNTP) pool results in the formation of non-canonical, toxic dNTPs that can cause mutations, genome instability, and cell death. House-cleaning or sanitation enzymes that break down and detoxify non-canonical nucleotides play major protective roles in nucleotide metabolism and constitute key drug targets for cancer and various pathogens. We hypothesized that owing to their protective roles in nucleotide metabolism, these house-cleaning enzymes are key drug targets in the malaria parasite., Methods: Using the rodent malaria parasite Plasmodium berghei we evaluate here, by gene targeting, a group of conserved proteins with a putative function in the detoxification of non-canonical nucleotides as potential antimalarial drug targets: they are inosine triphosphate pyrophosphatase (ITPase), deoxyuridine triphosphate pyrophosphatase (dUTPase) and two NuDiX hydroxylases, the diadenosine tetraphosphate (Ap4A) hydrolase and the nucleoside triphosphate hydrolase (NDH)., Results: While all four proteins are expressed constitutively across the intraerythrocytic developmental cycle, neither ITPase nor NDH are required for parasite viability. dutpase and ap4ah null mutants, on the other hand, are not viable suggesting an essential function for these proteins for the malaria parasite., Conclusions: Plasmodium dUTPase and Ap4A could be drug targets in the malaria parasite.

Background: Anti-malarial compounds have not yet been identified that target the first obligatory step of infection in humans: the migration of Plasmodium sporozoites in the host dermis. This movement is essential to find and invade a blood vessel in order to be passively transported to the liver. Here, an imaging screening pipeline was established to screen for compounds capable of inhibiting extracellular sporozoites., Methods: Sporozoites expressing the green fluorescent protein were isolated from infected Anopheles mosquitoes, incubated with compounds from two libraries (MMV Malaria Box and a FDA-approved library) and imaged. Effects on in vitro motility or morphology were scored. In vivo efficacy of a candidate drug was investigated by treating mice ears with a gel prior to infectious mosquito bites. Motility was analysed by in vivo imaging and the progress of infection was monitored by daily blood smears., Results: Several compounds had a pronounced effect on in vitro sporozoite gliding or morphology. Notably, monensin sodium potently affected sporozoite movement while gramicidin S resulted in rounding up of sporozoites. However, pre-treatment of mice with a topical gel containing gramicidin did not reduce sporozoite motility and infection., Conclusions: This approach shows that it is possible to screen libraries for inhibitors of sporozoite motility and highlighted the paucity of compounds in currently available libraries that inhibit this initial step of a malaria infection. Screening of diverse libraries is suggested to identify more compounds that could serve as leads in developing 'skin-based' malaria prophylactics. Further, strategies need to be developed that will allow compounds to effectively penetrate the dermis and thereby prevent exit of sporozoites from the skin.

Parasites causing malaria need to migrate in order to penetrate tissue barriers and enter host cells. Here we show that the actin filament-binding protein coronin regulates gliding motility in Plasmodium berghei sporozoites, the highly motile forms of a rodent malaria-causing parasite transmitted by mosquitoes. Parasites lacking coronin show motility defects that impair colonization of the mosquito salivary glands but not migration in the skin, yet result in decreased transmission efficiency. In non-motile sporozoites low calcium concentrations mediate actin-independent coronin localization to the periphery. Engagement of extracellular ligands triggers an intracellular calcium release followed by the actin-dependent relocalization of coronin to the rear and initiation of motility. Mutational analysis and imaging suggest that coronin organizes actin filaments for productive motility. Using coronin-mCherry as a marker for the presence of actin filaments we found that protein kinase A contributes to actin filament disassembly. We finally speculate that calcium and cAMP-mediated signaling regulate a switch from rapid parasite motility to host cell invasion by differentially influencing actin dynamics.

During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(-) or uis3(-) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(-) parasites protected better than uis3(-) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy.

Using the fast measurement of a binary transmission matrix and a digital micromirror device, we demonstrate high-speed interferometric focusing through highly dynamic scattering media with binary intensity modulation. The scanning of speckles for reference optimization gives stable focusing, which can be used for focusing through a fast changing media or two dimensional scanning through a slowly changing scattering media. The system allows dynamic focusing at 12.5 Hz with 1024 input modes, and more than 60 times intensity enhancement. It was tested with a moving diffuser, a mouse brain and skull tissue. The experiment with a live drosophila embryo shows its potential in compensating dynamic scattering in live biological tissue.

We report a technique for measuring and correcting the wavefront aberrations introduced by a biological sample using a Shack-Hartmann wavefront sensor, a fluorescent reference source, and a deformable mirror. The reference source and sample fluorescence are at different wavelengths to separate wavefront measurement and sample imaging. The measurement and correction at one wavelength improves the resolving power at a different wavelength, enabling the structure of the sample to be resolved.

Introduction: We tested the feasibility of a new technique of direct left ventricular endocardial lead placement across the aortic valve in a chronic (six month) pig model. The potential for aortic valve damage, systemic embolization, and pacing lead maturation and function within the left ventricle are unknown., Methods: Ten minipigs were successfully implanted with a transaortic left ventricular lead (Medtronic CapSureFix, Minneapolis, MN, USA) placed in the left ventricular apex via the carotid artery. Each pig received either a polyurethane (n = 5) or silicone (n = 5) lead. Post implant each pig received clopidogrel and aspirin for seven days. After six months all surviving pigs underwent thorough necropsy., Results: Each pig had adequate sensing (12.1 +/- 4 mV) and pacing thresholds (0.79 +/- 0.2 @ 0.5 V) at implant. Postoperatively two pigs died of a respiratory illness. One pig died postoperatively due to sepsis. At the six-month follow-up, all surviving pigs (n = 7) were in a healthy state. Of the pigs without dislodgement (n = 5) there was adequate sensing, but a rise in pacing thresholds. Echocardiography revealed a normal ejection fraction and only trace to mild aortic insufficiency in all pigs. Of the seven surviving pigs there were no thromboembolic events noted. One silicone lead was noted to have thrombosis along the lead screw and shaft., Conclusion: Direct transaortic placement of a left ventricular lead is feasible. After six months, there was no significant aortic regurgitation and no evidence of thromboembolism despite no anticoagulation. Lead function was acceptable and only one silicone lead (and no polyurethane lead) was noted to have significant thrombosis.

Focal epileptic seizures can be the first manifestation of a diabetic disorder. Metabolic disturbances, including hyperglycemia, mild hyperosmolality, hyponatremia, and lack of ketoacidosis contribute to the development of partial focal seizures. A review of the medical literature for partial focal seizures is presented, followed by a case study of a patient who developed clonic seizures of the right foot secondary to hyperglycemia, hyponatremia, and hyperosmolality.