Young guard cells function dynamically despite low mechanical anisotropy but gain efficiency during stomatal maturation in Arabidopsis thaliana.

Stomata are pores at the leaf surface that enable gas exchange and transpiration. The signaling pathways that regulate the differentiation of stomatal guard cells and the mechanisms of stomatal pore formation have been characterized in Arabidopsis thaliana. However, the process by which stomatal complexes develop after pore formation into fully mature complexes is poorly understood. We tracked the morphogenesis of young stomatal complexes over time to establish characteristic geometric milestones along the path of stomatal maturation. Using 3D-nanoindentation coupled with finite element modeling of young and mature stomata, we found that despite having thicker cell walls than young guard cells, mature guard cells are more energy efficient with respect to stomatal opening, potentially attributable to the increased mechanical anisotropy of their cell walls and smaller changes in turgor pressure between the closed and open states. Comparing geometric changes in young and mature guard cells of wild-type and cellulose-deficient plants revealed that although cellulose is required for normal stomatal maturation, mechanical anisotropy appears to be achieved by the collective influence of cellulose and additional wall components. Together, these data elucidate the dynamic geometric and biomechanical mechanisms underlying the development process of stomatal maturation.

Wolbachia depletion blocks transmission of lymphatic filariasis by preventing chitinase-dependent parasite exsheathment.

Lymphatic filariasis is a vector-borne neglected tropical disease prioritized for global elimination. The filarial nematodes that cause the disease host a symbiotic bacterium, Wolbachia, which has been targeted using antibiotics, leading to cessation of parasite embryogenesis, waning of circulating larvae (microfilariae [mf]), and gradual cure of adult infection. One of the benefits of the anti-Wolbachia mode of action is that it avoids the rapid killing of mf, which can drive inflammatory adverse events. However, mf depleted of Wolbachia persist for several months in circulation, and thus patients treated with antibiotics are assumed to remain at risk for transmitting infections. Here, we show that Wolbachia-depleted mf rapidly lose the capacity to develop in the mosquito vector through a defect in exsheathment and inability to migrate through the gut wall. Transcriptomic and Western blotting analyses demonstrate that chitinase, an enzyme essential for mf exsheathment, is down-regulated in Wolbachia-depleted mf and correlates with their inability to exsheath and escape the mosquito midgut. Supplementation of in vitro cultures of Wolbachia-depleted mf with chitinase enzymes restores their ability to exsheath to a similar level to that observed in untreated mf. Our findings elucidate a mechanism of rapid transmission-blocking activity of filariasis after depletion of Wolbachia and adds to the broad range of biological processes of filarial nematodes that are dependent on Wolbachia symbiosis.

PECTATE LYASE LIKE12 patterns the guard cell wall to coordinate turgor pressure and wall mechanics for proper stomatal function in Arabidopsis.

Plant cell deformations are driven by cell pressurization and mechanical constraints imposed by the nanoscale architecture of the cell wall, but how these factors are controlled at the genetic and molecular levels to achieve different types of cell deformation is unclear. Here, we used stomatal guard cells to investigate the influences of wall mechanics and turgor pressure on cell deformation and demonstrate that the expression of the pectin-modifying gene PECTATE LYASE LIKE12 (PLL12) is required for normal stomatal dynamics in Arabidopsis thaliana. Using nanoindentation and finite element modeling to simultaneously measure wall modulus and turgor pressure, we found that both values undergo dynamic changes during induced stomatal opening and closure. PLL12 is required for guard cells to maintain normal wall modulus and turgor pressure during stomatal responses to light and to tune the levels of calcium crosslinked pectin in guard cell walls. Guard cell-specific knockdown of PLL12 caused defects in stomatal responses and reduced leaf growth, which were associated with lower cell proliferation but normal cell expansion. Together, these results force us to revise our view of how wall-modifying genes modulate wall mechanics and cell pressurization to accomplish the dynamic cellular deformations that underlie stomatal function and tissue growth in plants.

Progesterone after mifepristone: A pilot prospective single arm clinical trial for women who have changed their mind after commencing medical abortion.

AIM: This pilot study aimed to assess the utility of an oral progesterone treatment protocol for women who commenced medical abortion and then changed their mind and wished instead to maintain their pregnancy. METHODS: The Progesterone-After-Mifepristone-pilot for efficacy and reproducibility (PAMper) trial was designed as a prospective single-arm pilot clinical trial, conducted via telehealth. Women aged 18 to 45 years in Australia who reported ingesting mifepristone within the last 72 h to initiate medical abortion and had not taken misoprostol were included. Initial contact was by a web-based form. Following informed consent, participants were prescribed oral progesterone to be taken 400 mg twice per day for 3 days then 400 mg at night until completion of a 19 day course. Pregnancy viability was assessed by ultrasound scan after 14 days of progesterone treatment. RESULTS: Between October 2020 and June 2021, nine women contacted the PAMper trial, of whom six enrolled and commenced progesterone treatment. These women reported ingesting mifepristone at 40-70 days of gestation, with progesterone being commenced within 5.7-72 h of mifepristone ingestion. Five participants had ongoing, live pregnancies at the primary endpoint (ultrasound at >2 weeks). One participant had a miscarriage after 9 days of progesterone treatment. There were no clinically significant adverse events. CONCLUSION: This small study demonstrated a clinically sound protocol for researching the use of progesterone-after-mifepristone for women in this circumstance. Results of this pilot study support the need for further larger scale trials in this field.

Conductive Polymer-Coated 3D Printed Microneedles: Biocompatible Platforms for Minimally Invasive Biosensing Interfaces.

Conductive polymeric microneedle (MN) arrays as biointerface materials show promise for the minimally invasive monitoring of analytes in biodevices and wearables. There is increasing interest in microneedles as electrodes for biosensing, but efforts have been limited to metallic substrates, which lack biological stability and are associated with high manufacturing costs and laborious fabrication methods, which create translational barriers. In this work, additive manufacturing, which provides the user with design flexibility and upscale manufacturing, is employed to fabricate acrylic-based microneedle devices. These microneedle devices are used as platforms to produce intrinsically-conductive, polymer-based surfaces based on polypyrrole (PPy) and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS). These entirely polymer-based solid microneedle arrays act as dry conductive electrodes while omitting the requirement of a metallic seed layer. Two distinct coating methods of 3D-printed solid microneedles, in situ polymerization and drop casting, enable conductive functionality. The microneedle arrays penetrate ex vivo porcine skin grafts without compromising conductivity or microneedle morphology and demonstrate coating durability over multiple penetration cycles. The non-cytotoxic nature of the conductive microneedles is evaluated using human fibroblast cells. The proposed fabrication strategy offers a compelling approach to manufacturing polymer-based conductive microneedle surfaces that can be further exploited as platforms for biosensing.

Protocol for mapping the variability in cell wall mechanical bending behavior in living leaf pavement cells.

Mechanical properties, size and geometry of cells, and internal turgor pressure greatly influence cell morphogenesis. Computational models of cell growth require values for wall elastic modulus and turgor pressure, but very few experiments have been designed to validate the results using measurements that deform the entire thickness of the cell wall. New wall material is synthesized at the inner surface of the cell such that full-thickness deformations are needed to quantify relevant changes associated with cell development. Here, we present an integrated, experimental-computational approach to analyze quantitatively the variation of elastic bending behavior in the primary cell wall of living Arabidopsis (Arabidopsis thaliana) pavement cells and to measure turgor pressure within cells under different osmotic conditions. This approach used laser scanning confocal microscopy to measure the 3D geometry of single pavement cells and indentation experiments to probe the local mechanical responses across the periclinal wall. The experimental results were matched iteratively using a finite element model of the experiment to determine the local mechanical properties and turgor pressure. The resulting modulus distribution along the periclinal wall was nonuniform across the leaf cells studied. These results were consistent with the characteristics of plant cell walls which have a heterogeneous organization. The results and model allowed the magnitude and orientation of cell wall stress to be predicted quantitatively. The methods also serve as a reference for future work to analyze the morphogenetic behaviors of plant cells in terms of the heterogeneity and anisotropy of cell walls.

Effect of inclined positioning on first-pass success during endotracheal intubation: a systematic review and meta-analysis.

BACKGROUND: Endotracheal intubation is a high-risk procedure. Optimisation of all aspects of the procedure, including patient positioning, is important to facilitate success and minimise complications. The objective of this systematic review was to determine the association between inclined patient positioning and first-pass success and other clinically important outcomes among patients undergoing endotracheal intubation. METHODS: A search of PubMed, CINAHL, SCOPUS, EMBASE and Cochrane, from inception through October 2020 was conducted. Studies were assessed independently by two authors to determine eligibility for inclusion. Included studies were any randomised or observational study that compared supine to inclined patient positioning for endotracheal intubation and assessed one of our predefined outcomes. Simulation studies were excluded. Study results were meta-analysed using a random effects model. The quality of the evidence for outcomes of interest was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: A total of 5113 studies were identified, of which 10 studies representing 18 371 intubations were included for meta-analysis. There was no statistically significant difference in the primary outcome of first-pass success rate (relative risk 1.02, 95% CI 0.98 to 1.05) or secondary outcomes of oesophageal intubation, glottic view, hypotension, hypoxaemia, mortality or peri-intubation arrest. Likewise, there were no statistically significant differences in any of the outcomes in predefined subgroup analyses of randomised controlled trials, intubations in acute settings or intubations performed with >45 degrees of incline. Overall quality of evidence was rated as low or very low for most outcomes. CONCLUSIONS: This systematic review and meta-analysis found no evidence of benefit or harm with inclined versus supine patient positioning during endotracheal intubation in any setting.

Cell twisting during desiccation reveals axial asymmetry in wall organization.

Plant cell size and shape are tuned to their function and specified primarily by cellulose microfibril (CMF) patterning of the cell wall. Arabidopsis thaliana leaf trichomes are unicellular structures that act as a physical defense to deter insect feeding. This highly polarized cell type employs a strongly anisotropic cellulose wall to extend and taper, generating sharply pointed branches. During elongation, the mechanisms by which shifts in fiber orientation generate cells with predictable sizes and shapes are unknown. Specifically, the axisymmetric growth of trichome branches is often thought to result from axisymmetric CMF patterning. Here, we analyzed the direction and degree of twist of branches after desiccation to reveal the presence of an asymmetric cell wall organization with a left-hand bias. CMF organization, quantified using computational modeling, suggests a limited reorientation of microfibrils during growth and a maximum branch length limited by the wall axial stiffness. The model provides a mechanism for CMF asymmetry, which occurs after the branch bending stiffness becomes low enough that ambient bending affects the principal stresses. After this stage, the CMF synthesis results in a constant bending stiffness for longer branches. The bending vibration natural frequencies of branches with respect to their length are also discussed.

Eosinophil-Mediated Immune Control of Adult Filarial Nematode Infection Can Proceed in the Absence of IL-4 Receptor Signaling.

Helminth infections are accompanied by eosinophilia in parasitized tissues. Eosinophils are effectors of immunity to tissue helminths. We previously reported that in the context of experimental filarial nematode infection, optimum tissue eosinophil recruitment was coordinated by local macrophage populations following IL-4R-dependent in situ proliferation and alternative activation. However, in the current study, we identify that control of chronic adult filarial worm infection is evident in IL-4Rα-deficient (IL-4Rα-/-) mice, whereby the majority of infections do not achieve patency. An associated residual eosinophilia was apparent in infected IL-4Rα-/- mice. By treating IL-4Rα-/- mice serially with anti-CCR3 Ab or introducing a compound deficiency in CCR3 within IL-4Rα-/- mice, residual eosinophilia was ablated, and susceptibility to chronic adult Brugia malayi infection was established, promoting a functional role for CCR3-dependent eosinophil influx in immune control in the absence of IL-4/IL-13-dependent immune mechanisms. We investigated additional cytokine signals involved in residual eosinophilia in the absence IL-4Rα signaling and defined that IL-4Rα-/-/IL-5-/- double-knockout mice displayed significant eosinophil deficiency compared with IL-4Rα-/- mice and were susceptible to chronic fecund adult filarial infections. Contrastingly, there was no evidence that either IL-4R-dependent or IL-4R-independent/CCR3/IL-5-dependent immunity influenced B. malayi microfilarial loads in the blood. Our data demonstrate multiplicity of Th2-cytokine control of eosinophil tissue recruitment during chronic filarial infection and that IL-4R-independent/IL-5- and CCR3-dependent pathways are sufficient to control filarial adult infection via an eosinophil-dependent effector response prior to patency.

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

Influence of tessellation morphology on ultrasonic scattering.

Material properties, such as hardness, yield strength, and ductility, depend on the microstructure of the material. If the microstructural organization can be quantified nondestructively, for example, with ultrasonic scattering techniques, then it may be possible to predict the mechanical performance of a component. Three-dimensional digital microstructures have been increasingly used to investigate the scattering of mechanical waves within a numerical framework. These synthetic microstructures can be generated using different tessellation algorithms that result in different grain shapes. In this study, the variation of ultrasonic scattering is calculated for microstructures of different morphologies for a nickel polycrystal. The ultrasonic properties are calculated for the Voronoi, Laguerre tessellations, and voxel-based synthetic microstructures created by DREAM.3D. The results show that the differences in the two-point statistics and ultrasonic attenuation for different morphologies become more significant at wider size distributions and higher frequencies.

High-Pressure Injection Injury to the Hand With Resulting Pneumomediastinum: A Case Report.

BACKGROUND: High-pressure injection injury is an uncommon but potentially limb-threatening presentation that in many cases should be treated as a surgical emergency. CASE REPORT: We present a 46-year-old patient with a high-pressure injection injury from SCUBA equipment who developed pneumomediastinum. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: High-pressure injection injuries are rare and may have significant morbidity. Injection injuries from air are uncommon, may be managed differently than injection with other materials, and may be associated with unique complications.

Onchocerca ochengi male worms implanted in SCID mice and Gerbil: Relationship between microfilaridermia status of cows, nodular worm viability and fertility and worm survival in the rodents.

BACKGROUND: Current treatment options for onchocerciasis are sub-optimal, prompting research and development of a safe cure (macrofilaricide). Onchocerca ochengi, a parasite of cattle, is used as a close surrogate for the human parasite O. volvulus in a murine model for pre-clinical screening of macrofilaricides. Skin from naturally infected cattle have been used in previous studies as a reliable source of parasite material. However, there is limited knowledge on how source-related factors such as the microfilaridermia status of the cattle, the nodule load and nodular worm viability may affect survival of male O. ochengi worms implanted in the rodent hosts. Such relationships were investigated in this study. METHODS: Dermal tissue and nodules were obtained from Gudali cattle, dissected and cultured to obtain migrating microfilariae (mf) and male worms. Emerged male worms were implanted into SCID mice and Gerbils (Meriones unguiculatus) and recovery rates were determined upon 42 days post implantation. Finally, nodules were processed for histology and embryogram analyses to assess the nodular worm viability and fertility, respectively. RESULTS: Of the 69 cattle sampled, 24 (34.8%) were mf+ and 45 (65.2%) were mf-. The mean nodule loads were 180.5 ± 117.7 (mf+) and 110.6 ± 102.7 (mf-) (p = 0.0186). The mean male worm harvest from nodules were 76.8 ± 120.3 and 47.2 ± 33.4 (p = 0.2488) for mf+ and mf- cattle, respectively. The number of male worms per 100 nodules were 57/100 and 46/100 nodules for mf+ and mf- cows, respectively. Female worms from nodules of mf- cows had higher counts of both normal and abnormal embryos with higher proportions of dead nodular worms evinced by histology compared to those from mf+ cows. A total of 651 worms were implanted into mice and gerbils, out of which 129 (19.81%) were recovered. Logistic regression analysis indicated that the microfilaridermia status of the cattle (presence of mf) (OR = 4.3319; P = 0.001) is the single most important predictor of the success of male worm recovery after implantation into rodents. CONCLUSION: Microfilaridermic cattle provide a promising source of adult O. ochengi. Male worms from this group of cattle have a better success rate of survival in a murine implant model. Nevertheless, in the programmatic point of view, amicrofilaridermic Gudali cattle would still constitute an important source of O. ochengi male worms with relatively good viability after implantation into rodents.

Frequency of safety net errors in the emergency department: Effect of patient handoffs.

OBJECTIVES: The objective of this study was to determine physician awareness of abnormal vital signs and key clinical interventions (oxygen provision, intravenous access) in the emergency department, and to measure the effect of patient handoffs on this awareness. METHODS: This was a prospective observational study at two large, urban, academic emergency departments. Emergency department physicians were asked the following about each of the physician's patients: 1) the number of IV lines, 2) whether the patient was on supplemental oxygen, and 3) whether the patient had any abnormal vital signs. Physicians were blind to the nature of the study prior to enrollment. Error rates between physician responses and actual patient status were calculated, and logistic regression, adjusted for physician clustering, was used to calculate association of errors with multiple situational factors, including handoff status. RESULTS: We analyzed 463 patient encounters from 74 physicians. Physicians missed abnormal vital signs in 19.4% of encounters. They made errors in oxygen status and number of IV lines in 16.6% and 35.8% of encounters, respectively. Physicians were significantly more likely to make all types of errors on patients who had undergone handoff as opposed to their primary patients. CONCLUSION: Emergency physicians make frequent errors regarding awareness of their patients' vital signs, oxygen and vascular status and patient handoffs are associated with an increased frequency of such errors.

Misrepresentation of contraceptive effectiveness rates for fertility awareness methods of family planning.

AIM: Simplified contraceptive method-efficacy and/or typical-use effectiveness rates are commonly used for direct comparison of the various contraceptive methods. Use of such effectiveness rates in this manner is, however, problematic in relation to the fertility awareness methods (FAMs). The aim of this review is to critically examine current international representation of contraceptive effectiveness for the various FAMs in clinical use. This review also details important issues when appraising and interpreting studies on FAMs used for avoiding pregnancy. METHODS: Current international literature regarding contraceptive effectiveness of FAMs was surveyed and appraised. This included World Health Organization and Centers for Disease Control (USA) resources, key clinical studies and recent systematic reviews. Chinese literature was also searched, since these data have not been reported in the English literature. RESULTS: Reliance on certain historical studies has led to the misrepresentation of contraceptive effectiveness of FAMs by perpetuation of inaccurate figures in clinical guidelines, the international literature and the public domain. Interpretation of published study results for FAMs is difficult due to variability in study methodology and other clinical trial quality issues. Recent systematic analyses have noted the considerable issues with study designs and limitations. Several non-English published studies using the Billings Ovulation Method have demonstrated that a broader review of the literature is required to better capture the data potentially available. CONCLUSION: A deeper understanding by clinicians and the public of the applicability of contraceptive effectiveness rates of the various FAMs is needed, instead of reliance on the inaccurate conglomerate figures that are widely presented.

Propagation of leaky Rayleigh waves along a curved fluid-solid interface.

A characteristic equation is derived for a leaky Rayleigh wave (LRW), propagating on a curved fluid-solid interface. The equations of motion for the curved solid and fluid are formulated using the constitutive equations of a homogenous isotropic curved solid and an inviscid fluid, respectively. The displacement potential functions are used to simplify the derivation. The interface conditions are used to ensure continuities of the mass, momentum, and energy across the interface. Then, with the consideration of the interface radius of the curvature, the characteristic equation for the LRW is established and solved numerically by Muller's method. One important outcome is that there is weaker directional dependence for the velocity of the LRWs on the radius of curvature in comparison with the Rayleigh waves at an air-solid interface. However, the numerical results show a strong directional dependence for the attenuation due to the LRW leakage on the complex curvatures. Moreover, a quantitative relation between the curvature and attenuation caused by the leakage for different materials is shown. The results are significant especially with respect to relevant future applications of ultrasonic testing.

Ultrasound in situ characterization of hybrid additively manufactured Ti6Al4V.

A major barrier for the full utilization of metal additive manufacturing (AM) technologies is quality control. Additionally, in situ real time nondestructive monitoring is desirable due to the typical high value and low volume of components manufactured with metal AM. Depending on the application, characteristics such as the geometrical accuracy, porosity, defect size and content, and material properties are quantities of interest for in situ nondestructive evaluation (NDE). In particular, functionally tailored components made with hybrid processing require quantitative NDE of their microstructure and elastic properties. Ultrasonic NDE is able to quantify these relevant characteristics. In this work, an ultrasonic measurement system is used to collect in situ real time measurements during the manufacturing of samples made with a hybrid process, which combines directed energy deposition with milling. In addition to quantifying ultrasonic properties, the measurements are used to gather insight on other geometry, material, and process effects. The results show the utility of ultrasound to evaluate relevant properties during manufacturing of a functionalized material domain, while providing perspective on additional material evolution information obtained from ultrasonic signals.

Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia.

Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection.

Characterization of E-cigarette coil temperature and toxic metal analysis by infrared temperature sensing and scanning electron microscopy - energy-dispersive X-ray.

INTRODUCTION: Electronic cigarettes (e-cigarettes) have rapidly evolved since their introduction to the U.S. market. The rebuildable atomizer (RBA) offers user-driven modification to the heating element (coil) and wicking systems. Different coil materials can be chosen based on user needs and preferences. However, the heating element of an e-cigarette is believed to be one-source for toxic metal exposure. METHODS: E-cigarette coils from Kanthal and nichrome wires were constructed in a contact and non-contact configuration and heated at four voltages. The maximum temperatures of the coils were measured by infrared temperature sensing when dry and when saturated with 100% vegetable glycerin or 100% propylene glycol. The metal composition of each coil was analyzed with Scanning Electron Microscopy-Energy-Dispersive X-Ray (SEM-EDX) when new, and subsequently after 1, 50, and 150 heat cycles when dry. RESULTS: The coils reached temperatures above 1000 °C when dry, but were below 300 °C in both liquid-saturated mediums. Metal analysis showed a decrease of 9-19% chromium and 39-58% iron in Kanthal wire and a decrease of 12-14% iron and 39-43% nickel in nichrome wire after 150 heat cycles. Significant metal loss was observed after one heat cycle for both coil alloys and configurations. CONCLUSIONS: The loss of metals from these heat cycles further suggests that the metals from the coils are potentially entering the aerosol of the e-cigarette, which can be inhaled by the user.

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis.

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.