RNA from paramyxoviruses, coronaviruses and filoviruses. Paramyxovirus RNA was detected in 4 of 248 (1%) and 11 of 222 (4.9%) bat faecal and urine samples, respectively. Coronavirus RNA was detected in 55 of 248 (22%) of bat faecal samples; filovirus RNA was not detected in any of the bat samples. Further, coronavirus RNA was detected in 12 of 270 (4.4%) of rat faecal samples; all samples tested negative for paramyxovirus. Phylogenetic analysis revealed that the bat paramyxoviruses and bat and rat coronaviruses were related to viruses circulating in bat and rodent populations globally, but showed no cross‐species mixing of viruses between bat and rat populations within Viet Nam. Our study shows that potentially novel variants of paramyxoviruses and coronaviruses commonly circulate in bat and rat populations in Viet Nam. Further characterization of the viruses and additional human and animal surveillance is required to evaluate the likelihood of viral spillover and to assess whether these viruses pose a risk to human health.Bats and rodents are being increasingly recognized as reservoirs of emerging zoonotic viruses. Various studies have investigated bat viruses in tropical regions, but to date there are no data regarding viruses with zoonotic potential that circulate in bat and rat populations in Viet Nam. To address this paucity of data, we sampled three bat farms and three wet markets trading in rat meat in the Mekong Delta region of southern Viet Nam. Faecal and urine samples were screened for the presence of  Bats and rodents are known reservoirs of highly diverse viral and bacterial populations, and a number of these viruses have been implicated in the emergence of novel infectious diseases in humans.The close proximity of humans to bat and rodent populations in South‐East Asia creates frequent opportunities for viral spillover and thus poses an unknown risk to human health.Viral surveillance in animal reservoirs is an important step to understanding the exposure of humans to potential zoonoses, the types of human–animal interaction that impact potential for spillover infection and the factors that determine the transmissibility and pathogenicity of viral zoonoses in humans.1A large proportion of the agents of emergent infectious disease have a zoonotic origin. These zoonotic pathogens fall into a wide spectrum of genera, but due to their high genetic variability and wide circulation, RNA viruses arguably pose the most significant threat to human health. Further, due to the close proximity between animals and humans in low‐ and middle‐income countries, human populations in these locations are disproportionally at risk of exposure from these viral pathogens , thus increasing the likelihood of exposure to infectious agents  rather than individual bats were targeted for screening; three bat guano farms were identified in three geographically distinct sampling locations in the south of Viet Nam. These farms were selected because they were the only bat guano farms identified and consenting to participate in regular sampling within the catchment area for Dong Thap Provincial Hospital, a primary site of ongoing human sampling for the identification of zoonotic infections under the VIZIONS project , Rattus argentiventer (n = 234), Rattus losea (n = 20) and Rattus tanezumi (n = 8).The rodent surveys and sampling were conducted as previously described by Van Cuong et al. . Briefly2.3Total nucleic acid was extracted from the bat urine, bat faecal and rat faecal samples using an automated extracted system  with MagNA Pure 96 Viral RNA Small Volume Kits (Roche). Following extraction, nucleic acid samples were screened for target viruses using pan‐family primers for paramyxoviruses, coronaviruses and filoviruses. The primer sequences of viral targets and the nested PCR conditions were as previously described , a 153‐sequence data set for alphacoronaviruses and a 93‐sequence data set for betacoronaviruses , using Seqotron  bat faecal samples and 11 of 222 (4.9%) urine samples tested positive for paramyxovirus RNA. The paramyxovirus‐positive faecal samples were identified in sampling round two on a single farm and in sampling round three on two farms. The positive urine samples were detected on three bat guano farms during the sixth round of sampling. Screening of bat faeces and urine for coronaviruses indicated that 55 of 248 (22.2%) of faecal samples were positive for coronavirus RNA; none of the urine samples contained detectable coronavirus RNA. Coronavirus RNA was detected in bat faecal samples isolated from all three sampled farms at all of the sampling time points. The bat urine and faecal samples were also screened for filoviruses, but no PCR amplification for filovirus RNA was detected despite amplification of appropriate controls. Specific information on coronavirus and paramyxovirus positivity by sampling site, time and species is indicated in Tables 3.2R. argentiventer.Of the 270 rat faecal samples screened for coronaviruses and paramyxoviruses, 12 of 270 (4.4%) were positive for coronavirus RNA, while none of the samples had detectable paramyxovirus RNA. The cDNA amplicons were sequenced and all twelve positive samples produced sequences suitable for phylogenetic analysis. Notably, all coronavirus‐positive faecal samples were obtained from rats of one species, 3.3Fifteen RNA sequences obtained from the bat paramyxovirus RNA‐positive samples   of 21 insectivorous and fruit‐eating bat species sampled . Our sampling was further limited by the use of faecal and urine samples, which are unlikely to be optimum materials in which to detect filoviruses. Thus, a much larger and more comprehensive sampling of multiple bat species using more direct sampling methods would be necessary to detect and understand the potential circulation of filoviruses in the region.Although none of the bat samples tested in this study indicate the presence of filoviruses, this does not provide conclusive evidence that these viruses are not circulating in Viet Nam. While fruit bats have been implicated as the primary reservoirs of filoviruses, a previous survey of multiple bat species in the Philippines confirmed Ebola Reston virus infection in one insectivorous bat species . These data do not exclude the possibility that other rat species carry this coronavirus virus, particularly as our sampling was biased towards R. argentiventer (234/270).In contrast to previous investigations (Woo et al., Despite a lack of appropriate control measures for zoonotic viruses in Viet Nam, viral spillover from bats and/or rats has not, as yet, been observed, although these preliminary findings suggest that both coronaviruses and paramyxoviruses may be endemic in Vietnamese bat populations. While we are unable to comment on the pathogenic potential of these novel viruses in humans, it is likely that if such infections do arise, they are rare and go undiagnosed. Paramyxoviruses in particular are known to cause infections in humans, and the spillover of Hendra virus and Nipah virus from bats to horses or pigs, respectively, and subsequently to humans has been reported in Australia and Malaysia (Edson et al., In conclusion, we have detected the presence of bat paramyxoviruses, bat coronaviruses and rodent‐associated coronaviruses within a limited geographic area and time frame in Viet Nam. Consequently, we suggest that larger‐scale surveillance is needed to fully understand the role played by rodents and bats in the evolution, emergence and dissemination of paramyxoviruses and coronaviruses in Viet Nam.The authors state that they have no competing interests. Click here for additional data file.


The purpose of this study was to evaluate the visibility and artifact created by gold, carbon, and polymer fiducial markers in a simple phantom across computed tomography (CT), kilovoltage (kV), and megavoltage (MV) linear accelerator imaging and MV tomotherapy imaging. Three types of fiducial markers  were investigated for their visibility and artifacts in images acquired with various modalities and with different imaging parameters . The imaging modalities include kV CT, 2D linac‐based kilovoltage and megavoltage X‐ray imaging systems, kV cone‐beam CT, and normal and fine tomotherapy imaging. The images were acquired on a phantom constructed using Superflab bolus in which markers of each type were inserted into the center layer. The visibility and artifacts produced by each marker were assessed qualitatively and quantitatively. All tested markers could be identified clearly on the acquired CT and linac‐based kV images; gold markers demonstrated the highest contrast. On the CT images, gold markers produced a significant artifact, while no artifacts were observed with polymer markers. Only gold markers were visible when using linac‐based MV and tomotherapy imaging. For linac‐based kV images, the contrast increased with kV and mAs values for all the markers, with the gold being the most pronounced. On CT images, the contrast increased with kV for the gold markers, while decreasing for the polymer and carbon marker. With the bolus phantom used, we found that when kV imaging‐based treatment verification equipment is available, polymer and carbon markers may be the preferred choice for target localization and patient treatment positioning verification due to less image artifacts. If MV imaging will be the sole modality for positioning verification, it may be necessary to use gold markers despite the artifacts they create on the simulation CT images.PACS number: 87 Inter‐ and intrafractional target motion has been observed in radiation oncology treatment therapy of various disease sites.Image‐guided radiotherapy (IGRT) has been increasingly used in the radiation treatment of cancer patients to assist with correcting inter‐ and intrafractional motion. Various techniques of IGRT have been explored including transabdominal ultrasound,Fiducial markers have been used in radiotherapy to assist with the registration process.To address these unknowns and to provide guidelines on the selection of an optimal type of fiducial makers for a given imaging modality, this study was designed to evaluate the impacts of fiducial markers constructed of different materials on the image quality of several commonly used imaging modalities.30×31×15 cm3 phantom was constructed using 2 cm thick layers of Superflab bolus . The near‐constant density of the Superflab phantom allowed us to quantify the artifacts introduced purely by the fiducial markers without the inconsistencies and artifacts of patient anatomy. Three of each type of the tested fiducial markers were inserted into the central layer of the phantom and were placed about 5 cm apart from each other. The phantom was then imaged under the following conditions: 3D CT imaging with the GE CT simulator ; 2D kV imaging with the linac‐based OBI system ; 3D linac‐based OBI kV cone‐beam CT ; 2D MV X‐ray imaging (1 and 2 MU) using the linac‐based MV portal imager; and the normal and fine 3D MV imaging with the TomoTherapy Hi•Art system.Cylindrical fiducial markers made of gold, carbon, and polymer  were evaluated. These types of fiducial markers have been used clinically or are being approved for clinical use. The diameters and lengths of the gold, carbon, and polymer markers are 0.9 and 3 mm, 1 and 3 mm, 1 and 5 mm, respectively. The evaluated imaging modalities include a GE LightSpeed 16 CT simulator , a linac‐based on‐board imaging (OBI) system , a linac‐based MV portal imaging system , and a MV 3D imaging system from a TomoTherapy Hi•Art treatment system . A simple Qualitative and quantitative assessments of the visibility and artifacts produced by each marker were performed. To determine the visibility of each marker, a 15 cm by 15 cm area profile was drawn around each marker using the Eclipse treatment planning system's off‐line review image analysis tools , and the statistical information within that area was used to calculate the contrast‐to‐noise ratio. The contrast‐to‐noise ratio (CNR) is defined as, where is the maximum signal intensity produced by the markers, is the average background signal intensity, and is the standard deviation of the background noise. The maximum signal intensity was used to insure that the most visible part of each marker was recorded and analyzed. To quantitatively analyze the artifacts created by each marker, the standard deviation of the pixel values along a ring of increasing radius around each marker on a 2D image was computed. One thousand rings with radiuses ranging from 1 to 15 mm around each seed were used.Figures –(c) dispThe pixel value distributions were measured for 1000 rings with radii ranging from 1 to 15 mm around each seed on the CT images acquired at 120 kVp and 1.25 mm slice thickness, and their standard deviations were computed for each ring. Figure Figures –(e) showOnly the gold fiducial markers were visible on the linac‐based 2D MV images , as kVp increases, the photon material interaction probability tends to become similar among materials of different Z per mass (in the Compton range) or approximately proportional to Z per thickness. On the other hand, since photoelectric interaction probability is proportional to Z3, although increase of kVp increases the probability of Compton interaction, at a certain kVp range, that increase may be slower in high‐Z materials, such as gold, than the surrounding phantom material, causing there to be more photoelectric interactions in the high‐Z material than the surrounding materials and leading to an increase in the contrast. For the carbon and polymer markers, since their Z values are close to the surrounding material, the increase of kVp increases the Compton interactions in a similar rate for the markers and the medium, leading to a decrease in the contrast. This phenomenon indicates that the impact of fiducial markers on the CT image quality can be adjusted for the gold type by adjusting CT parameters, but not substantially for the carbon and polymer type of markers. When kV imaging‐based treatment verification equipment is available, polymer and carbon markers may be the preferred choice for target localization and patient treatment positioning verification because they produce fewer artifacts than gold markers on the simulation CT images but are still clearly identifiable on the kV verification images. If MV imaging will be the sole modality for positioning verification, including both linac‐based MV portal imaging and tomotherapy MVCT imaging, it may be necessary to use gold markers despite the artifacts they create on the simulation CT images, because the carbon and polymer markers cannot be clearly identified without any ambiguity.Comparing three types of fiducial markers, our study showed that the contrast of gold markers was highly dependent on CT slice thickness and significantly increased with the increase of X‐ray kVp and slice thickness until it reached a limit. Conversely, the contrasts of carbon and polymer markers showed little variations with the X‐ray kVp and slice thickness. In the kV range, if photoelectric interactions dominate, the materials with higher atomic number Z absorb more photons leading to significant contrast differences among materials of different Z. The photoelectric interaction probability is approximately proportional to Aside from affecting organ delineation during treatment planning and patient setup, the artifacts from fiducial markers can also cause perturbation of the dose distribution in the patient. One experimental study found that in a phantom embedded with a gold seed and irradiated with a 6 MV photon beam, there was about a 21% increase in dose 0.35 mm proximal to the gold seed and about a 22% decrease distal to the seed.Metal artifact reduction (MAR) methods have been employed to improve CT image quality when gold marker‐introduced image artifacts are presentThere are several limitations in the current study. First, images were only acquired and examined on a cubic phantom constructed from a bolus material. Therefore, the results of this study may be only applicable to soft tissue and not necessarily valid for cases where the fiducial markers are placed inside or near bone or lung. The near constant density bolus phantom allowed us to quantify the artifacts purely introduced by the fiducial markers and exclude effects from patient anatomy. Another limitation of the study is that the examinations were performed on digital images acquired by imaging modalities manufactured by a limited number of vendors. Since the quality of digital images may be very dependent on methods of signal detection and image reconstruction, the results may be different for similar types of imaging devices of different models. A clinic may want to perform their own similar study with the imaging modalities utilized in their department using several types of fiducial markers.Our data show the dependence of three selected fiducial marker materials on various imaging parameters and can serve as guidelines for marker type selection under a certain IGRT environments. It can also serve as guidelines for the improvement of imaging quality by adjusting certain imaging parameters when markers are present. It is recommended that this study be used as a starting point for future studies using patient data or a phantom more anatomical similar to a human. With the uniform bolus phantom used, we found that when kV imaging‐based treatment verification equipment is available, polymer and carbon markers may be the preferred choice for target localization and patient treatment positioning verification due to less image artifacts. If MV imaging is the sole modality used for positioning verification, it may be necessary to use gold markers despite the artifacts they create on the simulation CT images. In a clinic where mixed kV and MV‐based imaging schemes are used, additional evaluations may be needed, depending on the imaging energy levels available and specific techniques used, to identify an optimal combination with the chosen fiducial markers.


Induction of labour is carried out worldwide for a broad range of maternal and fetal indications, so as to improve pregnancy outcomes. Oral misoprostol has been widely discussed as a method of labour induction. It is recommended for this indication by the World Health Organization (WHO), the International Federation of Gynecology and Obstetrics (FIGO), and the Society of Obstetricians and Gynaecologists of Canada (SOGC).μg) and frequency of administration (1–6 hourly). Some protocols use a single dose for the whole induction period, whereas others escalate the dose until the desired effect is achieved. Some use misoprostol purely for cervical ripening and replace it with an oxytocin infusion once membrane rupture is feasible, whereas others use oral misoprostol continuously until delivery. But the variation doesn't stop there. Until recently there was no commercially produced low‐dose misoprostol tablet, and so clinicians developed their own ways of preparing and administering the intended dose. Some practitioners divided the small and notoriously crumbly 200‐ or 100‐μg tablets into fragments. Others made up 1‐μg/ml solutions by dissolving tablets in tap water. It is only recently that commercially available 25‐μg tablets have become available , but these are not yet widely available.‘Oral misoprostol’, however, is not a single entity and systematic reviewers have struggled to cope with the wide variation in protocols Table . Publishμg.μg, even if they may result in a slower induction process. This is supported by a systematic review of just the studies that used 20–25 μg of oral misoprostol, which found lower caesarean section and lower hyperstimulation rates compared with standard induction methods.μg tablets or solution, high‐quality 25‐μg tablets are now available. Findings from a non‐inferiority randomised controlled trial (RCT) of oral misoprostol 50mcg versus Foley catheter for induction of labour showed equivalent safety and effectiveness,μg) has recently been found to be more an effective than Foley catheter when given orally in a large Medical Research Council (MRC) labour induction study.Is there evidence to suggest that any of these protocols are superior? Subgroup analyses of some important clinical outcomes show a clear dose effect. For example, when comparing oral misoprostol with dinoprostone, the rate of hyperstimulation increases as the initial dose rises from 25 to 200 The use of regimens in which misoprostol is given every 2 hours is supported by pharmacokinetic studies that show that oral misoprostol reaches its peak serum level within 30 minutes, but that its half‐life is only 90 minutes as misoprostol acid is rapidly metabolised by the liver and excreted by the kidneys.It remains untested whether the low dose of oral misoprostol will perform better if titrated to clinical response, and whether there are benefits of continuing its use through to the end of labour. Most studies have used oxytocin to continue with the induction process once cervical ripening is complete. There is no question that there are considerable logistic and safety challenges with both approaches, particularly in low‐resource settings.μg solution given every 2 hours, which found no difference in major outcomes, but reduced rates of hyperstimulation in the misoprostol group.Oxytocin infusions are notorious for causing hyperstimulation, especially when, as in many parts of the world, they are used without electronic rate controllers. In settings where labour ward staff numbers are very limited, an oxytocin infusion can run unsupervised for many hours without a member of staff checking on its rate or effect on uterine contractions.μg tablet licensed for labour induction would therefore be a major advance and would provide a definitive protocol. Until that time we recommend the use of 25‐μg tablets or solution used every 2 hours. It appears to be safe to use it up to the time of birth rather than simply for cervical ripening; however, use of this ‘extended’ protocol should include close observation and the use of acute tocolytics when hyperstimulation is suspected. There are no direct comparisons of the extended protocol with the standard regimen, nor of the stepped increase in misoprostol dose up to 50 μg. However, they appear to be safe and effective in studies in which they have been used. More research is required into ways of reducing adverse outcomes in high‐risk groups (nulliparous women or those with a scarred uterus), potentially using a combination of mechanical and uterotonic methods.What is the way forward? Although off‐label drug use remains essential in pregnancy , clinicians continue to worry about using an off‐label drug when labelled alternatives are available. The development or import of a commercially available 25‐Ideally, formal pharmacokinetic studies would help to clarify the differences between tablets and oral solution, and to establish the optimal frequency of the lowest effective dose. Regrettably, such studies are unlikely to be supported by pharmaceutical companies as misoprostol is too cheap to justify the investment. Also, the association of misoprostol with termination of pregnancy does not help, despite the fact that its uterotonic properties are life‐saving in many low‐resource settings. Whether public funders in high‐resource settings will rise to the challenge remains to be seen. A large study of a combination of titrated low dose oral misoprostol followed by oxytocin in active phase of labour versus titrated oral misoprostol alone given until birth seems an obvious way forwards.Full disclosure of interests available to view online as supporting information.ZA had the original idea for the article. The first draft was written by ADW, with KN contributing research on the doses used. All authors contributed with further editing and approved the final version.There was no specific funding source for this work.None required. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Owning to their very high theoretical capacity, lithium metal anodes are expected to fuel the extensive practical applications in portable electronics and electric vehicles. However, unstable solid electrolyte interphase and lithium dendrite growth during lithium plating/stripping induce poor safety, low Coulombic efficiency, and short span life of lithium metal batteries. Lately, varies of micro/nanostructured lithium metal anodes are proposed to address these issues in lithium metal batteries. With the unique surface, pore, and connecting structures of different nanomaterials, lithium plating/stripping processes have been regulated. Thus the electrochemical properties and lithium morphologies have been significantly improved. These micro/nanostructured lithium metal anodes shed new light on the future applications for lithium metal batteries. The commercial applications of safe graphite anode in 1990s has sidelined lithium metal anode. However, recently, the high energy density lithium metal batteries have been regarded as among the most promising next‐generation batteries. Compared with the researches in 20Due to the well‐designed structures of all sorts of nanomaterials, micro/nanostructured lithium metal anodes have a lot of properties which are superior to that of the ordinary lithium metal anodes: FigureA family of micro/nanostructured lithium metal anode with different properties has been proposed to investigate and regulate the lithium plating/stripping in working rechargeable lithium metal‐based batteries. Here, some typical micro/nanostructured lithium metal anodes are reviewed based on different types of micro/nanostructures: 2Lithium ions get electrons at the active surface of the current collector and plate onto it during the lithium plating process, while in the lithium stripping process, lithium atoms loss electrons in turn and are dissolved into the electrolyte. It is obvious that a high electronic conductivity is highly required for the current collector. Therefore, among the various nanomaterials, the conductive nanomaterial is the first one to be considered and widely used as a current collector framework in lithium metal anode. The schematic diagram of conductive micro/nanostructured framework is showed in Figure D is the ambipolar diffusion coefficient, e is the electronic charge, J is the effective electrode current density, ta is the anionic transference number, C0 is the initial lithium ionic concentration.J leads to the larger Sand's time τ. Therefore, the formation of lithium dendrite will be delayed and even inhibited with low effective current density.Sand's time model has been proposed to describe the initial nucleation process for lithium dendrite growth as follows: The surface structure of the conductive micro/nanostructured framework is used to accommodate the plating of lithium metal due to its high electrical conductivity. With the high specific surface area of conductive nanomaterials, the active surface area for lithium plating is several orders of magnitude higher than ordinary lithium plate anode. As a result, when conducted at the same electrode current density, the local current density and local deposition rate of lithium atoms on the actually effective surface are significantly decreased.Some typical conductive nanomaterials including carbon‐based nanomaterials, metal‐based nanomaterials and porous lithium framework are introduced below.2.1Figure−1  and an excellent reversibility for over 1000 charge/discharge cycles with the Coulombic efficiencies above 99%.Koratkar and co‐workers described a thermally reduced, free‐standing porous graphene networks as high‐capacity nanostructured lithium metal anode Figure2a. The−2. They proposed that the unblocked ionic pathways and high electronic conductivities of graphene framework in the nanostructured anode led to the rapid transfer of lithium ions through the SEI layer and endowed the graphene‐based anode with an ionic conductivity of 7.81 × 10−2 mS cm−1.−5 mA cm−2, ten thousandth of that on routine Cu foil‐based anode at the same electrode current density (0.5 mA cm−2). Therefore, the dendrite‐free morphology after lithium plating was received. It was confirmed by controlled experiments and SEM images that the dendrite‐free morphology was induced by the ultralow local current density. Besides, the high pore volume has also endowed such nanostructured lithium metal anode with a high stable cycle capacity of 5 mA h cm−2.A distinctive graphene framework structure coated by an in situ formed SEI layer with lithium metal plating in the pores as the nanostructured lithium metal anode is recently proposed by Zhang and co‐workers Figure b. This gOther conductive 3D carbon  according to the following formula:  was maintained. These performance improvements were mainly attributed to the uniformly distributed lithium ions near the electrode surface induced by such non‐conductive micro/nanostructure with polar functional groups.2/Al2O3 nanoparticles while Li ion can be uneven diffuse and deposit on the Li metal anode,Typical non‐conductive micro/nanostructured lithium metal anodes have been proposed by Zhang's group. Glass fibers with plenty of polar functional groups  were employed as the interlayer of lithium metal anode and separator Figure6a,b. T cycles 1 h was ma−2 and an areal capacity of 1.0 mA h cm−2 for more than 120 cycles.−2. Such non‐conductive polymeric matrix with molten lithium infused was a new strategy for non‐conductive micro/nanostructured lithium metal anodes.Another typical stable cycling of lithium metal anodes by using a chemically inert and electronically insulating oxidized polyacrylonitrile (PAN) nanofiber network as a scaffold has been demonstrated by Cui and co‐workers to guide and confine the deposition of lithium. Homogeneous lithium deposition was embedded inside the nanostructure via attraction forces between the polar functional groups and lithium ions. The Coulombic efficiency could reach 97.4% at a current density of 3.0 mA cm2O3 composite separators,The separator attached with Li metal anode have outstanding role to regulate the stripping/plating of Li metal in a working battery.The insulating phase modulates the spatial charge distribution and guides the stripping/plating Li ions onto Li metal anode, which is an effective route to regulate the safe use of Li metal. However, the insulating components do not directly participate in the electrochemical reactions. In order to maintain a high‐energy‐density lithium metal battery, the amounts of insulating components in a cell should be minimized. More importantly, the surface chemistry of the insulating and lithiophilic framework is very complicated, which may result in some adverse interactions between them and the organic electrolyte. These interactions may affect the ionic concentration distributions and finally determine the transfer behavior of ions in electrolyte and the lithium plating/stripping process at the electrode surface. Therefore, we call for more attentions on the interfaces between the porous substrate and electrolyte to gain more intrinsic chemistry and physics and therefore to rational design of insulating substrate for safe battery with high energy density.4It is well known that SEI layer will be formed immediately when highly active lithium metal contacts with liquid electrolytes during charging/discharging processes. However, the in situ formed SEI layer is always unstable in both chemical components and physical structures. Thus, it is easily broken and reformed repeatedly during battery cycles, inducing continuous irreversible consumption of lithium metal and electrolytes, which brings low Coulombic efficiency and shorted battery life. In order to improve the protective nature of SEI layer, nanomaterials are employed as the micro/nanostructured solid electrolyte interphase to inhibit lithium dendrite growth and improve the electrochemical performance of lithium metal anode. The micro/nanostructured solid electrolyte interphases with high shear modulus and high elastic strength are always employed as the physical barrier to block the lithium dendrite growth and make lithium deposits smooth and compact.In the micro/nanostructured SEI layer that acts mainly as the physical barrier, the connecting structure built by the interconnected pores provides the channels for lithium ions to transport into and out from the current collector. The lithium dendrites cannot grow through these channels and will be blocked by the space limitations. While in the micro/nanostructured SEI layer that aims at improving lithium ion migration and plating performance, the surface structure with lithium ion selective permeability guarantees the high ionic conductivity and protects the lithium metal plated. This kind of micro/nanostructured layer is always with a thickness of nanoscale and a highly flexibility. So that the structure of artificial SEI layer can be reserved well during lithium plating/stripping cycles and play an efficient protection of lithium metal by shielding the electrolyte.Figure−2/1 mA h cm−2.A typical nanostructured solid electrolyte interphase layer was proposed by Cui and co‐workers. The artificial SEI was built by a monolayer of interconnected amorphous hollow carbon nanospheres Figure7a,b. S2CO3, LiOH, and Li2O can be found in the SEI layer with a porous structure. The composition of pristine SEI on the Li metal is highly depended on the electrolyte , operating voltage, and even the period of Li metal interacting with organic electrolyte.−2).3PO4 SEI layer can retard the formation of Li dendrites and reduce the side reaction between Li metal and the organic electrolyte amide (Py13TFSI) and ethers electrolyte . The Li dendrite growth and corrosion of Li metal have been efficiently restrained after more than 100 cycles in a Li|LiFePO4 battery.It is necessary to indicate that although the artificial SEI layers can reduce the Li dendrite growth and restrain the corrosion of bulk Li, the degeneration of artificial SEI layers is irreversible because the artificial SEI layers cannot regenerate in the electrolyte during cycling. Most recently, Guo and co‐workerse Figure c,d. The Besides, a bifunctional solid polymer electrolyte with an interpenetrating network of poly(ether‐acrylate) (ipn‐PEA) has been proposed by Guo's group.3,6,The use of additives imide‐5.0 wt% LiNO3‐0.020 m Li2S5 was applied, Li metal anode is well protected by an in situ formed LiF‐Li2Sx rich SEI layer.When Li metal exposed in an ether electrolyte for Li‐S batteries, the soluble polysulfides are dissolved into organic electrolyte. This renders the possibility on the facile use of large sulfur particles and the deposition of inorganic lithium sulfides onto the Li metal. However, the etching of Li anode is widely observed in most research. The addition of LiNOoperando and high space/time resolution characterization methods under electrochemical working condition, the evolution of SEI in a working cell is expected to be clearly described in the near future. The use of micro/nanostructured SEI with insulating interface, interconnected ion diffusion pathways, and ultra‐stable surface are verified to be effective to regulate the Li ion plating/stripping. It is highly expected to characterize the role of micro/nanostructured SEI layer in a working pouch cell and provide more mechanistic insights into Li metal anode.The SEI is strongly considered by the materials, chemistry, and engineering communities since the last 40 years. The SEI attached onto the Li metal is always at nanoscale with complex compositions and dynamic sizes. With the rapid development of 5The serious safety concern and poor lifespan of lithium metal anode have hindered the commercial applications of next‐generation energy storage systems with high theoretical energy density . Well‐designed micro/nanostructured lithium metal anodes could effectively improve the safety issue from lithium dendrite growth and enhance the battery cycling performance  to further meet the requirements of practical applications. The merits induced by the micro/nanostructured lithium metal anodes can be summarized: However, under the current level of nanomaterials and nanotechnologies, micro/nanostructured lithium metal anodes are still not up to the challenges to perfectly solve all the problems in lithium metal anodes. A vast variety of issues of both the original lithium metal anodes and newly introduced nanomaterials are still requested to be well addressed. Some promising strategies to address these challenges of micro/nanostructured lithium metal anode have also been proposed and investigated by the researchers, with more strategies still needed to be inspected. Finally, micro/nanostructured lithium metal anodes have brought remarkable improvements in both electrochemical properties of lithium metal batteries and the stable lithium plating/stripping process with dendrite‐free morphology. However, these micro/nanostructured electrodes were not mature and perfect enough to address the issues in lithium metal anodes. Future researches of micro/nanostructured lithium metal anode on its electrochemical mechanisms, characterizations, and regulations are still highly required to understand and design better electrodes. New forms of well‐designed micro/nanostructures, especially the composite micro/nanostructures are highly expected for their promising properties in both safety and electrochemistry to face the challenges in high‐energy‐density lithium metal batteries.


CKD) in Australia.This study aimed to examine the association between performance of self‐care activities and patient or disease factors as well as patient activation levels in patients with diabetes and chronic kidney disease (CKD (eGFR <60 mL/min/1.73m2) who were recruited from renal and diabetes clinics of four tertiary hospitals in Australia. Demographic and clinical data were collected, as well as responses to the Patient Activation Measure (PAM) and the Summary of Diabetes Self‐Care Activities (SDSCA) scale. Regression analyses were performed to determine the relationship between activation and performance of self‐care activities.A cross‐sectional study was conducted among adults with diabetes and SD=11.0) years participated. The mean (SD) PAM and composite SDSCA scores were 57.6 (15.5) % (range 0‐100) and 37.3 (11.2) (range 0‐70), respectively. Younger age, being male, advanced stages of CKD and shorter duration of diabetes were associated with lower scores in one or more self‐care components. Patient activation was positively associated with the composite SDSCA score, and in particular the domains of general diet and blood sugar checking (P<.05), but not specific diet, exercising and foot checking.A total of 317 patients (70% men) with a mean age of 66.9 (CKD, a high level of patient activation was positively associated with a higher overall level of self‐care. Our results identify subgroups of people who may benefit from tailored interventions to further improve their health outcomes. Further prospective studies are warranted to confirm present findings.In people with diabetes and  This gap is important given that multimorbidity is increasing globallyThe purpose of this study was to examine the association between performance of self‐care activities and patient or disease factors as well as patient activation levels in patients with diabetes and CKD.22.1The design and recruitment of participants for this study have been described in great detail previously.2) including dialysis. Exclusion criteria included age less than 18 years of age, severe cognitive impairment and inability to communicate in English. Participants were identified as having diabetes if this was recorded from previous hospital records with the diagnosis of diabetes consistent with World Health OrganizationParticipants were included if they received their routine care at these hospitals and had a diagnosis of diabetes (either type 1 or type 2) and CKD stages 3‐5 (estimated glomerular filtration rate <60 mL/min/1.73 m2.Participants were recruited prospectively from clinics and completed the Patient Activation Measure (PAM‐13)Socio‐economic measures were estimated using the Australian Bureau of Statistics data.2.2The American version of the PAM‐13® to calculate the PAM score.® scoring rules.The authors used a standardized spreadsheet provided by Insignia Health2.3Self‐management was evaluated by the SDSCA questionnaire,2.4P value of <.1 in the univariable analysis). Similar models assessed the relationship between the individual self‐care activities and the four levels of patient activation. A sensitivity analysis examined the effect of substitution of PAM score as a continuous variable into the models. All analyses were performed with Stata version 11 . Statistical significance was indicated by a P value of <.05.Results are presented as mean and standard deviation (SD) and median and interquartile range (IQR) for normal and non‐normally distributed data, respectively. Duration of diabetes was categorized into quartiles. First, chi‐squared or t tests (as appropriate) examined differences in patient and disease characteristics by performance of self‐care activities and levels of patient activation using PAM score as a continuous variable. Second, chi‐squared tests for linear trend examined differences in performance of self‐care activities across the four levels of patient activation (PAM score categories 1‐4). Third, univariable and multivariable linear regression models assessed the relationship between the performance of self‐care activities (composite SDSCA score) and the four levels of patient activation (PAM score categories 1‐4), and any potential effect of patient or disease characteristics (any variable with a 33.12) and three patients who had incomplete PAM data .A total of 3028 patients were screened and 305 were included in the analyses after exclusion of nine patients who had their eGFR misclassified . Male patients had lower scores in the blood sugar checking domain where they scored 1.6 points less than female patients. A shorter duration of diabetes was associated with lower composite scores, and with lower scores in the blood sugar checking and foot checking domains .  decreased significantly, whereas the mean scores for the domains of specific diet, exercising and foot checking did not  but not the domains of specific diet, exercising and foot checking (Table In univariable and multivariable analyses, the level of patient activation was positively associated with the composite self‐care score and the domains of general diet and blood sugar checking (all ng Table . When pa4In our study, among patients with comorbid diabetes and CKD, we have demonstrated an association between patient activation and diabetes self‐care activities. A higher patient activation level was associated with a higher overall self‐care score. However, this association was not observed for all specific self‐care domains; only for general diet and blood sugar checking. Additionally, different patient and disease characteristics were associated with diabetes self‐care: younger age and male gender were associated with less home blood glucose monitoring, more severe CKD was associated with less foot checking and exercising, and a shorter duration of diabetes was associated with lower overall self‐care score as well as less blood sugar checking and foot checking.In patients with comorbid diabetes and CKD, higher patient activation levels were associated with higher composite self‐care scores. Previous studies have only examined this association for single chronic diseases, such as diabetes.Interestingly, the association between patient activation levels and diabetes self‐care was not observed for all specific self‐care domains. While there was a positive association between general diet and blood sugar checking, there was no association between patient activation levels and specific diet, exercising and foot checking domains. This suggests that an activated patient may not necessarily or automatically participate in all self‐care activities—they not only need to have knowledge, motivation and skills to self‐manage, but they also need to have the physical and financial ability to self‐manage across all domains of diabetes self‐management. A possible reason for the lack of association between PAM and exercise and foot checking is that both these activities require a certain degree of physical fitness and ability, which is compromised in patients with diabetes and CKD due to comorbidity.We found an association between younger ages and lower self‐care scores in the domain of general diet independent of patient activation. The explanation is likely to be multifactorial, but we hypothesize that younger patients may be less motivated to self‐manage compared to older patients, as risk perception is altered in younger populations, especially in malesAdditionally, we found that a shorter duration of diabetes was associated with lower self‐care scores. Previous studies among patients with diabetes have not been consistent with some reporting an association between lower self‐care scores with a shorter duration of diabetes,More advanced CKD was associated with lower scores in the self‐care domains of exercising and foot checking. Exercising and foot checking require a certain level of mobility and physical fitness such that patients with advanced CKD with lower exercise tolerance, and functional capacity, and more muscle wasting cannot as easily complete self‐care activities without assistance.Our findings should be interpreted in the light of the strengths and limitations of our study. The strengths include that our study provides insight into the level of activation and utility of the PAM in patients with diabetes and moderate to severe CKD, a group of patients who may have a greater need for support to engage in their health‐care needs. Our data are consistent with and extends the findings of previous longitudinal studies by assessing patients across different stages of CKD. This informs the provision of targeted interventions to improve the activation levels of patients with more advanced renal disease. The other strengths include the inclusion of several demographic and clinical variables as potential predictors for diabetes self‐management behaviour, and the use of valid and reliable tools to measure patient activationOur findings have important implications for practice and future research. First, targeted multifactorial risk reduction interventions focusing on subgroups of patients identified in this study, who are likely to perform poorly in self‐care activities, may improve health outcomes. There is evidence that such interventions could be delivered optimally through collaborative care,In patients with comorbid diabetes and CKD, although a high level of patient activation in self‐care is associated with a high level of patient self‐management in general, this is not the case across all individual domains of diabetes self‐care. Patient age, gender, duration of diabetes and stage of CKD may also influence patient self‐management in comorbid diabetes and CKD.The authors declare no conflicts of interest in relation to this work.


Bioengineering & Translational Medicine focuses on the development of bioengineered therapeutics; specifically, design and discovery approaches, delivery platforms, and synthesis and manufacturing technologies. These three areas are essential in ensuring the successful clinical translation of new biotechnologies. As such, this first BioTM Buzz will highlight an article in each of these important areas—two articles from this special issue and another from the recent literature.This special issue of Bioengineering & Translational Medicine, engineers from the Jennifer Cochran lab at Stanford University describe an approach to engineer vascular endothelial growth factor (VEGF) for increased binding affinity to vascular endothelial growth factor receptor 2 (VEGFR2), which inhibits VEGF‐mediated signaling and thereby reduces angiogenesis. The authors had previously reported the design of VEGF‐proteins that enhance VEGF's natural antiangiogenesis properties. In the current study, high‐throughput yeast surface display was used to generate highly‐potent VEGF‐proteins that exhibit enhanced binding affinity to VEGFR2. Enhanced binding of VEGF‐variants was confirmed in mammalian cells, which also led to inhibition of VEGF‐mediated cell signaling and angiogenic processes in mice. The versatile approach will find utility in the design of new therapeutics to optimize ligand–receptor interactions or to improve binding interactions for already‐approved or currently investigated protein‐based therapeutics in the clinic.Design and discovery approaches are essential in isolating and selecting lead candidates that hold promise as robust therapeutics. In this issue of 10.1002/btm2.10051DOI: Biological barriers and other physiological challenges often limit the ability of therapeutics to interact optimally, or at all, with diseased tissues. Chemical engineer Julie Champion and coworkers from the Georgia Institute of Technology describe methods to systematically investigate how the physical properties of particle‐based drug delivery systems influence their fate and function. The particle‐based drug delivery systems that have been clinically approved or investigated each possess unique physicochemical properties; as such, defining particle properties that exhibit enhanced biological performance in humans is a significant challenge that if addressed could aid in the design of future delivery systems. In the current study, a layer‐by‐layer templating approach that enabled control over particle size, shape, and stiffness, while maintaining identical surface chemistry, was used to investigate the individual and combined contributions these modifications have on particle internalization by macrophages. Complex relationships between size, shape, and stiffness were revealed—for example, spherical particles of increased size exhibited reduced internalization by macrophages, while modifications to stiffness exhibited no differences in internalization. The implications described in this paper highlight how current efforts in particle‐delivery must consider all physicochemical properties of particles in tandem, since the interplay between these properties and their biological performance is a complex relationship.10.1002/btm2.10052DOI: Synthesis and manufacturing technologies that enable the scaled‐synthesis of both therapeutics and delivery platforms are a prerequisite for clinical impact. Often times, complex approaches at the lab‐scale face difficulties in translation towards industrial and commercial processes. An approach developed by Eric Appel at Stanford University and collaborators including Robert Langer at the Massachusetts Institute of Technology enables the scalable manufacturing of hydrogel materials with complex viscoelastic properties. Hydrogels are widely used as a vehicle to enable the controlled release of drugs in a variety of delivery applications. However, cost issues and scalability related to consistency of the synthesized hydrogels have limited their clinical translation. In this study, hydrogels are formed by mixing polymers and hard nanoparticles ; since polymer adsorption to nanoparticles is transient and reversible the resulting hydrogels exhibit both shear‐thinning and self‐healing properties. These shear‐thinning hydrogels have great potential for biotechnology applications since they can be readily injected and capable of flowing under high stress, but then form a gel when relaxed. The approach described represents a strategy that could be readily translated to enable the large‐scale synthesis of hydrogels for biomedical applications, such as combination therapies relying on the delivery of drugs of distinct physical properties.Yu et al., Proc Natl Acad Sci USA. 2016; doi:10.1073/pnas.1618156113


To scope systematically and collate qualitative studies on family experience and need during end of life care in intensive care, from the perspective of family members.Scoping review of qualitative research.Standardized processes of study identification, data extraction and data synthesis were used. Multiple bibliographic databases were accessed during 2011 and updated in 2013.From an initial 876 references, 16 studies were identified for inclusion. These were predominantly single site, North American studies that explored issues relating to the temporal stages in the end of life trajectory and the requirement for information and emotional support at end of life. With a strong focus on family need and experience during the transition from active treatment to end of life care, more work is required to understand how doctors and nurses can support families from treatment withdrawal through to death. Internationally there has been increasing attention placed on improving end of life care as evidenced by the many international health initiatives  or relative of the person receiving intensive care. The term ‘family member’ was used due to the lack of consensus definition in the literature on the term ‘family’. Intensive care was defined as a clinical area providing ‘the monitoring and support of critically ill patients who have illnesses with the potential to endanger life’ , Medline, EMBASE, Psychlit, PschINFO, Web of Science, Web of Knowledge. Other data sources, for example, Google Scholar were used to uncover additional material. Further electronic searches of major research registers were also undertaken including: National Institute for Health Research, Cochrane Library, together with high profile clinical academic centre websites with output in this area . Manual searching of key international UK, Australasian and North American) critical care and palliative care journals together with review of international critical care organizations websites  was undertaken. The searches were conducted during 2011 and updated in 2013.Studies were selected using specific inclusion and exclusion criteria Table . These wKey search words included: (MeSH heading) intensive care or critical care + ITU (abbreviation for Intensive Therapy Unit) or intensive care or critical care or ITU (keywords), (MeSH heading) family + relative or family member or carer or caregiver (keywords), (Mesh heading) experience + needs or need or coping or burden (keywords), (MeSH heading) death + bereavement + terminal care or end of life or death or dying (keywords). Boolean operators and SMART search facilities were used to further refine the searches. A subject librarian provided expert advice on the search terms and later reviewed the search strategy.The references of all potential papers were read, duplicate references deleted and all remaining titles of papers reviewed for suitability. Any papers not immediately meeting the selection criteria, for example, primary research in the neonatal intensive care population were excluded from the review. The abstracts of remaining papers were retrieved and read for suitability against the inclusion criteria. Every fifth abstract underwent a further independent review by another researcher to ensure rigour and consistency in the review process. All remaining papers identified as suitable for full review were retrieved through web based or library resource. Bibliographic details, keywords and abstract of all suitable papers were imported into a bibliographic software package (Endnote). All final papers underwent two independent reviews by the author of this paper and another researcher. There was full agreement on all decisions regarding papers for inclusion and exclusion. Papers were read to identify study aims and purpose, methodology, analytical strategies and findings. Data extraction sheets were completed for each paper and presented as a summary of: author and year of publication; study population; purpose of study; methods including analytical approach; original study findings and commentary (including knowledge contribution and gaps: method and theory). Each data sheet was read and key areas were collated. Consistent with Arksey and O'Malley's  approachEthics approval was not required.n = 23) and via inter‐library loans (n = 4). Following critique of the full text papers, 16 were selected for this scoping review. Eleven papers were excluded at this stage as reading of the full text identified detail indicating that the papers did not meet the original inclusion criteria.The search strategy produced an initial 876 references Figure . No new n = 14). Other studies were from Canada (n = 1) and Sweden (n = 1). No papers were retrieved from other countries in Europe nor from Australasia. Predictably, most publications were located in specialized palliative care or critical care American journals (n = 14) with two papers being published in UK based journals  with two using prospective sample identification. Six papers used prospective sampling with a prospective data collection approach.Thirteen papers gave accounts of primary research undertaken while three were secondary analysis Table . In papeThere was little consensus about definition of terms used in the studies that directed the research question and informed the sampling criteria. Life‐support, life‐sustaining, treatment limitation, treatment withdrawal and end of life were all used in the studies with little clarification offered. Similarly, although adult family members were the focus of all the studies, terms such as ‘surrogate decision makers’ and ‘loved ones’ were also used to describe the population. There was also variation across the age characteristics used to select the bereaved family member population; for example, one study excluded family members under 55 years of age.With regard to data collection, most studies sampled at one time point with only two studies using longitudinal data collection. Two studies used statistical analysis mainly to describe demographic details of family members and to determine inter‐rater coding reliability during the analysis of interviews. Studies had sample sizes between 8–56 participants and most were conducted in single sites. Consistent with the interpretive paradigm used, most studies used recognized data analysis approaches, for example, constant comparison technique, axial coding. Rigour and ethics was variably detailed across the papers.Finally, there was little detail of the underpinning theoretical frameworks that informed the research. There were examples of models generated in some of the studies and evidence of theory that underpinned some discussions. When such models and theories were used, more robust implications for future research and practice initiatives were often presented.et al. et al. et al. The aim of this review was to scope and collate qualitative research that explored the experience and needs of families in end of life care in critical care. While some studies focussed on exploring family experience or family need, others were less defined in their approach. Across the 15 studies, nine were explicitly focussed on family experience at end of life, one paper focussed exclusively on family need during this time ]:substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data;drafting the article or revising it critically for important intellectual content.All authors have agreed on the final version and meet at least one of the following criteria [recommended by the ICMJE (


To develop a purpose‐built quiet echo planar imaging capability for fetal functional and diffusion scans, for which acoustic considerations often compromise efficiency and resolution as well as angular/temporal coverage.The gradient waveforms in multiband‐accelerated single‐shot echo planar imaging sequences have been redesigned to minimize spectral content. This includes a sinusoidal read‐out with a single fundamental frequency, a constant phase encoding gradient, overlapping smoothed CAIPIRINHA blips, and a novel strategy to merge the crushers in diffusion MRI. These changes are then tuned in conjunction with the gradient system frequency response function.Maintained image quality, SNR, and quantitative diffusion values while reducing acoustic noise up to 12 dB (A) is illustrated in two adult experiments. Fetal experiments in 10 subjects covering a range of parameters depict the adaptability and increased efficiency of quiet echo planar imaging.Purpose‐built for highly efficient multiband fetal echo planar imaging studies, the presented framework reduces acoustic noise for all echo planar imaging‐based sequences. Full optimization by tuning to the gradient frequency response functions allows for a maximally time‐efficient scan within safe limits. This allows ambitious in‐utero studies such as functional brain imaging with high spatial/temporal resolution and diffusion scans with high angular/spatial resolution to be run in a highly efficient manner at acceptable sound levels. Magn Reson Med 79:1447–1459, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. While acoustic noise reduction is a general aim for MRI examinations to enhance patient comfort or to avoid unwanted activation in functional MRI (fMRI) studies External noise protection techniques for the fetus in‐utero are either not feasible  or not generally applicable (wrapping the mother's abdomen). Therefore, reducing the acoustic noise output of the scanner is particularly desirable in this subject group. In clinical practice, this is typically achieved by imposing constraints on gradient slew rate and amplitude. Control of acoustic output in this way is associated with decreased temporal and spatial resolution as well as limited scan efficiency for most sequences, it specifically restricts the performance of echo‐planar‐imaging (EPI) sequences.Single‐shot EPI is widely used for advanced applications such as fMRI and diffusion MRI (dMRI), and as such is a key tool for connectome type studies I, driven through the gradient coils by the gradient amplifiers lead to interactions with the static magnetic field B and thus to Lorentz forces (F=I×B). These forces work against the coil stiffness and lead to the generation of sound pressure approximately proportional to the velocity of the coil former surface. These effects depend on the geometry and material properties of the individual scanner setup. As the resulting fluctuations and displacements are typically small, sound generation may be approximated as a linear system FRFi(f)) for each gradient coil i=x,y,z, where t is time and f is temporal frequency Ri(f) of a gradient coil running waveform gi(t) can then be expressed as:The acoustic noise in the scanner is mainly generated by the gradient system, particularly if there is extremely rapid switching of gradient amplitude and polarity Supporting Figure S1 for an example read‐out train (both read‐out and phase encoding gradients).This process is illustrated in Ways to reduce the acoustic noise can be mainly split into two types, hardware based and software based sound reduction. The former include the use of sound‐attenuating materials Potential modifications include changes to sequence timings to avoid resonance peaks in the FRF Ott et al. For the requirements of fetal MRI, increases in scan time, and specifically in single shot EPI read‐out time, should be kept as small as possible due to expected high prevalence of fetal motion.In addition, none of the above mentioned studies include MB acceleration This article describes an efficient, MB accelerated single shot EPI acquisition scheme both for gradient echo (GE‐) EPI used for fMRI and diffusion‐weighted Spin Echo (dSE) EPI used for dMRI, which we term quiet EPI (QuEPI). Our approach reshapes all gradient waveforms and tunes the obtained more controlled spectral properties of the sequence elements to the specific scanner FRF. It results in an important reduction of the acoustic noise while maintaining high scanning efficiency.Methodological description of the gradient reshaping to narrow the spectral content.Replacing CAIPIRINHA blips with overlapping sin‐shifted profiles.A novel crusher strategy for dMRI with joint re‐winder and butterfly crushers aimed to keep echo time (TE) short despite the reduced crusher amplitudes.Simulations to optimize the resulting flexible acquisition to the scanner specific FRF with consideration of the implications on the planned versus played out gradient waveforms.In vivo experiments both in adults and fetuses to demonstrate the maintained image quality.A small fetal diffusion study with 120 directions using QuEPI to illustrate its practical use.Noise measurements to quantify achieved sound reduction.It specifically includesGradient FRFs can have complex characteristics that change rapidly with frequency, and this is the case for the Philips 3T Achieva scanner employed in the current study. To avoid high acoustic output, the spectra of the gradient waveforms, including all harmonics, should not have high intensity values that coincide with peaks in the FRF. This requirement motivates a core strategy that has been adopted in several studies, that is designing the spectral properties of the gradient profiles to make the resulting acoustic spectrum as narrow as possible and avoid generation of higher harmonics. It then becomes feasible to tune the gradient spectrum to match favorable local minima of the FRF.Design individual gradient objects to obtain single dominant frequencies reducing harmonic content Expand and combine objects as far as possible given efficiency constraints to avoid rapid transitions in amplitudeTune the main sequence frequencies to coincide with minima in the scanner specific FRF.To achieve the required spectral properties, the gradient waveforms for the imaging axes  have been modified following three principles:r, phase p, and slice s in the following. A standard EPI read‐out train that encodes e lines of k‐space is composed of e gradient areas with switching sign to realize the required k‐space transversals in the rk‐direction as illustrated in Figure pk‐direction. The read and phase areas depend on the chosen resolution and the number of samples . This is illustrated in Figure Let the readout direction be tϵ are introduced between successive sampling periods to control overlap with the phase gradients. These reduce the available sampling time to teff=techo−tϵ<techo and increase the required total area as illustrated in Figure Time gaps Aprer, Aprep, Apres as well as, in the case of spin echo EPI, spoiler gradients of area Abs employed both around the refocusing radio‐frequency pulse, and area Apostr after the read‐out to de‐phase remaining magnetization. These are marked out in Figure Finally, additional gradients required for navigation in k‐space include the read‐out, phase and slice pre‐winders of areas To maximize efficiency and minimize echo time, all gradients are typically realized with trapezoids with maximal slew rate within the constraints given by hardware and peripheral nerve stimulation limits as shown in Figure a and b with a > b, r=ba and amplitude rG  and, specifically for CAIPIRINHA blips, also on the chosen shift pattern, giving rise to a more complex frequency distribution. Finally, the relatively large areas required for crusher gradients and the need to keep these short in duration to promote temporal efficiency for the sequence as a whole typically leads to selection of fast rising, high‐amplitude gradient pulses, which contribute substantially to the acoustic output.f, where the duration of a half sin wave corresponds to the echo spacing techo sampled at time points it, at increments of the dwell time of the scanner real‐time control system and with the corresponding amplitude taking the required acquisition pause for phase blips into account  sampled between [−π2 and 3π2]  and for illustrative purposes with ρ=0.95 (green). In Figure Figure Npre cycles, followed by the required k‐space transversal in Nepi cycles and the end period has Npost cycles.Wherever possible, all remaining gradients were smoothed and extended while keeping time extensions to a minimum. Therefore, the read‐out module is constructed of three blocks all of which are constrained to conform to the timing of a single continuous sine wave to achieve maximally narrow frequency components Fig. . The staNpre cycles. Both the phase and slice rewinder gradients are stretched to the corresponding time and implemented as sine waves. The phase pre‐winder was calculated to allow for the center of each complete read‐out traversal to be symmetric around the k‐space center. Where required, spoilers on all axes were converted to extended sinusoids matching the length of Npost cycles. These changes are illustrated in Figure Within this framework, the read‐out pre‐winder is realized as a ramp‐up period for the Npre directly impacts on the achievable echo time and together with Npost also increases total acquisition time per slice, and so it is important to balance this cost with impact on the acoustics and harmonic generation of having rapid transitions. It is particularly important to minimize Npre as increasing echo time reduces signal strength, in this study Npre=2.The value of b‐values separated by a bmin. In our examples, bmin was chosen as 50 s/mm2.Specifically for dMRI, significant acoustic contributions arise from the butterfly crushers around the refocusing radio‐frequency pulse. These dedicated crushers are required to provide sufficient dephasing to attenuate the Free Induction Decay (FID) resulting from imperfect refocusing. They can be omitted when the diffusion lobe areas before and after the 180° pulse fulfill this requirement, defining two cases for Apres and butterfly crushers of area Abs, the combined area A1s=Apres+Abs needs to be achieved before and the area A2s=Abs after the refocusing pulse.Omitting these dedicated crushers significantly reduces acoustic noise and can also decrease echo time. For QuEPI, this is achieved by combining the crusher pre‐refocusing gradient with the slice rewinder gradient see Fig.  and streSupporting Figure S3a,b. The described trajectory combined with data sampling at fixed time increments results in the data not being on a regular grid in k‐space and thus there is a need for re‐gridding. Additionally, the continuous phase encoding gradient and its start at the very beginning of the sinusoidal read‐out waveform results in a shift of half a yk increment  of the k‐space center as compared to conventional trajectories obtained using blips.Our datasets contain both in‐plane and MB EPI accelerated acquisitions, so our general reconstruction method follows the extended SENSE framework proposed in Zhu et al. To limit the discrepancies between the conventional grid and the sample points in QuEPI, an additional half‐blip area is included into the phase encode pre‐winder to assure alignment of the k‐space centers. Furthermore, the outermost parts of the k‐space trajectory—and thus the parts differing most from the conventional grid—are not sampled and thus do not require further correction.xk direction does not differ much from what is needed for conventional trapezoidal ramp‐sampling. The exact shape of the trapezoidal waveforms, especially the length of the plateau, depends on slew and Gmax settings and underlying limitations and thus requires adaptive re‐gridding.The required re‐gridding in the xk gridding algorithm as any conventional EPI sequence. Regarding EPI ghost correction, different algorithms were tested in phantoms with only minor differences. Finally, a correction for non‐ideal gradient performance is included using a pre‐calibrated time delay.QuEPI employs exactly the same vendor‐implemented Supporting Table S1, Prot. 1 and Prot. 2) This protocol was used to compare image quality when operating under conditions differing maximally in acoustic noise.The scanner optimized sequence together with the QuEPI sequence were acquired on adult 1  were used to allow for Signal to Noise Ratio (SNR) and quantitative diffusion parameter evaluation. The use of matched fundamental frequency readout waveforms allowed comparisons to be made using matched bandwidth with similar spatial distortions.The fetal dSE QuEPI sequence and an EPI sequence with matched fundamental readout frequency, in addition to the scanner optimized EPI sequence, all with matched repetition time (TR), TE and diffusion parameters were acquired on adult 2 (Prot. 3). Here, the three lower shells  is provided in the supplementary material and on the lab's GitHub page.The acoustic output was simulated using custom‐made Matlab scripts fed with the scanner waveform output and the manufacturer supplied FRFs. The script  was also measured. A further goal of this step is to validate the sound reduction achievable at the same frequency. The trapezoidal versions were always run at maximal slew rate but otherwise precisely matched to allow direct comparison.The acoustic noise measurements were performed using an MR‐compatible Optoacoustics Fiber Optic Microphone (Optimic 1155) with a resolution of 0.1 dB, A and C weighting, with a sensor positioned at isocenter in the empty scanner bore, which is the typical location of the fetal head in a well‐planned examination. This experiment results in an optimal frequency choice which was then used for systematic testing of the acoustic output of both EPI and QuEPI versions including all described modifications, CAIPIRINHA blips and the different options for the slice rewinder and crushers.Both acoustically optimized acquisitions were successfully used on 12 healthy pregnant volunteers using a 32‐channel cardiac coil for signal reception. Informed consent was obtained for each examination. Fat suppression was achieved using SPIR pre‐pulses Supporting Table S1 for all subject data shown in the result section. These include both GE and SE EPI acquisitions, varying resolutions and acceleration strategies.QuEPI was applied for a range of in‐utero studies with several purposes, all sharing the need for an efficient, quiet EPI acquisition. Therefore, the employed parameters vary and the parameters are summarized in b‐value shells . This 6‐shell approach was chosen over a more conventional 2–4 shell approach with higher angular resolution to allow comprehensive study of the fetal data signal content. The acquisition time for these datasets was 17 min. No additional averages were used, but increasing the number of angular samples with the b‐value provides oversampling in shells with more signal attenuation to reduce the noise in advanced models.To illustrate the use of the developed protocols for efficient connectome studies high resolution multi‐shell acquisition, a high spatial and angular resolution dMRI protocol (Prot. 5) was acquired in six fetal subjects (subject 7–12). The parameters for this full dMRI protocol included 120 diffusion directions arranged across 6 b = 0 image. The multi‐shell HARDI data were subsequently decomposed into two sources using convex non‐negative spherical factorization All data sets were corrected for motion and eddy‐current induced distortion with FSL Simulation results for the gradient spectra from all gradient axes are shown in Figure Whereas dSE‐EPI generates strong harmonics as well as the peak at the read‐out frequency of 507 Hz, only one dominant peak at the fundamental frequency can be seen in the spectra of the dSE‐QuEPI read‐out  compared to 112.6 dB (A) (most efficient setting at 877 Hz) or 111.8 dB (A) with matched echo spacing.While the combination of all elements leads to the stated reduction in sound, Table Finally, the different slice refocusing/spoiling strategies as discussed for dSE‐QuEPI were individually evaluated. The acoustic noise of the QuEPI sequence with trapezoidal slice rewinders and spoilers [106.8 dB (A)] could be decreased to 105.8 dB (A) using a sinusoidal rewinder gradient and even to 103.6 dB (A) when the combined spoiler and rewinder strategy is applied. In this concrete example, the combined crusher strategy also reduced the echo time by 1 ms.Supporting Figure S4 shows the imaging results of the first adult‐experiment in which acoustically optimized QuEPI is compared to scanner optimized EPI, which entails operating at differing fundamental frequencies. Despite a 9 and 12.9 dB (A) reduction in generated acoustic noise, image quality is comparable. The increased distortion effects in QuEPI are attributable to the use of a lower bandwidth in the Phase Encode direction. This is due to a lower fundamental frequency (and thus echo‐spacing) in order to decrease acoustic noise. It was notable that the perceived sound quality was noticeably different, with a muted mellow tone for QuEPI compared to a harder more metallic sound for conventional EPI.Calculated fractional anisotropy and apparent diffusion coefficient results are shown in Figure Results from the dMRI experiment using dSE‐QuEPI can be seen in Figure In this study, the use of gradient design with the guiding principal of minimizing generated spectral content of gradient waveforms in EPI sequences and then tuning the fundamental frequency to coincide with a minimum of the FRF of the gradient system has been explored as a means of decreasing acoustic noise. We term this approach QuEPI. QuEPI allows highly efficient fetal fMRI and dMRI acquisitions that are significantly less noisy than standard scanner EPI sequences.Although there have been a number of previous strategies for reducing acoustic output from MRI sequences, these are either not feasible for EPI Furthermore, most studies are focused on fMRI experiments only, whereas our approach decreases acoustic noise for all single shot EPI sequences which is a vital requirement for connectome type fetal studies. The dMRI‐specific modifications proposed in QuEPI, such as the combined crusher strategy, go beyond previously proposed alternations for single shot dMRI The proposed QuEPI framework is fully compatible with further acceleration techniques such as partial Fourier and SENSE in addition to MB, as was in fact demonstrated in the in vivo examples presented. A feature of QuEPI as implemented is its flexibility to optimize the read‐out frequency, diffusion gradients, and MB blips to the scanner specific FRF depending on the target acoustic noise output. The QuEPI approach provides a flexible platform for comprehensive fetal connectome examinations where high data rate with acceptable acoustic performance is needed, as well as other examinations where reducing acoustic noise output is important. The possibility to tune all elements of the sequence independently and synergistically to the scanner hardware allows to achieve optimal combinations of acoustic performance and efficiency. The range of experiments conducted for this study illustrates the high flexibility of the proposed framework.b>bmin) enables a significant reduction in sound level and can even result in a slight decrease in echo time. By taking MB acceleration into account and optimizing all gradients including CAIPIRINHA blips the framework provides a minimal sound solution to a key mode of accelerated acquisition that is increasingly used with EPI sequences. As demonstrated in Supporting Figure S4 and Table 2, the changes introduced in QuEPI to reduce acoustic noise did not result in changes in performance, other than those that must occur when echo time, readout bandwidth, and so forth are changed. This illustrates, that the use of QuEPI does not alter any calculated diffusion properties as a reduction in SNR could evoke The development of a merged crusher and rewinder gradient strategy, which switches structure as soon as the diffusion gradients intrinsically provide enough spoiling  for our large fetal studies. This greatly simplifies, and so speeds up, planning and allows the acoustic noise contributions of individual gradient coil directions to be optimally fine tuned to the gradient system. The prevalence of fetal motion and the long scan durations needed for comprehensive diffusion and functional examinations often result in a change in the actually acquired fetal scan plane even when there is a precisely planned initial fetal brain geometry. These two factors support the concept of imaging in pure scanner planes combined with post‐processing reconstruction techniques The QuEPI approach can also be applied to conventional EPI sequences by formulating the optimization on the full acoustic response without also re‐designing the waveform structure. This more modest approach can still provide significant gains. Full inclusion of QuEPI combined with frequency tuning for low sound generation within scanner optimization code would be beneficial and will allow even more precise control of the acoustic sound output than is currently available. A possible further enhancement would be to optimize the diffusion gradients either by directly modifying the slew rate, or by adapting the trapezoidal ratio to help eliminate or control certain harmonic frequencies.Previous studies have targeted general improvements in patient comfort or decreased acoustic stimulation for fMRI experiments. The QuEPI framework developed in this study was purpose‐built not only to enhance acceptability for fetal scanning, but also to render it efficient for connectome style prolonged EPI based studies. Previously such studies required to compromise in either efficiency, the number of possible diffusion directions sampled or number of complete volumes sampled. The shown fetal in vivo diffusion data illustrates the versatility and efficiency of QuEPI. It allows to run ambitious studies aimed to reveal for example the microstructural connectivity in‐utero by reducing fetal MRI scan time while allowing high angular or temporal coverage in an acoustically optimized and safe setup. This will greatly improve future functional and diffusion studies.Table S1. Imaging Protocols Used for the Experiments Shown in the Results Section. Subjects 1–2 Are Adult Volunteers, Subject 3–12 Are Fetal Volunteers. Abbreviations Used: MB, Multiband; PF, Partial Fourier; Res.: Resolution; SB: SinglebandFig. S1. Acoustic simulation for a conventional EPI readout gradient with trapezoids for the case of flat top to base ratio of r = 0.8 and fundamental frequency of f=500 Hz. Left box: the gradient waveform g(t); Right box: corresponding frequency spectrum (FT(g(f))), the gradient system acoustic frequency response function (FRF(f)) and, finally, the resulting acoustic output R(f). These results were generated using the Supporting script acousticResponse.m.Fig. S2. Simulations of gradient performance using measured gradient impulse response functions. Planned and achieved waveforms for a single EPI readout lobe for (a) EPI and (b) QuEPI. Native waveforms and differences between planned and achieved waveforms are shown for all axes for GE‐EPI in (c) and differences only for GE‐QuEPI in (d).Fig. S3. Illustration of gradient waveforms and resulting k‐space trajectories for EPI and QuEPI. a: Sequence details for EPI (left) and QuEPI (right). For QuEPI both the nonshifted and the half‐blip corrected version are shown. b: Resulting k‐space trajectories for all three mentioned versions together with the k‐space center (in xk direction) in orange.Fig. S4. In vivo results from a healthy adult volunteer. Imaging data from EPI and QuEPI sequences  for both SE and GE sequences. The acquired axial imagine planes are shown as well as reformatted coronal/sagittal views.acousticResponse.mScript . Matlab script developed to simulate the acoustic response of pulse sequences. Requires the waveform on all three axes as well as the scanner individual FRFs as input.Click here for additional data file.


However, the genes for these resistance factors also serve scientific needs. They have been used as selectable markers in recombinant DNA techniques as their inception , hot (68°C), salty (26%), acidic (5.3), dark, anoxic and as if that is not harsh enough, it also contains concentrations of some heavy metals about 1000× that of typical seawater. Members of the Gammaproteobacteria and Euryarchaeota dominate within this environment  and a Red Sea brine aminoglycoside kinase‐related protein (RSB AK) were selected for detailed investigation. Active sites for predicted enzyme activities were found to be conserved, and 3D modelling reinforced the predicted enzyme classifications and identified modifications possibly associated with enhanced thermal stability, such as increased numbers of salt bridges. The authors then went on to work with purified proteins produced following overexpression of the cloned genes. Enzyme kinetic and thermal stability measurements revealed exceptional characteristics in particular for the RSB AK. This included micromolar et al., Microbial Biotechnology article. More importantly, this work provides a dramatic example of the evolution of antibiotic resistance far removed from the human application of these chemicals. Geothermal cooking of organics at this location does result in the abiotic synthesis of aromatic compounds, but surely these chemical alterations do not lead to the presence of complex organic structures with the finely tuned activities of microbially synthesized antibiotics (Wang et al., et al., The value of this work is twofold. It presents a strategy for obtaining antibiotic resistance genes that could be used as selectable markers in thermophiles and other extremophiles. That this environment is a good place to hunt for resistance factors was previously demonstrated by the discovery of a thermotolerant and halotolerant mercury reductase derived from the same metagenome (Sayed None declared.


One of the central goals of the field of population ecology is to identify the drivers of population dynamics, particularly in the context of predator–prey relationships. Understanding the relative role of top‐down versus bottom‐up drivers is of particular interest in understanding ecosystem dynamics. Our goal was to explore predator–prey relationships in a boreal ecosystem in interior Alaska through the use of multispecies long‐term monitoring data. We used 29 years of field data and a dynamic multistate site occupancy modeling approach to explore the trophic relationships between an apex predator, the golden eagle, and cyclic populations of the two primary prey species available to eagles early in the breeding season, snowshoe hare and willow ptarmigan. We found that golden eagle reproductive success was reliant on prey numbers, but also responded prior to changes in the phase of the snowshoe hare population cycle and failed to respond to variation in hare cycle amplitude. There was no lagged response to ptarmigan populations, and ptarmigan populations recovered quickly from the low phase. Together, these results suggested that eagle reproduction is largely driven by bottom‐up processes, with little evidence of top‐down control of either ptarmigan or hare populations. Although the relationship between golden eagle reproductive success and prey abundance had been previously established, here we established prey populations are likely driving eagle dynamics through bottom‐up processes. The key to this insight was our focus on golden eagle reproductive parameters rather than overall abundance. Although our inference is limited to the golden eagle–hare–ptarmigan relationships we studied, our results suggest caution in interpreting predator–prey abundance patterns among other species as strong evidence for top‐down control. This long‐term dataset provides a unique opportunity to assess the relationships between this apex predator and its primary spring prey. Eagles in this population are migratory, wintering at more southern latitudes and returning to their breeding grounds in late winter or early spring  using a standardized approach for the entire period , as well as trends through time (year), would be the predominant drivers of occupancy dynamics based on the work of McIntyre and Schmidt  or successful reproduction in yeart (β2γ24 = −0.52). This indicated that the probability of golden eagle nesting attempts and successful reproduction did not track current hare numbers alone, but began to slow prior to each peak in the hare cycle and increase more rapidly after the hare cycle reached its nadir than would be expected based on hare and ptarmigan numbers in yeart alone. There was no corresponding lagged response to ptarmigan numbers. Trends in occupancy states over time indicated that occupancy without reproduction increased, while nesting attempts and successful reproduction decreased after accounting for prey abundance. Interestingly, the proportion of territories with attempted nesting did not vary appreciably in relation to prey abundance, although the probability of nesting declined slowly through time (Table The full model was the next best model compared to our top model ΔDIC = 13), indicating little model selection uncertainty relative to the current and lagged effects of these two prey species on occupancy state. The probability of eagles successfully raising fledglings was positively related to the indices of hare and ptarmigan abundance (Table 3, indica4Long‐term datasets on the dynamics of naturally occurring populations of both predators and their primary prey within a single system are rare. Golden eagle population ecology in Denali has been studied extensively for almost 30 yrs (e.g., McIntyre & Adams, The boreal forest ecosystem in North America is dominated by the hare–lynx cycle which is generally thought to be driven primarily by lynx predation (e.g., Krebs, Boonstra, et al., Further investigation into demographic rates is needed for other predator populations in this system, particularly for lynx. Declines in predator abundance often lag behind those of prey (Krebs, Boonstra, et al., Strong associations between raptors and their prey have been observed in a variety of systems (e.g., Hoy, Millon, Petty, Whitfield, & Lambin, Golden eagles have several life history characteristics that differ from those of other apex predators in our study area, potentially focusing the effects of prey on specific vital rates such as reproduction. First, although golden eagles may be classified as generalist predators in the sense that they utilize a variety of prey species throughout the year (Kochert et al., Overall, our work contributes to the basic understanding of predator–prey dynamics in boreal ecosystems. The dependence of golden eagle reproductive success on prey abundance has been well established (e.g., McIntyre & Adams, https://irma.nps.gov/DataStore/.The data used in this manuscript will be archived at: CLM designed the field study and collected the data. JHS analyzed the data and wrote the manuscript. All authors contributed to the conceptual integration of datasets, discussed the results, and made substantive contributions to manuscript development and content.None declared.