The windsor definition for hyperemesis gravidarum: A multistakeholder international consensus definition.

OBJECTIVE: To develop an international definition for hyperemesis gravidarum to assist in clinical diagnosis and harmonize hyperemesis gravidarum definition for study populations. STUDY DESIGN: A mixed-methods approach was used to identify potential hyperemesis gravidarum definition criteria (i.e. systematic review, semi-structured interviews and closed group sessions with patients and Project Steering Committee input). To reach consensus on the definition we used a web-based Delphi survey with two rounds, followed by a face-to-face consensus development meeting, held in Windsor UK, and a web-based consultation round, in which the provisional hyperemesis gravidarum definition was fed back to the stakeholders. Four stakeholder groups were identified 1) researchers; 2) women with lived experience of hyperemesis gravidarum and their families; 3) obstetric health professionals (obstetricians, gynecologists, midwives); and 4) other health professionals involved in care for women with hyperemesis gravidarum (general practitioners, dieticians, nurses). To reflect the opinions of the international community, stakeholders from countries in all global regions were invited to participate. RESULTS: Twenty-one identified potential criteria entered the Delphi survey. Of the 277 stakeholders invited, 178 completed round one, and 125 (70%) also completed round two. Twenty stakeholders attended the consensus development meeting, representing all stakeholder groups. The consultation round was completed by 96 (54%) stakeholders, of which 92% agreed with the definition as presented. The consensus definition for hyperemesis gravidarum consisted of: start of symptoms in early pregnancy (before 16 weeks gestational age); nausea and vomiting, at least one of which severe; inability to eat and/or drink normally; strongly limits daily living activities. Signs of dehydration were deemed contributory for the definition for hyperemesis gravidarum. CONCLUSIONS: The proposed definition for hyperemesis gravidarum will help clinical studies to achieve more uniformity, and ultimately increasing the value of evidence to inform patient care.

A core outcome set for hyperemesis gravidarum research: an international consensus study.

OBJECTIVE: To develop a core outcome set for trials on the treatment of hyperemesis gravidarum (HG). DESIGN: Identification of outcomes is followed by a modified Delphi survey combined with a consensus development meeting and a consultation round. SETTING: An international web-based survey combined with a consensus development meeting. POPULATION: Stakeholders including researchers; women with lived experience of HG and their families; obstetric health professionals; and other health professionals. METHODS: We used systematic review, semi-structured patient interviews, closed group sessions and Steering Committee input to identify potential core outcomes. We conducted two web-based survey rounds, followed by a face-to-face consensus development meeting and a web-based consultation round. MAIN OUTCOME MEASURES: A core outcome set for research on HG. RESULTS: Fifty-six potential outcomes were identified. The modified Delphi process was completed by 125 stakeholders, the consensus development meeting by 20 stakeholders and the consultation round by 96 stakeholders. Consensus was reached in ten domains on 24 outcomes: nausea; vomiting; inability to tolerate oral fluids or food; dehydration; weight difference; electrolyte imbalance; intravenous fluid treatment; use of medication for hyperemesis gravidarum; hospital treatment; treatment compliance; patient satisfaction; daily functioning; maternal physical or mental or emotional wellbeing; short- and long-term adverse effects of treatment; maternal death; pregnancy complications; considering or actually terminating a wanted pregnancy; preterm birth; small for gestational age; congenital anomalies; neonatal morbidity and offspring death). CONCLUSIONS: This core outcome set will help standardise outcome reporting in HG trials. TWEETABLE ABSTRACT: A core outcome set for treatment of hyperemesis gravidarum in order to create high-quality evidence.

Image feature delocalization in defocused probe electron ptychography.

Electron ptychography can in principle convert a conventional scanning electron microscope (SEM) into a good quality transmission electron microscope (TEM). An improvement in resolution of about a factor of 5 over the lens-defined resolution of an SEM was first demonstrated by Humphry et al. (2012). However, the results from that work showed some delocalization in the atomic fringes of the gold particles used as a test specimen for the technique. Here we explore factors that result in the delocalization effect when a defocused probe is used for the ptychographic data collection: source incoherence, the effects of detector faults, data truncation and a poorly calibrated illumination step size (or camera length). Various mitigation strategies are tested, including modal decomposition of the incoherence in the beam. We reprocess the data from the original SEM experiment to show that these refinements significantly improve the reconstruction.

Ptychographic microscope for three-dimensional imaging.

Ptychography is a coherent imaging technique that enables an image of a specimen to be generated from a set of diffraction patterns. One limitation of the technique is the assumption of a multiplicative interaction between the illuminating coherent beam and the specimen, which restricts ptychography to samples no thicker than a few tens of micrometers in the case of visible-light imaging at micron-scale resolution. By splitting a sample into axial sections, we demonstrated in recent work that this thickness restriction can be relaxed and whats-more, that coarse optical sectioning can be realized using a single ptychographic data set. Here we apply our technique to data collected from a modified optical microscope to realize a reduction in the optical sectioning depth to 2 µm in the axial direction for samples up to 150 µm thick. Furthermore, we increase the number of sections that are imaged from 5 in our previous work to 34 here. Our results compare well with sectioned images collected from a confocal microscope but have the added advantage of strong phase contrast, which removes the need for sample staining.

Soft X-ray spectromicroscopy using ptychography with randomly phased illumination.

Ptychography is a form of scanning diffractive imaging that can successfully retrieve the modulus and phase of both the sample transmission function and the illuminating probe. An experimental difficulty commonly encountered in diffractive imaging is the large dynamic range of the diffraction data. Here we report a novel ptychographic experiment using a randomly phased X-ray probe to considerably reduce the dynamic range of the recorded diffraction patterns. Images can be reconstructed reliably and robustly from this setup, even when scatter from the specimen is weak. A series of ptychographic reconstructions at X-ray energies around the L absorption edge of iron demonstrates the advantages of this method for soft X-ray spectromicroscopy, which can readily provide chemical sensitivity without the need for optical refocusing. In particular, the phase signal is in perfect registration with the modulus signal and provides complementary information that can be more sensitive to changes in the local chemical environment.

Ptychographic transmission microscopy in three dimensions using a multi-slice approach.

Generally, methods of three-dimensional imaging such as confocal microscopy and computed tomography rely on two essentials: multiple measurements (at a range of focus positions or rotations) and a weakly scattering specimen (to avoid distortion of the focal spot in the confocal microscope or to satisfy the projection approximation in tomography). Here we show that an alternative form of multi-measurement imaging, ptychography, can be extended to three dimensions and can successfully recover images in the presence of multiple scattering and when the projection approximation is not applicable. We demonstrate our technique experimentally using visible light, where it has applications in imaging thick samples such as biological tissues; however the results also have important implications for x ray and electron imaging.

An annealing algorithm to correct positioning errors in ptychography.

Ptychography offers the possibility of improving the resolution of atomic-scale (electron and X-ray) transmission microscopy without any of the demands of high quality lenses: its resolution is in theory only limited by the effective synthetic numerical aperture determined by the angular size of the detector. However, it has been realised experimentally that a major weakness of the approach is that the obtainable resolution is only as good as the accuracy to which the illuminating beam can be moved relative to the specimen. This can be catastrophic in the electron case because of thermal drift and hysteresis in the probe scan coils. We present here a computationally efficient extension of the 'ePIE' ptychographic reconstruction algorithm for correcting these errors retrospectively. We demonstrate its effectiveness using simulations and results from visible light and electron beam experiments that show it can correct positioning errors tens of times larger than the pixel size in the resulting image.

Ptychographic electron microscopy using high-angle dark-field scattering for sub-nanometre resolution imaging.

Diffractive imaging, in which image-forming optics are replaced by an inverse computation using scattered intensity data, could, in principle, realize wavelength-scale resolution in a transmission electron microscope. However, to date all implementations of this approach have suffered from various experimental restrictions. Here we demonstrate a form of diffractive imaging that unshackles the image formation process from the constraints of electron optics, improving resolution over that of the lens used by a factor of five and showing for the first time that it is possible to recover the complex exit wave (in modulus and phase) at atomic resolution, over an unlimited field of view, using low-energy (30 keV) electrons. Our method, called electron ptychography, has no fundamental experimental boundaries: further development of this proof-of-principle could revolutionize sub-atomic scale transmission imaging.

Extended ptychography in the transmission electron microscope: possibilities and limitations.

The extended-ptychographical iterative engine (e-PIE) is a recently developed powerful phase retrieval algorithm which can be used to measure the phase transfer function of a specimen and overcome conventional lens resolution limits. The major improvement over PIE is the ability to reconstruct simultaneously both the object and illumination functions, robustness to noise and speed of convergence. The technique has proven to be successful at optical and X-ray wavelengths and we describe here experimental results in transmission electron microscopy supported by corresponding simulations. These simulations show the possibilities - even with strong phase objects - and limitations of ptychography; in particular issues arising from poorly-defined probe positions.

Association of standing and lying behavior patterns and incidence of intramammary infection in dairy cows milked with an automatic milking system.

The standing and lying behavior patterns of dairy cows, particularly the length of time cows spend standing after milking, have the potential to influence the incidence of intramammary infection (IMI). The objectives were to describe the standing and lying behavior patterns of cows milked with an automatic milking system (AMS) and to determine how these patterns relate to the incidence of IMI. One hundred and eleven lactating Holstein dairy cows were monitored over a 4-mo period. These cows were kept in a sand-bedded freestall barn with 2 pens, each with a free cow traffic AMS. Feed was delivered once daily, and pushed up 2 to 3 times daily. Quarter milk samples were collected for bacteriological culture from each cow once every 4 wk. A new IMI was defined as a positive culture sample following a negative culture. For 7 d before each of the last 3 milk samplings, standing and lying behavior, and times of milking and feed manipulation (feed delivery and push up) were recorded. Daily lying time and lying bout length were negatively related with milk yield (r=-0.23 and -0.20, respectively) and milking frequency (r=-0.32 and -0.20, respectively); milk yield was positively related to milking frequency (r=0.58). Feed manipulation near the time cows were milked (1h before 2h after) resulted in the longest post-milking standing times (mean=86 min; 95% confidence interval=78, 94 min), whereas feed manipulation occurring outside that time frame resulted in shorter post-milking standing times. Over the study period, 171 new IMI were detected. Of these new IMI detected, those caused by coagulase-negative staphylococci were the only ones associated with post-milking standing time; as post-milking standing time increased past 2.5h after milking, the odds of acquiring a new IMI tended to also increase. In summary, standing and lying behavior patterns of cows milked with an AMS were affected by both feed manipulation and their milking activity. Further, the post-milking standing time of cows milked with an AMS can be managed by providing fresh feed, as well as by pushing up feed, frequently throughout the day. Finally, cows that spend long periods of time (>2.5h) standing following milking may be at higher risk of acquiring a new CNS IMI.

The role of helium ion microscopy in the characterisation of complex three-dimensional nanostructures.

This work addresses two major issues relating to Helium Ion Microscopy (HeIM). First we show that HeIM is capable of solving the interpretation difficulties that arise when complex three-dimensional structures are imaged using traditional high lateral resolution techniques which are transmission based, such as scanning transmission electron microscopy (STEM). Secondly we use a nano-composite coating consisting of amorphous carbon embedded in chromium rich matrix to estimate the mean escape depth for amorphous carbon for secondary electrons generated by helium ion impact as a measure of HeIM depth resolution.

Influence of thick crystal effects on ptychographic image reconstruction with moveable illumination.

The properties of the iterative phase-retrieval ptychographical imaging technique are modelled. We use the multi-slice method to generate a series of diffraction patterns when a small convergent illumination spot is moved across a silicon crystal orientated in the 100 direction. These are then used to reconstruct the transmission function of the sample by solving the phase of diffraction patterns using the ptychographical iterative engine (PIE) algorithm [H.M.L. Faulkner, J.M. Rodenburg, Physical Review Letters 93 (2004) 023903], which assumes the object is a thin, two-dimensional grating. It is found that to obtain lattice-resolved reconstructions, the thickness of the crystal should be smaller than half of the corresponding extinction distance, the probe should be highly defocused to obtain a planar enough wave front and the movements of the probe should be as small as possible to minimize the changes in the transmission function of the sample for two adjacent illumination positions.

Hard-x-ray lensless imaging of extended objects.

We demonstrate a hard-x-ray microscope that does not use a lens and is not limited to a small field of view or an object of finite size. The method does not suffer any of the physical constraints, convergence problems, or defocus ambiguities that often arise in conventional phase-retrieval diffractive imaging techniques. Calculation times are about a thousand times shorter than in current iterative algorithms. We need no a priori knowledge about the object, which can be a transmission function with both modulus and phase components. The technique has revolutionary implications for x-ray imaging of all classes of specimen.

Transmission microscopy without lenses for objects of unlimited size.

We demonstrate experimentally, for the first time, a new form of lensless microscopy. The image we obtain contains the entire wavefunction emanating from the sample. Large scale, quantitative phase information can be measured, unlike in conventional (Zernike) methods. For light optical experiments, we can dispense with expensive high-quality lenses and the very large working distances available would allow remote monitoring of e.g., environmental cells without compromising resolution. In short wavelength microscopy (X-rays and electrons), where lens components are of very limited numerical aperture, the technique has revolutionary implications: objects of any lateral size or shape can be used and, for transmission electron imaging, resolution down to the scale of the wavelength is likely to be limited only by the presence of atomic vibrations.

Increased inflammatory markers in children with familial hypercholesterolaemia.

BACKGROUND: While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). MATERIALS AND METHODS: In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20-40 mg qd) or placebo on plasma levels of those markers. RESULTS: Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. CONCLUSION: These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.

Error tolerance of an iterative phase retrieval algorithm for moveable illumination microscopy.

This paper examines the behaviour of the new Ptychographical Iterative Engine (PIE) algorithm when part of the initial information it requires is inaccurately known. This could be the parameters describing the illuminating wavefunction, the precise location of the specimen relative to the illuminating wavefunction, or other information that is assumed about the physical system. The tolerance of the algorithm for unavoidable problems such as noise and source incoherence is also investigated, leading to the conclusion that this approach to phase retrieval is very robust. It can not only tolerate errors in the assumed parameters, but can often be used as a method of characterising the parameters more accurately.

Movable aperture lensless transmission microscopy: a novel phase retrieval algorithm.

We propose an iterative phase retrieval method that uses a series of diffraction patterns, measured only in intensity, to solve for both amplitude and phase of the image wave function over a wide field of view and at wavelength-limited resolution. The new technique requires an aperture that is scanned to two or more positions over the object wave function. A simple implementation of the method is modeled and demonstrated, showing how the algorithm uses overlapping data in real space to resolve ambiguities in the solution. The technique opens up the possibility of practical transmission lensless microscopy at subatomic resolution using electrons, x rays, or nuclear particles.

Familial hypercholesterolemia in children.

PURPOSE OF THIS REVIEW: This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. RECENT FINDINGS: A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. SUMMARY: Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.

A boy with autosomal recessive hypercholesterolaemia.

We describe a 9-year-old Iranian boy with tuberous xanthomas, elevated LDL-cholesterol levels of 15.5 mmol/l, and vague complaints of chest pain while playing soccer. The consanguineous parents of the boy had normal cholesterol concentrations, which indicated an autosomal recessive disorder rather than autosomal dominant familial hypercholesterolaemia. The diagnosis of autosomal recessive hypercholesterolaemia (ARH) was confirmed by the presence of a mutation in the phosphotyrosine binding domain of a putative adaptor protein, which prevents normal internalisation of the LDL receptor (LDLR) in the liver. The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia caused by defects in the LDLR gene, but it is more variable, generally less severe, and more responsive to lipid-lowering therapy. The patient's complaints of chest pain were not caused by ischaemia as was tested by an exercise and 24-hour electrocardiogram and by a myocardial perfusion scan. His LDL-C dropped by about 6o% after being treated with a combination of 40 mg atorvastatin and 10 mg ezetimibe.

The spectrum of statin therapy in hyperlipidemic children.

The recommended therapy of hypercholesterolemia in children consists of dietary modification and bile acid-binding resins. Unfortunately, the lipid-lowering efficacy of bile acid-binding resins is modest, and moreover, long-term compliance is poor because of side effects. In contrast, hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in adults and are considered to be the first choice in the treatment of hypercholesterolemia in that age category. In the last few years, several randomized trials have been conducted to evaluate the efficacy, safety, and tolerability of statin therapy in both children and adolescents. In this article, we review statin therapy in hypercholesterolemic children in terms of efficacy, safety, pharmacokinetics, and psychosocial functioning. Statins are not only effective in reducing low-density lipoprotein cholesterol levels in children with familial hypercholesterolemia but also improve endothelial function and reduce the progressive thickening of the intima media complex of the carotid arteries. Statins seem safe at the longer term in children in terms of plasma levels of liver enzymes and liver function, creatine kinase levels, and muscle function, as well as growth and sexual development. Long-term follow-up studies are needed to assess whether statin treatment started early in children with familial hypercholesterolemia can prevent future cardiovascular events.