Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials

STUDY QUESTION What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. reports: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work

A Model for the Stray Light Contamination of the UVCS Instrument on SOHO

We present a detailed model of stray-light suppression in the spectrometer channels of the Ultraviolet Coronagraph Spectrometer (UVCS) on the SOHO spacecraft. The control of diffracted and scattered stray light from the bright solar disk is one of the most important tasks of a coronagraph. We compute the fractions of light that diffract past the UVCS external occulter and non-specularly pass into the spectrometer slit. The diffracted component of the stray light depends on the finite aperture of the primary mirror and on its figure. The amount of non-specular scattering depends mainly on the micro-roughness of the mirror. For reasonable choices of these quantities, the modeled stray-light fraction agrees well with measurements of stray light made both in the laboratory and during the UVCS mission. The models were constructed for the bright H I Lyman alpha emission line, but they are applicable to other spectral lines as well.Comment: 19 pages, 5 figures, Solar Physics, in pres

Optical Resonances in Reflectivity near Crystal Modes with Spatial Dispersion

We study the effect of spatial dispersion of crystal modes on optical properties such as the reflectivity $R$. As an example for isotropic media, we investigate the simplest model for phonons in ionic crystals and compare with previous results for highly anisotropic plasmons, which are now understood from a more general point of view. As a consequence of the wave vector dependence of the dielectric function small changes in the lineshape are predicted. Beyond that, if the frequency of minimal $R$ is near a pole of the dispersionless dielectric function, the relative amplitude of dips in $R$ with normal and anomalous dispersion differ significantly, if dissipation and disorder are low.Comment: 4 pages, 7 eps figures, minor change

Can multi-TeV (top and other) squarks be natural in gauge mediation?

We investigate whether multi-TeV (1-3 TeV) squarks can be natural in models of gauge mediated SUSY breaking. The idea is that for some boundary condition of the scalar (Higgs and stop) masses, the Higgs (mass)$^2$, evaluated at the renormalization scale $\sim O(100)$ GeV, is not very sensitive to (boundary values of) the scalar masses (this has been called ``focussing'' in recent literature). Then, the stop masses can be multi-TeV without leading to fine-tuning in electroweak symmetry breaking. {\em Minimal} gauge mediation does {\em not} lead to this focussing (for all values of $\tan \beta$ and the messenger scale): the (boundary value of) the Higgs mass is too small compared to the stop masses. Also, in minimal gauge mediation, the gaugino masses are of the same order as the scalar masses so that multi-TeV scalars implies multi-TeV gauginos (especially gluino) leading to fine-tuning. We discuss ideas to {\em increase} the Higgs mass relative to the stop masses (so that focussing can be achieved) and also to {\em suppress} gaugino masses relative to scalar masses (or to modify the gaugino mass relations) in {\em non-minimal} models of gauge mediation -- then multi-TeV (top and other) squarks can be natural. Specific models of gauge mediation which incorporate these ideas and thus have squarks (and in some cases, the gluino) heavier than a TeV without resulting in fine-tuning are also studied and their collider signals are contrasted with those of other models which have multi-TeV squarks.Comment: LaTeX, 29 pages, 9 eps figures. Replacing an earlier version. In version 3, some references and a minor comment have been added and typos have been correcte

A Composite Little Higgs Model

We describe a natural UV complete theory with a composite little Higgs. Below a TeV we have the minimal Standard Model with a light Higgs, and an extra neutral scalar. At the TeV scale there are additional scalars, gauge bosons, and vector-like charge 2/3 quarks, whose couplings to the Higgs greatly reduce the UV sensitivity of the Higgs potential. Stabilization of the Higgs mass squared parameter, without finetuning, occurs due to a softly broken shift symmetry--the Higgs is a pseudo Nambu-Goldstone boson. Above the 10 TeV scale the theory has new strongly coupled interactions. A perturbatively renormalizable UV completion, with softly broken supersymmetry at 10 TeV is explicitly worked out. Our theory contains new particles which are odd under an exact "dark matter parity", (-1)^{(2S+3B+L)}. We argue that such a parity is likely to be a feature of many theories of new TeV scale physics. The lightest parity odd particle, or "LPOP", is most likely a neutral fermion, and may make a good dark matter candidate, with similar experimental signatures to the neutralino of the MSSM. We give a general effective field theory analysis of the calculation of corrections to precision electroweak observables.Comment: 28 page

Enhancement of pair correlation in a one-dimensional hybridization model

We propose an integrable model of one-dimensional (1D) interacting electrons coupled with the local orbitals arrayed periodically in the chain. Since the local orbitals are introduced in a way that double occupation is forbidden, the model keeps the main feature of the periodic Anderson model with an interacting host. For the attractive interaction, it is found that the local orbitals enhance the effective mass of the Cooper-pair-like singlets and also the pair correlation in the ground state. However, the persistent current is depressed in this case. For the repulsive interaction case, the Hamiltonian is non-Hermitian but allows Cooper pair solutions with small momenta, which are induced by the hybridization between the extended state and the local orbitals.Comment: 11 page revtex, no figur

Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.

Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites' biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case–control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates

Adaptation of Autocatalytic Fluctuations to Diffusive Noise

Evolution of a system of diffusing and proliferating mortal reactants is analyzed in the presence of randomly moving catalysts. While the continuum description of the problem predicts reactant extinction as the average growth rate becomes negative, growth rate fluctuations induced by the discrete nature of the agents are shown to allow for an active phase, where reactants proliferate as their spatial configuration adapts to the fluctuations of the catalysts density. The model is explored by employing field theoretical techniques, numerical simulations and strong coupling analysis. For d<=2, the system is shown to exhibits an active phase at any growth rate, while for d>2 a kinetic phase transition is predicted. The applicability of this model as a prototype for a host of phenomena which exhibit self organization is discussed.Comment: 6 pages 6 figur

Decoupling in the 1D frustrated quantum XY model and Josephson junction ladders: Ising critical behavior

A generalization of the one-dimensional frustrated quantum XY model is considered in which the inter and intra-chain coupling constants of the two infinite XY (planar rotor) chains have different strengths. The model can describe the superconductor to insulator transition due to charging effects in a ladder of Josephson junctions in a magnetic field with half a flux quantum per plaquette. From a fluctuation-effective action, this transition is expected to be in the universality class of the two-dimensional classical XY-Ising model. The critical behavior is studied using a Monte Carlo transfer matrix applied to the path-integral representation of the model and a finite-size-scaling analysis of data on small system sizes. It is found that, unlike the previous studied case of equal inter and intra-chain coupling constants, the XY and Ising-like excitations of the quantum model decouple for large interchain coupling, giving rise to pure Ising model critical behavior for the chirality order parameter and a superconductor-insulator transition in the universality class of the 2D classical XY model.Comment: 15 pages with figures, RevTex 3.0, INPE-93/00