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

Maternal occupation in agriculture and risk of limb defects in Washington State, 1980-1993

Objectives. This study examined the association between maternal occupational exposure to agricultural chemicals and the risk of limb defects among offspring. Methods. A retrospective cohort study was conducted using Washington State birth records for the years 1980 through 1993. The exposed group, consisting of 4466 births to mothers employed in agriculture, was compared with 2 reference groups: (i) 23 512 births in which neither parent worked in agriculture (″nonagricultural″ group) and (ii) 5994 births in which only the father worked in agriculture (″paternal agriculture″ group). The outcome of interest was limb defects [syndactyly, polydactyly, adactyly, and ″other limb reductions″ (as listed in the birth record)]. Results. An elevated risk of limb defects was observed for the exposed group in comparison with both the nonagricultural and paternal agriculture groups, with ethnicity-adjusted prevalence ratios of 2.6 [95% confidence interval (95% CI) 1.1-5.8] and 2.6 (95% CI 0.7-9.5), respectively. Conclusions. These results support the hypothesis that maternal occupational exposure to agricultural chemicals may increase the risk of giving birth to a child with limb defects

Interruption of the Arterial Inferior Alveolar Flow and its Effects on Mandibular Collateral Circulation and Dental Tissues

The interruption of circulation through the inferior alveolar artery was followed by the establishment of a fast retrograde blood flow through the vessel. The mental artery and the mandibular branch of the sublingual artery were the main vessels to contribute to that flow. No histopathologic changes were found in the experimental hemimandibles; however, temporary regressive changes were found in the dental pulps of molars.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67920/2/10.1177_00220345750540040301.pd

Flexible VWAP Executions in Electronic Trading

For the execution of large equity orders, institutional investors often use the Volume Weighted Average Price (VWAP) as a benchmark to measure execution quality. To achieve this, they have the possibility to either cross their orders in a nonintermediated electronic system or to submit a VWAP agency order to a broker that executes the orders manually. Though more expensive in explicit costs, agency VWAP is still more attractive to investors than VWAP crossings, in particular due to higher flexibility. This work proposes a new electronic crossing model addressing and solving the flexibility restrictions present in today’s VWAP crossing

Dynamical compactification from de Sitter space

We show that D-dimensional de Sitter space is unstable to the nucleation of non-singular geometries containing spacetime regions with different numbers of macroscopic dimensions, leading to a dynamical mechanism of compactification. These and other solutions to Einstein gravity with flux and a cosmological constant are constructed by performing a dimensional reduction under the assumption of q-dimensional spherical symmetry in the full D-dimensional geometry. In addition to the familiar black holes, black branes, and compactification solutions we identify a number of new geometries, some of which are completely non-singular. The dynamical compactification mechanism populates lower-dimensional vacua very differently from false vacuum eternal inflation, which occurs entirely within the context of four-dimensions. We outline the phenomenology of the nucleation rates, finding that the dimensionality of the vacuum plays a key role and that among vacua of the same dimensionality, the rate is highest for smaller values of the cosmological constant. We consider the cosmological constant problem and propose a novel model of slow-roll inflation that is triggered by the compactification process.Comment: Revtex. 41 pages with 24 embedded figures. Minor corrections and added reference

A unique bacteriohopanetetrol stereoisomer of marine anammox

Anaerobic ammonium oxidation (anammox) is a major process of bioavailable nitrogen removal from marine systems. Previously, a bacteriohopanetetrol (BHT) isomer, with unknown stereochemistry, eluting later than BHT using high performance liquid chromatography (HPLC), was detected in ‘Ca. Scalindua profunda’ and proposed as a biomarker for anammox in marine paleo-environments. However, the utility of this BHT isomer as an anammox biomarker is hindered by the fact that four other, non-anammox bacteria are also known to produce a late-eluting BHT stereoisomer. The stereochemistry in Acetobacter pasteurianus, Komagataeibacter xylinus and Frankia sp. was known to be 17β, 21β(H), 22R, 32R, 33R, 34R (BHT-34R). The stereochemistry of the late-eluting BHT in Methylocella palustris was unknown. To determine if marine anammox bacteria produce a unique BHT isomer, we studied the BHT distributions and stereochemistry of known BHT isomer producers and of previously unscreened marine (‘Ca. Scalindua brodeae’) and freshwater (‘Ca. Brocadia sp.’) anammox bacteria using HPLC and gas chromatographic (GC) analysis of acetylated BHTs and ultra high performance liquid chromatography (UHPLC)-high resolution mass spectrometry (HRMS) analysis of non-acetylated BHTs. The 34R stereochemistry was confirmed for the BHT isomers in Ca. Brocadia sp. and Methylocella palustris. However, ‘Ca. Scalindua sp.’ synthesise a stereochemically distinct BHT isomer, with still unconfirmed stereochemistry (BHT-x). Only GC analysis of acetylated BHT and UHPLC analysis of non-acetylated BHT distinguished between late-eluting BHT isomers. Acetylated BHT-x and BHT-34R co-elute by HPLC. As BHT-x is currently only known to be produced by ‘Ca. Scalindua spp.’, it may be a biomarker for marine anammox

Measures for a Transdimensional Multiverse

The multiverse/landscape paradigm that has emerged from eternal inflation and string theory, describes a large-scale multiverse populated by "pocket universes" which come in a huge variety of different types, including different dimensionalities. In order to make predictions in the multiverse, we need a probability measure. In $(3+1)d$ landscapes, the scale factor cutoff measure has been previously shown to have a number of attractive properties. Here we consider possible generalizations of this measure to a transdimensional multiverse. We find that a straightforward extension of scale factor cutoff to the transdimensional case gives a measure that strongly disfavors large amounts of slow-roll inflation and predicts low values for the density parameter $\Omega$, in conflict with observations. A suitable generalization, which retains all the good properties of the original measure, is the "volume factor" cutoff, which regularizes the infinite spacetime volume using cutoff surfaces of constant volume expansion factor.Comment: 30 pages, 1 figure Minor revisions, reference adde

Bubbles from Nothing

Within the framework of flux compactifications, we construct an instanton describing the quantum creation of an open universe from nothing. The solution has many features in common with the smooth 6d bubble of nothing solutions discussed recently, where the spacetime is described by a 4d compactification of a 6d Einstein-Maxwell theory on S^2 stabilized by flux. The four-dimensional description of this instanton reduces to that of Hawking and Turok. The choice of parameters uniquely determines all future evolution, which we additionally find to be stable against bubble of nothing instabilities.Comment: 19 pages, 6 figure

Decay of flux vacua to nothing

We construct instanton solutions describing the decay of flux compactifications of a $6d$ gauge theory by generalizing the Kaluza-Klein bubble of nothing. The surface of the bubble is described by a smooth magnetically charged solitonic brane whose asymptotic flux is precisely that responsible for stabilizing the 4d compactification. We describe several instances of bubble geometries for the various vacua occurring in a $6d$ Einstein-Maxwell theory namely, AdS_4 x S^2, R^{1,3} x S^2, and dS_4 x S^2. Unlike conventional solutions, the bubbles of nothing introduced here occur where a {\em two}-sphere compactification manifold homogeneously degenerates.Comment: 31 pages, 15 figure