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

Correlation Functions for an Elastic String in a Random Potential: Instanton Approach

We develop an instanton technique for calculations of correlation functions characterizing statistical behavior of the elastic string in disordered media and apply the proposed approach to correlations of string free energies corresponding to different low-lying metastable positions. We find high-energy tails of correlation functions for the case of long-range disorder (the disorder correlation length well exceeds the characteristic distance between the sequential string positions) and short-range disorder with the correlation length much smaller then the characteristic string displacements. The former case refers to energy distributions and correlations on the distances below the Larkin correlation length, while the latter describes correlations on the large spatial scales relevant for the creep dynamics.Comment: 5 pages; 1 .eps figure include

Dark matter and sub-GeV hidden U(1) in GMSB models

Motivated by the recent PAMELA and ATIC data, one is led to a scenario with heavy vector-like dark matter in association with a hidden $U(1)_X$ sector below GeV scale. Realizing this idea in the context of gauge mediated supersymmetry breaking (GMSB), a heavy scalar component charged under $U(1)_X$ is found to be a good dark matter candidate which can be searched for direct scattering mediated by the Higgs boson and/or by the hidden gauge boson. The latter turns out to put a stringent bound on the kinetic mixing parameter between $U(1)_X$ and $U(1)_Y$: $\theta \lesssim 10^{-6}$. For the typical range of model parameters, we find that the decay rates of the ordinary lightest neutralino into hidden gauge boson/gaugino and photon/gravitino are comparable, and the former decay mode leaves displaced vertices of lepton pairs and missing energy with distinctive length scale larger than 20 cm for invariant lepton pair mass below 0.5 GeV. An unsatisfactory aspect of our model is that the Sommerfeld effect cannot raise the galactic dark matter annihilation by more than 60 times for the dark matter mass below TeV.Comment: 1+15 pages, 4 figures, version published in JCAP, references added, minor change

Corrigendum to “Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants” [NeuroImage: Clinical 8 (2015) 462–472]

Why preserve bamboos? Bamboos are a natural material and under natural conditions will gradually decay. If they are used as structural components they will need to be replaced after a period of time. The costs of this may prove prohibitive and the status of the bamboo will need constant monitoring to determine when it needs to be replaced. Preserving bamboos extends their life, reduces costs in the long run and improves safety of the structures they are used to form. What are sap displacement preservation methods? Sap displacement methods replace the sap in the vessels of a fresh bamboo culm with preservative. The culms are then left to stand for two weeks in order that the preservative can diffuse into the surrounding tissues and the preserving salts can be fixed in the cells. Sap displacement can be done by using natural capillary action or by one of a small range of simple pressurised techniques. What is the role of a sap displacement preservation unit in rural development? The unit itself offers employment opportunities to its employees and to many people in its forward and backward linkages. The unit can only treat freshly harvested bamboos and so a source of bamboos near to the unit is required. Local bamboo plantations can be established to supply the unit and create further income generating opportunities. Bamboos can be intercropped with food plants and the plantations can thereby increase the food security of the rural people that manage them. How do I establish a sap displacement unit? A sap displacement preservation unit can be established very cheaply. The only requirements are a supply of freshly harvested bamboos, labour and information from the secondary processors of their requirements. If a pressurised unit is to be established then a source of energy for the compressor will be needed. A pressurised unit capable of treating 50 bamboos per day can be established for USD $500, including a compressor, and non-pressurised units can be established for considerably less.Preserving bamboos extends their life, reduces costs in the long run and improves safety of the structures they are used to for

Effects of comorbid cardiovascular disease and diabetes on hand osteoarthritis, pain, and functional state transitions: The Johnston county osteoarthritis project

Objective. The purpose of this study is to examine the course of hand osteoarthritis (HOA) and its relationship with cardiovascular disease (CVD) and diabetes (DM). Methods. Data were collected at 3 timepoints from 845 Johnston County Osteoarthritis Project participants (two-thirds women, one-third African Americans, mean age 60 yrs) with and without HOA, CVD, or DM. A diagnosis of radiographic HOA (rHOA) required a Kellgren-Lawrence severity grade of ≥ 2 in at least 3 joints in each hand. A 4-state progressive model included transitions based on rHOA and pain or function as defined using the Australian/Canadian HOA Index (AUSCAN). Markov multistate models estimated HR (aHR) and 95% CI for associations between DM or CVD and specific state transitions, adjusting for baseline and time-varying covariates. Results. Participants with DM (vs those without DM) were more likely to experience worsening pain with rHOA. Individuals who had or developed CVD (vs those who did not) were significantly less likely to experience symptomatic improvement, regardless of rHOA status. Those with DM or CVD (vs those without these comorbidities) were less likely to experience improvement in function, although this was statistically significant only for those with DM and no rHOA. Conclusion. Overall, having or developing DM and/or CVD reduced the likelihood of symptomatic and functional improvement over time, suggesting an effect of comorbid CVD and DM on the clinical and radiographic course of HOA. Additional studies are needed to confirm these findings

A Pure-Glue Hidden Valley I. States and Decays

It is possible that the standard model is coupled, through new massive charged or colored particles, to a hidden sector whose low energy dynamics is controlled by a pure Yang-Mills theory, with no light matter. Such a sector would have numerous metastable "hidden glueballs" built from the hidden gluons. These states would decay to particles of the standard model. We consider the phenomenology of this scenario, and find formulas for the lifetimes and branching ratios of the most important of these states. The dominant decays are to two standard model gauge bosons, or by radiative decays with photon emission, leading to jet- and photon-rich signals.Comment: 34 pages, 4 figure

Theory of finite temperature crossovers near quantum critical points close to, or above, their upper-critical dimension

A systematic method for the computation of finite temperature ($T$) crossover functions near quantum critical points close to, or above, their upper-critical dimension is devised. We describe the physics of the various regions in the $T$ and critical tuning parameter ($t$) plane. The quantum critical point is at $T=0$, $t=0$, and in many cases there is a line of finite temperature transitions at $T = T_c (t)$, $t < 0$ with $T_c (0) = 0$. For the relativistic, $n$-component $\phi^4$ continuum quantum field theory (which describes lattice quantum rotor ($n \geq 2$) and transverse field Ising ($n=1$) models) the upper critical dimension is $d=3$, and for $d<3$, $\epsilon=3-d$ is the control parameter over the entire phase diagram. In the region $|T - T_c (t)| \ll T_c (t)$, we obtain an $\epsilon$ expansion for coupling constants which then are input as arguments of known {\em classical, tricritical,} crossover functions. In the high $T$ region of the continuum theory, an expansion in integer powers of $\sqrt{\epsilon}$, modulo powers of $\ln \epsilon$, holds for all thermodynamic observables, static correlators, and dynamic properties at all Matsubara frequencies; for the imaginary part of correlators at real frequencies ($\omega$), the perturbative $\sqrt{\epsilon}$ expansion describes quantum relaxation at $\hbar \omega \sim k_B T$ or larger, but fails for $\hbar \omega \sim \sqrt{\epsilon} k_B T$ or smaller. An important principle, underlying the whole calculation, is the analyticity of all observables as functions of $t$ at $t=0$, for $T>0$; indeed, analytic continuation in $t$ is used to obtain results in a portion of the phase diagram. Our method also applies to a large class of other quantum critical points and their associated continuum quantum field theories.Comment: 36 pages, 4 eps figure

Comorbid conditions and the transition among states of hip osteoarthritis and symptoms in a community-based study: A multi-state time-to-event model approach

Background: We examined the association of three common chronic conditions (obesity, diabetes mellitus [DM], and cardiovascular disease [CVD]) with transitions among states of hip osteoarthritis (HOA). Methods: This longitudinal analysis used data from the Johnston County Osteoarthritis Project (JoCo OA, n = 3857), a community-based study in North Carolina, USA, with 18.4 ± 1.5 years of follow-up. Transitions across the following states were modeled: development of radiographic HOA (rHOA; Kellgren-Lawrence grade [KLG] of&lt; 2); development of hip symptoms (self-reported hip pain, aching, or stiffness on most days) or symptomatic HOA (sxHOA; rHOA and symptoms in the same hip), and resolution of symptoms. Obesity (body mass index ≥ 30 kg/m2) and self-reported DM and CVD were the time-dependent comorbid conditions of interest. Markov multi-state models were used to estimate adjusted hazard ratios and 95% confidence intervals to describe the associations between the conditions and HOA states. Results: The sample included 33% African Americans, 39% men, with a mean (SD) age of 62.2 (9.8) years; the frequencies of the comorbidities increased substantially over time. When considered individually, obesity was associated with incident hip symptoms, while CVD and DM were associated with reduced symptom resolution. For those with &gt; 1 comorbidity, the likelihood of incident sxHOA increased, while that of symptom resolution significantly decreased. When stratified by sex, the association between obesity and incident symptoms was only seen in women; among men with DM versus men without, there was a significant (~ 75%) reduction in symptom resolution in those with rHOA. When stratified by race, African Americans with DM, versus those without, were much more likely to develop sxHOA. Conclusions: Comorbid chronic conditions are common in individuals with OA, and these conditions have a significant impact on the persistence and progression of HOA. OA management decisions, both pharmacologic and non-pharmacologic, should include considerations of the inter-relationships between OA and common comorbidities such as DM and CVD

Evidence for osteocyte-mediated bone-matrix degradation associated with periprosthetic joint infection (PJI)

Osteomyelitis associated with periprosthetic joint infection (PJI) signals a chronic infection and the need for revision surgery. An osteomyelitic bone exhibits distinct morphological features, including evidence for osteolysis and an accelerated bone remodelling into poorly organised, poor-quality bone. In addition to immune cells, various bone cell-types have been implicated in the pathology. The present study sought to determine the types of bone-cell activities in human PJI bones. Acetabular biopsies from peri-implant bone from patients undergoing revision total hip replacement (THR) for chronic PJI (with several identified pathogens) as well as control bone from the same patients and from patients undergoing primary THR were analysed. Histological analysis confirmed that PJI bone presented increased osteoclastic activity compared to control bone. Analysis of osteocyte parameters showed no differences in osteocyte lacunar area between the acetabular bone taken from PJI patients or primary THR controls. Analysis of bone matrix composition using Masson's trichrome staining and second-harmonic generation microscopy revealed widespread lack of mature collagen, commonly surrounding osteocytes, in PJI bone. Increased expression of known collagenases, such as matrix metallopeptidase (MMP) 13, MMP1 and cathepsin K (CTSK), was measured in infected bone compared to non-infected bone. Human bone and cultured osteocyte-like cells experimentally exposed to Staphylococcus aureus exhibited strongly upregulated expression of MMP1, MMP3 and MMP13 compared to non-exposed controls. In conclusion, the study identified previously unrecognised bone-matrix changes in PJI caused by multiple organisms deriving from osteocytes. Histological examination of bone collagen composition may provide a useful adjunct diagnostic measure of PJI.R.T. Ormsby, A.R. Zelmer, D. Yang, N.J. Gunn, Y. Starczak, S.P. Kidd ... et al