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

Surface layering of liquids: The role of surface tension

Recent measurements show that the free surfaces of liquid metals and alloys are always layered, regardless of composition and surface tension; a result supported by three decades of simulations and theory. Recent theoretical work claims, however, that at low enough temperatures the free surfaces of all liquids should become layered, unless preempted by bulk freezing. Using x-ray reflectivity and diffuse scattering measurements we show that there is no observable surface-induced layering in water at T=298 K, thus highlighting a fundamental difference between dielectric and metallic liquids. The implications of this result for the question in the title are discussed.Comment: 5 pages, 4 figures, to appear in Phys. Rev. B. 69 (2004

Optical investigation of the charge-density-wave phase transitions in NbSe3NbSe_{3}

We have measured the optical reflectivity $R(\omega)$ of the quasi one-dimensional conductor $NbSe_{3}$ from the far infrared up to the ultraviolet between 10 and 300 $K$ using light polarized along and normal to the chain axis. We find a depletion of the optical conductivity with decreasing temperature for both polarizations in the mid to far-infrared region. This leads to a redistribution of spectral weight from low to high energies due to partial gapping of the Fermi surface below the charge-density-wave transitions at 145 K and 59 K. We deduce the bulk magnitudes of the CDW gaps and discuss the scattering of ungapped free charge carriers and the role of fluctuations effects

Bitangential interpolation in generalized Schur classes

Bitangential interpolation problems in the class of matrix valued functions in the generalized Schur class are considered in both the open unit disc and the open right half plane, including problems in which the solutions is not assumed to be holomorphic at the interpolation points. Linear fractional representations of the set of solutions to these problems are presented for invertible and singular Hermitian Pick matrices. These representations make use of a description of the ranges of linear fractional transformations with suitably chosen domains that was developed in a previous paper.Comment: Second version, corrected typos, changed subsection 5.6, 47 page

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

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< 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 > 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

Charge conservation and time-varying speed of light

It has been recently claimed that cosmologies with time dependent speed of light might solve some of the problems of the standard cosmological scenario, as well as inflationary scenarios. In this letter we show that most of these models, when analyzed in a consistent way, lead to large violations of charge conservation. Thus, they are severly constrained by experiment, including those where $c$ is a power of the scale factor and those whose source term is the trace of the energy-momentum tensor. In addition, early Universe scenarios with a sudden change of $c$ related to baryogenesis are discarded.Comment: 4 page

Associations of Comorbid Conditions and Transitions Across States of Knee Osteoarthritis in a Community-Based Cohort

Objective: To examine relationships between knee osteoarthritis (KOA) and obesity, diabetes mellitus (DM), and cardiovascular disease (CVD). Methods: Associations of time-dependent obesity, DM, and CVD with KOA transition states over approximately 18 years were examined among 4093 participants from a community-based cohort. Transition states were 1) no knee symptoms and no radiographic KOA (rKOA; Kellgren-Lawrence grade ≥2 in at least one knee), 2) asymptomatic rKOA, 3) knee symptoms only, 4) symptomatic rKOA (sxKOA; rKOA and symptoms in same knee). Markov multistate models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for associations between comorbid conditions and transitions across states, adjusting for baseline age, sex, race, education, enrollment cohort, birth year, and time-dependent knee injury history. Results: At baseline, 40% of participants had obesity, 13% had DM, and 22% had CVD (mean age = 61 years; 34% Black; 37% male). Compared with those without obesity, those with obesity had a higher hazard of worsening from no rKOA/no symptoms to asymptomatic rKOA (aHR = 1.7; 95% CI = 1.3-2.2) and from knee symptoms to sxKOA (aHR = 1.7; 95% CI = 1.3-2.3), as well as a lower hazard of symptom resolution from sxKOA to asymptomatic rKOA (aHR = 0.5 [95% = CI 0.4-0.7]). Compared with those without CVD, those with CVD had a higher hazard of worsening from no rKOA/symptoms to knee symptoms (aHR = 1.5; 95% CI = 1.1-2.1). DM was not associated with transitions of rKOA. Conclusion: Prevention of obesity and CVD may limit the development or worsening of rKOA and symptoms

Weakly coupled one-dimensional Mott insulators

We consider a model of one-dimensional Mott insulators coupled by a weak interchain tunnelling $t_\perp$. We first determine the single-particle Green's function of a single chain by exact field-theoretical methods and then take the tunnelling into account by means of a Random Phase Approximation (RPA). In order to embed this approximation into a well-defined expansion with a small parameter, the Fourier transform $T_\perp(k)$ of the interchain coupling is assumed to have a small support in momentum space such that every integration over transverse wave vector yields a small factor $\kappa_0^2 \ll 1$. When \tp(0) exceeds a critical value, a small Fermi surface develops in the form of electron and hole pockets. We demonstrate that Luttinger's theorem holds both in the insulating and in the metallic phases. We find that the quasi-particle residue $Z$ increases very fast through the transition and quickly reaches a value of about $0.4-0.6$. The metallic state close to the transition retains many features of the one-dimensional system in the form of strong incoherent continua.Comment: 14 pages, 13 figure

The Prevalence of Knee Symptoms, Radiographic, and Symptomatic Osteoarthritis at Four Time Points: The Johnston County Osteoarthritis Project, 1999-2018

Objective: To describe point prevalence of knee symptoms, radiographic knee osteoarthritis (rKOA), severe rKOA, and symptomatic rKOA at four time points in the longitudinal, population-based Johnston County Osteoarthritis Project (JoCo OA). Methods: Data were from 2573 JoCo OA participants with up to 18 years of follow-up (1999-2018) and standardized fixed-flexion knee radiographs read by a single, reliable expert musculoskeletal radiologist. The four outcomes were 1) self-reported knee symptoms, defined by “On most days, do you have pain, aching, or stiffness in your right/left knee?”; 2) rKOA, defined as a Kellgren-Lawrence grade (KLG) of 2 to 4); 3) severe rKOA, defined as a KLG of 3 or 4; and 4) symptomatic rKOA, defined as both symptoms and rKOA in the same joint. Weighted prevalence estimates and 95% confidence intervals (CIs) were generated overall and by age group, sex, race, and body mass index (BMI). Results: Most recently (2017-2018, T4), the overall prevalence (percentage) of knee symptoms, rKOA, severe rKOA, and symptomatic rKOA was 41% (95% CI: 35-47%), 61% (95% CI: 56-67%), 35% (95% CI: 30-40%), and 30% (95% CI: 24-35%), respectively. From time point T1 to T4, prevalence increased for rKOA, severe rKOA, and symptomatic rKOA but not for knee symptoms. The prevalence of both severe rKOA (17-39%) and symptomatic rKOA (23-30%) was consistently higher among women. The prevalence of all outcomes was higher among those with higher BMI and among Black participants at all time points, particularly rKOA (35-69%) and severe rKOA (22-46%). Conclusion: These updated estimates demonstrate a large and increasing burden of knee OA, particularly among women and Black individuals