The perspective of women with an increased risk of OHSS regarding the safety and burden of IVF: a discrete choice experiment.

STUDY QUESTION: What are the preferences of women with an increased risk of ovarian hyperstimulation syndrome (OHSS) for characteristics of IVF treatments? SUMMARY ANSWER: In women with increased risk of OHSS, the chance of OHSS is a strong attribute in determining women's preference for IVF treatment and women are willing to trade off burden (side effects), costs and chance of pregnancy for lower risks of OHSS. WHAT IS KNOWN ALREADY: OHSS is the most serious iatrogenic complication of ovarian stimulation. Polycystic ovaries, high antral follicle count (AFC) and previous OHSS increase the risk of developing OHSS. IVM of oocytes offers great potential for patients with high AFC, since there is no risk of OHSS. With regard to patients' perspectives on fertility treatments, it has been shown that women undergoing IVF place different values on treatment characteristics, such as effectiveness (pregnancy rate), cancellation risk, safety (OHSS risk) and burden (side effects). To our knowledge, the preferences for different IVF treatments in women with increased risk of OHSS have not been studied yet. STUDY DESIGN SIZE DURATION: A multicentre discrete choice experiment (DCE) was performed between 2012 and 2016. The selected attributes offered were chance of OHSS, which represents safety; number of injections; chance of cycle cancellation (the latter two represent burden); chance of pregnancy; and out-of-pocket costs/willingness to pay. A target sample size was calculated by including 20 patients for five attributes resulting in the aim to include 100 women. PARTICIPANTS/MATERIALS SETTING METHODS: We invited subfertile women who were diagnosed with normogonadotrophic ovulation disorder and were undergoing treatment with gonadotrophins and/or had experienced (imminent) OHSS in a previous IVF treatment in the fertility clinic of four hospitals (three teaching and one academic). Women received a printed questionnaire with fictional scenarios and were asked, for each scenario, to choose their preferred treatment. We used a multinominal logit model to determine the preferences of women and investigated heterogeneity in preferences through latent class analysis. The decrease in OHSS risk required for women to accept an increased level of an undesirable attribute, i.e. their willingness to trade off, was calculated. MAIN RESULTS AND THE ROLE OF CHANCE: We distributed 120 questionnaires with a response rate of 79% (95/120). There were 91 questionnaires included in the analysis. All five attributes influenced women's treatment preference. About half of the women considered chance of pregnancy to be more important, while the other half considered prevention of OHSS and lower costs to be more important. Women were willing to trade off cancellation rate, number of injections, chance of pregnancy and costs for lower OHSS chances. We found that women were willing to accept 5% more chance on cycle cancellation if the OHSS rate dropped with 2%. Women were willing to accept one extra treatment for a reduction of 3.9% in OHSS risk. With respect to costs, women were willing to pay €1000 instead of no costs for a decrease in OHSS rate of 5.4%. LIMITATIONS REASONS FOR CAUTION: The sample size of our study is relatively small which may limit the generalizability and sensitivity of the study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this DCE help us to understand the trade-off that women at risk of OHSS make in their preference for characteristics on IVF treatments. This knowledge may be used during the counselling of couples about their treatment options. STUDY FUNDING/COMPETING INTERESTS: B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. J.P.d.B. reports personal fees from the Ferring Medical Advisory Board and grants from Ferring B. V and Merck Serono B. V outside the submitted work. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: None.

Interpretation of field potentials measured on a multi electrode array in pharmacological toxicity screening on primary and human pluripotent stem cell-derived cardiomyocytes.

Multi electrode arrays (MEAs) are increasingly used to detect external field potentials in electrically active cells. Recently, in combination with cardiomyocytes derived from human (induced) pluripotent stem cells they have started to become a preferred tool to examine newly developed drugs for potential cardiac toxicity in pre-clinical safety pharmacology. The most important risk parameter is proarrhythmic activity in cardiomyocytes which can cause sudden cardiac death. Whilst MEAs can provide medium- to high- throughput noninvasive assay platform, the translation of a field potential to cardiac action potential (normally measured by low-throughput patch clamp) is complex so that accurate assessment of drug risk to the heart is in practice still challenging. To address this, we used computational simulation to study the theoretical relationship between aspects of the field potential and the underlying cardiac action potential. We then validated the model in both primary mouse- and human pluripotent (embryonic) stem cell-derived cardiomyocytes showing that field potentials measured in MEAs could be converted to action potentials that were essentially identical to those determined directly by electrophysiological patch clamp. The method significantly increased the amount of information that could be extracted from MEA measurements and thus combined the advantages of medium/high throughput with more informative readouts. We believe that this will benefit the analysis of drug toxicity screening of cardiomyocytes using in time and accuracy.

How long should we continue clomiphene citrate in anovulatory women?

STUDY QUESTION: What is the effectiveness of continued treatment with clomiphene citrate (CC) in women with World Health Organization (WHO) type II anovulation who have had at least six ovulatory cycles with CC but did not conceive? SUMMARY ANSWER: When women continued CC after six treatment cycles, the cumulative incidence rate of the ongoing pregnancy rate was 54% (95% CI 37-78%) for cycles 7-12. WHAT IS KNOWN ALREADY: If women with WHO type II anovulation fail to conceive with CC within six ovulatory cycles, guidelines advise switching to gonadotrophins, which have a high risk of multiple gestation and are expensive. It is however not clear what success rate could be achieved by continued treatment with CC. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of women with WHO II anovulation who visited the fertility clinics of five hospitals in the Netherlands between 1994 and 2010. We included women treated with CC who had had at least six ovulatory cycles without successful conception (n = 114) after which CC was continued using dosages varying from 50 to 150 mg per day for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follow-up was a total of 12 treatment cycles. Primary outcome was the cumulative incidence rate of an ongoing pregnancy at the end of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: We recruited 114 women that had ovulated on CC for at least six cycles but had not conceived. Of these 114 women, 35 (31%) had an ongoing pregnancy resulting in a cumulative incidence rate of an ongoing pregnancy of 54% after 7-12 treatment cycles with CC. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are its retrospective approach. WIDER IMPLICATIONS OF THE FINDINGS: Randomized trials comparing continued treatment with CC with the relatively established second line treatment with gonadotrophins are justified. In the meantime, we suggest to only begin this less convenient and more expensive treatment for women who do not conceive after 12 ovulatory cycles with CC. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes.

Unexpected induction of arrhythmias in the heart is still one of the major risks of new drugs despite recent improvements in cardiac safety assays. Here we address this in a novel emerging assay system. Eleven reference compounds were administrated to spontaneously beating clusters of cardiomyocytes from human pluripotent stem cells (hPSC-CM) and the responses determined using multi-electrode arrays. Nine showed clear dose-dependence effects on field potential (FP) duration. Of these, the Ca(2+) channel blockers caused profound shortening of action potentials, whereas the classical hERG blockers, like dofetilide and d,l-sotalol, induced prolongation, as expected. Unexpectedly, two potent blockers of the slow component of the delayed rectifier potassium current (I(Ks)), HMR1556 and JNJ303, had only minor effects on the extracellular FP of wild-type hPSC-CM despite evidence of functional I(Ks) channels. These compounds were therefore re-evaluated under conditions that mimicked reduced "repolarization reserve," a parameter reflecting the capacity of cardiomyocytes to repolarize and a strong risk factor for the development of ventricular arrhythmias. Strikingly, in both pharmacological and genetic models of diminished repolarization reserve, HMR1556 and JNJ03 strongly increased the FP duration. These profound effects indicate that I(Ks) plays an important role in limiting action potential prolongation when repolarization reserve is attenuated. The findings have important clinical implications and indicate that enhanced sensitization to repolarization-prolonging compounds through pharmacotherapy or genetic predisposition should be taken into account when assessing drug safety.

Migration of the humeral component of the Souter-Strathclyde elbow prosthesis: a long-term RSA study.

Mechanical loosening which begins with early-onset migration of the prosthesis is the major reason for failure of the Souter-Strathclyde elbow replacement. In a prospective study of 18 Souter-Strathclyde replacements we evaluated the patterns of migration using roentgen stereophotogrammetric analysis. We had previously reported the short-term results after a follow-up of two years which we have now extended to a mean follow-up of 8.2 years (1 to 11.3). Migration was assessed along the co-ordinal axes and overall micromovement was expressed as the maximum total point movement. The alignment of the prosthesis and the presence of radiolucent lines were examined on conventional standardised radiographs. All the humeral components showed increased and variable patterns of migration at the extended follow-up and four humeral components were revised. The maximum total point movement at two years in the revised prostheses was 1.8 mm (sd 1.0) and in the non-revised 0.7 mm (sd 0.5, p = 0.01). Most humeral components migrated into external rotation resulting in an anterior and varus tilt. The ulnar components remained stable.

Paclitaxel and vincristine potentiate adenoviral oncolysis that is associated with cell cycle and apoptosis modulation, whereas they differentially affect the viral life cycle in non-small-cell lung cancer cells.

Chemotherapy, including microtubule (MT)-interacting agents, can enhance the tumor-eradicating activity of replication-competent adenoviruses. The purpose of this study was to obtain more insight into the mechanism underlying this enhancement that may be exploited for the development of improved therapy. Two MT-interacting agents with opposite activity, paclitaxel (PTX) that stabilizes and vincristine (VCR) that destabilizes MTs, were found to synergistically enhance adenoviral oncolysis in non-small-cell lung cancer (NSCLC) cells. To explore the possibility that these drugs affect the viral life cycle by modulating adenoviral gene expression, we used a quantitative reverse transcription-polymerase chain reaction assay and found that PTX, but not VCR, increased the expression of E1A13S, ADP and Penton genes, which correlated with an increase in viral particle assembly and release. Next, the effect of combined treatment on cell-cycle progression was studied. Both drugs suppressed adenovirus-induced S-phase arrest and instead caused G2/M arrest, which was accompanied by an increase in apoptotic cells. Taken together, the enhancement of oncolysis by MT-interacting drugs appears not to require specific MT transport or scaffold functions. Our findings suggest that MT-interacting drug-induced cellular signals that modulate cell-cycle arrest and apoptosis are primarily on the basis of their oncolysis-enhancing activity.

The effects of specific versus nonspecific reinforcement on verbal behavior.

The current study is a systematic replication and extension of previous research on the differences between specific (mand) and nonspecific (tact) reinforcement. The focus was on the role that these different consequences played in the acquisition of verbal behavior. Using both a within-subject and a between-subjects design, the current researchers trained eight essentially nonverbal individuals to tact a variety of foods under two different reinforcement conditions. The results showed no significant differences between the four matched-pairs in rates of acquisition, or in the resistance to extinction. However, subjects in the specific reinforcement condition emitted more untrained mand-compliance responses, while subjects in the nonspecific group demonstrated increased generalization to multiply controlled mand conditions. The results supported previous findings which indicated that the two types of consequences were equally effective in the acquisition of tacting, but each had unique features and implications for language training with nonverbal populations.

A preliminary investigation of the consequences that define the mand and the tact.

Skinner (1957) proposed that the mand and the tact differed with respect to their unique antecedents and consequences. The present study examined the specific reinforcement characteristic of the mand, and the nonspecific reinforcement characteristic of the tact. A severely mentally impaired individual who used sign language served as subject. A concurrent-chain with latency measures and choice was used. The results showed that specific reinforcement produced stronger verbal behavior than nonspecific reinforcement, but only when response strength was measured in terms of latency and choice. These data lend support to Skinner's assertion that the mand and the tact are different operants. These results also have practical significance in that they may lead to more effective work with individuals who have speech and language impairments.

Development of intraverbal behavior in mentally retarded individuals through transfer of stimulus control procedures: classification of verbal responses.

Intraverbal behavior, in which an antecedent verbal stimulus is followed by a verbal response that lacks point-to-point correspondence with that stimulus, is often lacking in mentally retarded individuals. The present studies examine the use of transfer of stimulus control procedures for developing one type of intraverbal responding (classification of verbal responses) in mentally retarded participants who employed manual signs as their primary mode of verbal communication. In Experiment 1, a delayed prompting procedure was used to transfer control from nonverbal stimuli (pictures) to verbal stimuli (signs). This procedure was modified so that transfer of stimulus control was effected without errors in Experiment 2. In Experiment 3, a delayed prompting procedure was employed to train intraverbal behavior that involved a conditional discrimination. In all cases, transfer of stimulus control procedures produced rapid and enduring improvement in participants' intraverbal responding.

Training and generalization of laundry skills: a multiple probe evaluation with handicapped persons.

An instructional procedure composed of a graded sequence of prompts and token reinforcement was used to train a complex chain of behaviors which included sorting, washing, and drying clothes. A multiple probe design with sequential instruction across seven major components of the laundering routine was used to demonstrate experimental control. Students were taught to launder clothing using machines located in their school and generalization was assessed later on machines located in the public laundromat. A comparison of students' laundry skills with those of normal peers indicated similar levels of proficiency. Follow-up probes demonstrated maintenance of laundry skills over a 10-month period.