Flies adaptively control flight to compensate for added inertia.

Animal locomotion is highly adaptive, displaying a large degree of flexibility, yet how this flexibility arises from the integration of mechanics and neural control remains elusive. For instance, animals require flexible strategies to maintain performance as changes in mass or inertia impact stability. Compensatory strategies to mechanical loading are especially critical for animals that rely on flight for survival. To shed light on the capacity and flexibility of flight neuromechanics to mechanical loading, we pushed the performance of fruit flies (Drosophila) near its limit and implemented a control theoretic framework. Flies with added inertia were placed inside a virtual reality arena which permitted free rotation about the vertical (yaw) axis. Adding inertia increased the fly's response time yet had little influence on overall gaze stabilization performance. Flies maintained stability following the addition of inertia by adaptively modulating both visuomotor gain and damping. By contrast, mathematical modelling predicted a significant decrease in gaze stabilization performance. Adding inertia altered saccades, however, flies compensated for the added inertia by increasing saccade torque. Taken together, in response to added inertia flies increase reaction time but maintain flight performance through adaptive neural control. Overall, adding inertia decreases closed-loop flight robustness. Our work highlights the flexibility and capacity of motor control in flight.

Effects of parity on preterm delivery in twin gestations conceived with in vitro fertilization.

Objective: To determine the relationship between prior obstetrical history and gestational age at delivery in a twin pregnancy. Design: Retrospective cohort study using the United States Society for Assisted Reproductive Technology Clinic Outcomes Reporting System database. Setting: Clinic-based data. Patients: Patients undergoing in vitro fertilization (IVF) in the United States with live delivery of twins. Interventions: None. Main outcome measures: The main outcome measures are median gestational age at delivery and rate of preterm delivery (before 37 weeks). Results: The median gestational age at delivery of IVF-conceived twins was 36.3 (interquartile rate 34.4, 37.6) weeks for nulliparous women, 35.9 (34.0, 37.1) weeks for parous women with a prior preterm birth, and 36.7 (35.1, 37.7) weeks for parous women without a prior preterm birth. The rate of preterm delivery was 61% for nulliparous women, 70% for parous women with a prior preterm birth, and 55% for parous women without a prior preterm birth. Conclusions: Parous women without a history of preterm delivery had lower rates of preterm delivery in a subsequent twin pregnancy than nulliparous women. Nulliparous women had lower rates of preterm delivery compared with parous women with a history of preterm delivery.

Flies trade off stability and performance via adaptive compensation to wing damage.

Physical injury often impairs mobility, which can have dire consequences for survival in animals. Revealing mechanisms of robust biological intelligence to prevent system failure can provide critical insights into how complex brains generate adaptive movement and inspiration to design fault-tolerant robots. For flying animals, physical injury to a wing can have severe consequences, as flight is inherently unstable. Using a virtual reality flight arena, we studied how flying fruit flies compensate for damage to one wing. By combining experimental and mathematical methods, we show that flies compensate for wing damage by corrective wing movement modulated by closed-loop sensing and robust mechanics. Injured flies actively increase damping and, in doing so, modestly decrease flight performance but fly as stably as uninjured flies. Quantifying responses to injury can uncover the flexibility and robustness of biological systems while informing the development of bio-inspired fault-tolerant strategies.

Complementary feedback control enables effective gaze stabilization in animals.

Visually active animals coordinate vision and movement to achieve spectacular tasks. An essential prerequisite to guide agile locomotion is to keep gaze level and stable. Since the eyes, head and body can move independently to control gaze, how does the brain effectively coordinate these distinct motor outputs? Furthermore, since the eyes, head, and body have distinct mechanical constraints (e.g., inertia), how does the nervous system adapt its control to these constraints? To address these questions, we studied gaze control in flying fruit flies (Drosophila) using a paradigm which permitted direct measurement of head and body movements. By combining experiments with mathematical modeling, we show that body movements are sensitive to the speed of visual motion whereas head movements are sensitive to its acceleration. This complementary tuning of the head and body permitted flies to stabilize a broader range of visual motion frequencies. We discovered that flies implement proportional-derivative (PD) control, but unlike classical engineering control systems, relay the proportional and derivative signals in parallel to two distinct motor outputs. This scheme, although derived from flies, recapitulated classic primate vision responses thus suggesting convergent mechanisms across phyla. By applying scaling laws, we quantify that animals as diverse as flies, mice, and humans as well as bio-inspired robots can benefit energetically by having a high ratio between head, body, and eye inertias. Our results provide insights into the mechanical constraints that may have shaped the evolution of active vision and present testable neural control hypotheses for visually guided behavior across phyla.

Mechanisms of punctuated vision in fly flight.

To guide locomotion, animals control gaze via movements of their eyes, head, and/or body, but how the nervous system controls gaze during complex motor tasks remains elusive. In many animals, shifts in gaze consist of periods of smooth movement punctuated by rapid eye saccades. Notably, eye movements are constrained by anatomical limits, which requires resetting eye position. By studying tethered, flying fruit flies (Drosophila), we show that flies perform stereotyped head saccades to reset gaze, analogous to optokinetic nystagmus in primates. Head-reset saccades interrupted head smooth movement for as little as 50 ms-representing less than 5% of the total flight time-thereby enabling punctuated gaze stabilization. By revealing the passive mechanics of the neck joint, we show that head-reset saccades leverage the neck's natural elastic recoil, enabling mechanically assisted redirection of gaze. The consistent head orientation at saccade initiation, the influence of the head's angular position on saccade rate, the decrease in wing saccade frequency in head-fixed flies, and the decrease in head-reset saccade rate in flies with their head range of motion restricted together implicate proprioception as the primary trigger of head-reset saccades. Wing-reset saccades were influenced by head orientation, establishing a causal link between neck sensory signals and the execution of body saccades. Head-reset saccades were abolished when flies switched to a landing state, demonstrating that head movements are gated by behavioral state. We propose a control architecture for active vision systems with limits in sensor range of motion. VIDEO ABSTRACT.

Long-term imatinib diminishes ovarian reserve and impacts embryo quality.

PURPOSE: Tyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model. METHODS: Adult female mice were treated with daily IP injections of imatinib for 4-6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts. RESULTS: Long-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells. CONCLUSION: This pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.

Fly eyes are not still: a motion illusion in Drosophila flight supports parallel visual processing.

Most animals shift gaze by a 'fixate and saccade' strategy, where the fixation phase stabilizes background motion. A logical prerequisite for robust detection and tracking of moving foreground objects, therefore, is to suppress the perception of background motion. In a virtual reality magnetic tether system enabling free yaw movement, Drosophila implemented a fixate and saccade strategy in the presence of a static panorama. When the spatial wavelength of a vertical grating was below the Nyquist wavelength of the compound eyes, flies drifted continuously and gaze could not be maintained at a single location. Because the drift occurs from a motionless stimulus - thus any perceived motion stimuli are generated by the fly itself - it is illusory, driven by perceptual aliasing. Notably, the drift speed was significantly faster than under a uniform panorama, suggesting perceptual enhancement as a result of aliasing. Under the same visual conditions in a rigid-tether paradigm, wing steering responses to the unresolvable static panorama were not distinguishable from those to a resolvable static pattern, suggesting visual aliasing is induced by ego motion. We hypothesized that obstructing the control of gaze fixation also disrupts detection and tracking of objects. Using the illusory motion stimulus, we show that magnetically tethered Drosophila track objects robustly in flight even when gaze is not fixated as flies continuously drift. Taken together, our study provides further support for parallel visual motion processing and reveals the critical influence of body motion on visuomotor processing. Motion illusions can reveal important shared principles of information processing across taxa.

Imatinib treatments have long-term impact on placentation and embryo survival.

Imatinib is an oral chemotherapeutic used primarily to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). The potential effects of cancer treatments on a patient's future fertility  are a major concern affecting the quality of life for cancer survivors. The effects of imatinib on future fertility are unknown. It is teratogenic. Therefore, patients are advised to stop treatment before pregnancy. Unfortunately, CML and GIST have high rates of recurrence in the absence of the drug, therefore halting imatinib during pregnancy endangers the mother. Possible long-term (post-treatment) effects of imatinib on reproduction have not been studied. We have used a mouse model to examine the effects of imatinib on the placenta and implantation after long-term imatinib exposure. We found significant changes in epigenetic markers of key imprinted genes in the placenta. There was a significant decrease in the labyrinth zone and vasculature of the placenta, which could impact fetal growth later in pregnancy. These effects on placental growth occurred even when imatinib was stopped prior to pregnancy. These results indicate potential long-term effects of imatinib on pregnancy and implantation. A prolonged wash-out period prior to pregnancy or extra monitoring for possible placental insufficiency may be advisable.

Blastulation timing is associated with differential mitochondrial content in euploid embryos.

PURPOSE: Preimplantation genetic screening (PGS) and assessment of mitochondrial content (MC) are current methods for selection of the best embryos for transfer. Studies suggest that time-lapse morphokinetics (TLM) may also be helpful for selecting embryos more likely to implant. In our study, we sought to examine the relationship between TLM parameters and MC to determine if they could be used adjunctively in embryo selection. We also examined the relationship between MC with ploidy and blastulation. METHODS: Cryopreserved human embryos at the zygote stage were thawed and cultured in a time-lapse system. Blastomere and trophectoderm biopsies were performed on days 3 and 6. Biopsied cells and all whole embryos from day 6 were analyzed for MC (ratio of mitochondrial to nuclear DNA) and ploidy using next-generation sequencing. RESULTS: In embryos, MC per cell declined between day 3 and day 6. While early cleavage parameters did not predict MC, embryos with longer blastulation timing had higher MC on day 6. Day 6 MC was lower in euploid vs. aneuploid embryos and lower in blastocysts vs. arrested embryos. CONCLUSIONS: A lower MC at the blastocyst stage was associated with euploid status and blastocyst formation, indicating better embryo quality compared to those with a higher MC. Higher MC in aneuploid and arrested embryos may be explained by slower cell division or degradation of genomic DNA over time. Blastulation timing may be helpful for selection of higher quality embryos. Combining blastulation timing and MC along with morphologic grading and euploid status may offer a new direction in embryo selection.

Cancer survivors of gynecologic malignancies are at risk for decreased opportunity for fertility preservation.

BACKGROUND: Cancer survivors rate fertility as one of the most important determinants of their quality of life in the years after cancer treatment. We seek to describe the reproductive goals of women affected by gynecologic cancers and investigate their specific challenges during fertility preservation (FP) counseling. METHODS: Univariate & multivariate logistic regression were used for quantitative analysis of objective FP counseling measures between women with gynecologic (GYN) and non-gynecologic (non-GYN) cancers from a cross sectional survey. Framework analysis was conducted on patient perception of physician-patient interactions. RESULTS: Of the 2537 women contacted, 1892 responded and 1686 reported treatment with potential to impact fertility. Among women with GYN cancers 52% wanted future children. Women <35 years were interested in FP (74%). Women with Gyn cancers received less FP counseling than women with non Gyn cancer (OR 0.5 95% CI 0.4-0.6). Three hundred twenty-four patients gave qualitative answers. Patient identified barriers included incomplete FP information (59%), nondisclosure (29%), a disinterest in FP (5%), and a perceived urgency to start treatment (7%). CONCLUSIONS: Women with gynecologic cancers are less likely to be counseled about FP in comparison to women not affected by gynecologic cancers despite having similar fertility goals. We have identified patient perceived barriers to optimal FP counseling which may be improved upon to increase the value of FP and optimize quality of life for cancer survivors of gynecologic malignancies.

A comparison of live birth rates and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos.

PURPOSE: Prior studies suggest that pregnancy outcomes after autologous oocyte cryopreservation are similar to fresh in vitro fertilization (IVF) cycles. It is unknown whether there are differences in pregnancy and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos. METHODS: This is a retrospective cohort study comparing pregnancy and perinatal outcomes between oocyte and embryo cryopreservation at a university-based fertility center. We included 42 patients and 68 embryo transfers in patients who underwent embryo transfer after elective oocyte preservation (frozen oocyte-derived embryo transfer (FOET)) from 2005 to 2015. We compared this group to 286 patients and 446 cycles in women undergoing cryopreserved embryo transfer (frozen embryo transfer (FET)) from 2012 to 2015. RESULTS: Five hundred fourteen transfer cycles were included in our analysis. The mean age was lower in the FOET vs FET group (34.3 vs 36.0 years), but there were no differences in ovarian reserve markers. Thawed oocytes had lower survival than embryos (79.1 vs 90.1%); however, fertilization rates were similar (76.2 vs 72.8%). In the FOET vs FET groups, clinical pregnancies were 26.5 and 30%, and live birth rates were 25 and 25.1%. Miscarriages were higher in the FET group, 8.1 vs 1.5%. There were no differences in perinatal outcomes between the two groups. The mean gestational age at delivery was 39.1 vs 38.6 weeks, mean birth weight 3284.2 vs 3161.1 gms, preterm gestation rate 5.9 vs 13.4%, and multiple gestation rate 5.9 vs 11.6%. CONCLUSIONS: In our study, live birth rates and perinatal outcomes were not significantly different in patients after oocyte and embryo cryopreservation.

Regret around fertility choices is decreased with pre-treatment counseling in gynecologic cancer patients.

PURPOSE: Data have demonstrated an association between regret and lack of fertility counseling among patients undergoing treatment for non-gynecologic cancers. We sought to determine if fertility-related regret is reduced with pre-treatment counseling or fertility-sparing surgery (FSS) in patients with gynecologic cancers. METHODS: A cross-sectional survey was administered to 593 reproductive-age survivors (18-40 years old at diagnosis) of localized cervix, ovarian, or endometrial cancers that were eligible for FSS. A validated decision regret score was used to evaluate regret in patients. RESULTS: Four hundred seventy women completed the survey. Forty-six percent received pre-treatment counseling about treatment's effects on fertility. Having received counseling (adjusted ß-coefficient of -1.24, 95 % CI = -2.29 to -0.18, p = 0.02), satisfactory counseling (adjusted ß-coefficient of -2.71, 95 % CI = -3.86 to -1.57, p < 0.001), and FSS (adjusted ß-coefficient of -1.26, 95 % CI = -2.39 to -0.14, p = 0.03) were associated with lower regret post-treatment, after adjusting for age. Time since diagnosis, prior parity, socioeconomic status and cancer type were not associated with regret (p > 0.05). While 50 % of women reported desiring more children after diagnosis, desire for children after treatment was associated with increased regret (adjusted ß-coefficient of 3.97, 95 % CI = 2.92-5.02, p < 0.001). CONCLUSIONS: Though less than half of study participants received counseling about the effect of cancer treatment on future fertility, both fertility counseling and FSS were associated with decreased regret in reproductive-aged women with gynecologic cancers. The desire for more children after treatment was associated with increased regret. IMPLICATIONS FOR CANCER SURVIVORS: Inquiring about fertility desires and providing counseling regarding reproductive outcomes following cancer treatment should be implemented as part of the treatment process.

Sexual satisfaction and quality of life in survivors of localized cervical and ovarian cancers following fertility-sparing surgery.

OBJECTIVE: To determine if sexual satisfaction and sexual quality of life (QOL) are different in survivors of localized cervical and ovarian cancers who undergo fertility-sparing surgery (FSS) as compared with standard surgery. METHODS: 470 survivors of localized cervical and ovarian cancers diagnosed between the ages of 18-40 were recruited from the California Cancer Registry to complete a cross-sectional survey. Validated questionnaires were used to assess sexual satisfaction and sexual QOL. RESULTS: 228 women with localized cervical cancer and 125 with localized ovarian cancer completed the survey. In the cervical cancer group, 92 underwent FSS. Compared with the 84 women who did not undergo FSS (had a hysterectomy, but retained at least one ovary), there was no significant difference in sexual satisfaction or sexual QOL mean scores in women who maintained their uterus (cold-knife cone or trachelectomy), after controlling for age and menopausal status. 82 women with ovarian cancer underwent FSS. Compared with the 39 women that had a bilateral salpingo-oophorectomy, we found no significant differences in sexual satisfaction or sexual QOL in women who maintained at least one ovary (USO or cystectomy), after controlling for age and menopausal status. CONCLUSIONS: While FSS may allow for post-treatment fertility, it may not confer a significant benefit with regard to sexual satisfaction or sexual QOL. Thus, the decision to perform FSS should not be dictated based on preservation of sexual functioning.

Fertility Sparing Surgery for Localized Ovarian Cancers Maintains an Ability to Conceive, but is Associated With Diminished Reproductive Potential.

BACKGROUND: Little is known about fertility outcomes after fertility sparing surgery (FSS) for localized ovarian cancers. METHODS: A random sample of 783 women treated for ovarian cancer were identified from the California Cancer Registry for survey (age 18-40 years at diagnosis; diagnosed from 1993-2007). We evaluated outcomes including post-treatment amenorrhea, infertility, early menopause (age <45), and disease recurrence. Logistic regression was used to determine the probability of amenorrhea, infertility, and recurrence. Censored data methods were used to determine the probability of early menopause. RESULTS: A total of 382 women replied. One hundred and sixteen and 266 completed our survey. Two hundred and forty-five reported treatment with potential to impact fertility (i.e., systemic chemotherapy ± radiation/surgery to the abdomen/pelvis). A total of 125 had disease/stage eligible for FSS and 82 (66%) underwent FSS. While many who attempted conception did conceive, 32% did not. Younger age at diagnosis was associated with higher rates of early menopause (P < 0.001) after FSS. Recurrence rates for those undergoing FSS were 8-10%, while none of the women who underwent non-FSS surgery had a recurrence. CONCLUSIONS: FSS maintains an ability to conceive for most patients. However, after FSS, there may be risks of infertility, early menopause with earlier age of treatment, and increased probability of disease recurrence.

Fertility after cesarean delivery among Somali-born women resident in the USA.

We evaluated the reproductive impact of cesarean versus vaginal delivery in Somali immigrants. Data were extracted for 106 Somali women delivering vaginally (64%) or by cesarean section (36%) between 1994 and 2006. Index delivery (vaginal versus cesarean) was compared to the cumulative incidence rate of subsequent deliveries. The incidence rate of a delivery after a vaginal delivery was 3.3% (CI:0-7.8%), 55.4% (CI:40.1-66.8%) and 74.4% (CI:59.0-84.0%) at 1, 2 and 3 years. Cesarean delivery lead to a second delivery incidence rate of 2.9%(95%CI:0-8.2%), 25.9%(95%CI:9.8-39.2%) and 58.1% (95%CI:27.0-72.2%) at 1, 2 and 3 years. Somali women delivering vaginally were 1.56 times (95% CI:0.94-2.57; P = 0.084) more likely to have a subsequent delivery. The likelihood of Somali women having a second child after cesarean section is lower at 2 and 3 year follow-up.