Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders.

STUDY QUESTION: Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER: The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY: ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION: This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE: All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04-3.98), B: 4.32 (±0.59; 3.31-5.64); C: 3.33 (±0.52; 2.45-4.54); D: 3.22 (±0.51; 2.36-4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58-1.2), B: 1.77 (±0.21; 1.42-2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION: The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS: We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S): The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01577472. TRIAL REGISTRATION DATE: 13 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: August 2013.

Inhibiting responses under the watch of a recently synchronized peer increases self-monitoring: evidence from functional near-infrared spectroscopy.

Developing motor synchrony with a peer (through interventions such as the mirror game) can yield collaborative, cognitive and social benefits. However, it is also well established that observation by an audience can improve cognition. The combined and relative advantages offered by motor synchronization and audience effects are not yet understood. It is important to address this gap to determine the extent to which synchronizing activities might interact with the positive effects of an audience. In this preregistered study, we investigate the extent to which response inhibition may be improved when observed by a peer after motor synchronization with this peer. We compare behavioural and cortical (functional near-infrared spectroscopy; fNIRS) measures of inhibition between synchronized and non-synchronized dyads and find that the presence of a synchronized peer-audience introduces a speed-accuracy trade-off, consisting of slower reaction times and improved accuracy. This co-occurs with cortical activation in bilateral inferior frontal and middle prefrontal cortices, which are implicated in monitoring and maintenance of social alignment. Our findings have implications for carers and support people, who may benefit from synchronizing activities for rehabilitating inhibition and social skills in clinical settings.

In infertile women with subclinical hypothyroidism, with or without thyroid peroxidase antibodies, serum TSH during pregnancy follows preconception values and thyroid hormones remain stable.

STUDY QUESTION: How does subclinical hypothyroidism, defined in infertile women during preconception by thyroid-stimulating hormone (TSH) >2.5 or >4.5 mIU/l, with or without thyroid peroxidase antibodies (anti-TPO) >100 IU/ml, impact thyroid hormone levels during pregnancy and after birth? SUMMARY ANSWER: During pregnancy, TSH levels remain similar to those in preconception, even with supplementary thyroxine, whereas the serum levels of anti-TPO progressively decline. WHAT IS KNOWN ALREADY: Overt hypothyroidism impacts both pregnancy and offspring but randomized clinical trials and cohort studies failed to detect the benefit of treatment with thyroxine in cases with low-threshold TSH or with anti-TPO during pregnancy. STUDY DESIGN SIZE DURATION: First, the prevalence and reproducibility of two candidate cut-off levels of subclinical hypothyroidism in a cohort of 177 infertile women was compared with 171 women not aiming for pregnancy. Second, the impact of distinct setpoints of TSH in preconception (with or without anti-TPO) was monitored during pregnancy in 87 previously infertile women by high-frequency monitoring of thyroid function. Both studies were carried out from 2007 to 2019. PARTICIPANTS/MATERIALS SETTING METHODS: Reproducibility and prevalence of subclinical hypothyroidism were examined in infertile women presenting in the fertility care unit of an academic institution. Women not aiming for pregnancy participated as controls. In both groups, TSH and anti-TPO were measured two times on different occasions. In addition, a group of previously infertile women with known preconception setpoints of TSH (with or without anti-TPO) were followed up prospectively throughout pregnancy and after birth. During pregnancy, serum was sampled weekly until Week 12, then monthly until delivery, and once after birth. Only cases with preconception TSH >4.5 mIU/l were supplemented with thyroxine. After collection of all samples, the serum levels of anti-TPO and the major thyroid hormones were measured. Prolactin with known fluctuations during pregnancy was used as reference. MAIN RESULTS AND THE ROLE OF CHANCE: Measures of both TSH and anti-TPO at two different time points were accurate and reproducible. The odds of subclinical hypothyroidism in infertile women and controls were similar. During pregnancy, TSH closely followed preconception TSH levels, whereas serum levels of the thyroid hormones predominantly remained within or above (not below) the reference. Treatment of infertile women with preconception TSH >4.5 mIU/l with thyroxine resulted in higher free thyroxine (fT4) serum levels. The serum levels of anti-TPO declined as pregnancies evolved. LIMITATIONS REASONS FOR CAUTION: The numbers of participants both in the prevalence study and in pregnancy did not reach the a priori estimated numbers. For ethical reasons, the patients with preconception TSH >4.5 mIU/l were treated with thyroxine. The findings apply to infertile women only. WIDER IMPLICATIONS OF THE FINDINGS: We propose to use >4.5 mIU/l as the serum TSH threshold for supplementing women with thyroxine before pregnancy. During pregnancy, fT4 may be the better marker to monitor thyroid function. The consistent decrease of anti-TPO antibody levels during ongoing pregnancies must be considered a protective element. STUDY FUNDING/COMPETING INTERESTS: The prevalence part of this study was supported by Merck-Serono, Geneva (TH006/EMR200007-603). The hormone measurements of the serum samples collected during the follow-up pregnancies were made possible by financial support of Roche Diagnostica (November 1721, 2017, Rotkreuz, Switzerland). I.D.G. was supported by a grant of the Repronatal Foundation, Basel, Switzerland. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Research Database of UniBasel, project no. 576691 (2007).

Patient Perceptions about Professional Dental Services during the COVID-19 Pandemic.

BACKGROUND: Dental professionals are at high risk of being infected by and transmitting COVID-19 to patients. Patients' perceived risk for infection and attitudes about receiving dental care during the pandemic are important to understand as patients consider returning to routine dental care as the pandemic progresses. OBJECTIVE: The purpose of this study was to explore dental patients' perceptions of susceptibility to contracting COVID-19, their related attitudes and beliefs regarding dental care visits, and their considerations for returning to routine care during and after the pandemic. METHOD: Data for this cross-sectional study came from an electronic survey of 464 US adults. Survey variables include demographics, dental hygiene behaviors, perceived susceptibility to COVID-19, attitudes and beliefs regarding risk for attending dental appointments, and the necessary conditions and events for them to feel comfortable returning to regular dental appointments. RESULTS: Over half of study participants had a 4-y degree, an annual income of at least $50,000, and good oral hygiene practices of frequent brushing and routine dental visits. Older age and agreement with positive attitudinal statements and beliefs about professional dental care were positively related to perceived susceptibility for contracting COVID-19 in a dental setting. Perceptions of susceptibility, a higher valuation of dentistry, and agreement that COVID-19 is a serious infection were each positively related to attitudinal statements and beliefs reflecting caution in attending dental visits. Last, assurance from public health officials confirming the safety to return for routine dental care was the largest reported factor necessary for a return to routine dental visits. CONCLUSION: This study provides early data about patient perceptions of susceptibility and attitudes toward COVID-19 in a professional dental setting and necessary conditions for returning to regular visits. This information can help formulate messaging related to returning to professional dental care, specifically targeting fears among the most susceptible populations. KNOWLEDGE TRANSFER STATEMENT: Government and public health agencies can play an important role in alleviating concerns and instilling confidence that dental settings are safe. With this information from the public, dental professionals and public health agencies can work together to share messaging that will consistently inform the public regarding the safety of returning to professional dental care as it relates to the reopening of states and cities.

State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015.

Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.

Fertility preservation issues in pediatric hematopoietic stem cell transplantation: practical approaches from the consensus of the Pediatric Diseases Working Party of the EBMT and the International BFM Study Group.

Fertility preservation is an urgent challenge in the transplant setting. A panel of transplanters and fertility specialists within the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and the International BFM Study Group provides specific guidelines. Patients and families should be informed of possible gender- and age-specific cryopreservation strategies that should be tailored according to the underlying disease, clinical condition and previous exposure to chemotherapy. Semen collection should be routinely offered to all postpubertal boys at the diagnosis of any disease requiring therapy that could potentially impair fertility. Testicular tissue collection might be offered to postpubertal boys; nevertheless, its use has been unsuccessful to date. Oocyte collection after hormonal hyperstimulation should be offered to postpubertal girls facing gonadotoxic therapies that could be delayed for the 2 weeks required for the procedure. Ovarian tissue collection could be offered to pre-/post-pubertal girls. Pregnancies have been reported after postpubertal ovarian tissue reimplantation; however, to date, no pregnancy has been reported after the reimplantation of prepubertal ovarian tissue or in vitro maturation of pre-/post-pubertal ovarian tissue. Possible future advances in reproductive medicine could change this scenario. Health authorities should prioritize fertility preservation projects in pediatric transplantation to improve patient care and quality of life.

Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD.

Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients' health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT.

A control model for tibial cortex neovascularization in the bone chamber.

Neovascularization across a gap defect in a rabbit tibial cortex was monitored using the optical bone chamber implant (BCI). Cortical bone growing by apposition as trabeculae was observed weekly as it penetrated a slit into a tissue space in vivo and in situ. Each rabbit was viewed weekly with an intravital microscope from 3 to 8 weeks postimplantation. The constant field of view was the slit-gap tissue space, which was 100 microns thick and 2 mm in diameter. Vessels were imaged with epi-illuminated fluorescence microscopy as they carried FITC-dextran 70 that had been injected into an aural vein. Observations were videotaped and photographed. Videotape frames were analyzed with a digital image processing system to obtain measures of vessel length per unit volume (L/V) of fibroblastic granular tissue and trabeculae, caliber C, and flow velocity u, all as functions of time. Observations supported the conclusions that (1) neovascularization precedes neo-osteogenesis, (2) major vessels tend to align with the tibial axis, (3) bone apposition-generated destruction of fibrous granular tissue vessels stimulates fibrous granular tissue angiogenesis, which keeps its L/V constant, (4) L/V in trabeculae increases with time, and (5) blood supply (Q) and nutrient exchange in healing trabeculae are not positively correlated. Thus, O2 supply to the trabeculum cannot be predicted from Q alone because the nutrient exchange area is not constant. It was noted that an increase in the potential nutrient exchange area occurred in both fibrous granular tissue and osseous vessels and the volume fraction of blood decreased in the fibrous granular tissue and remained constant in the trabeculae.

Dew-point hygrometry system for measurement of evaporative water loss in infants.

Evaporation of water from the skin is an important mechanism in thermal homeostasis. Resistance hygrometry, in which the water vapor pressure gradient above the skin surface is calculated, has been the measurement method of choice in the majority of pediatric investigations. However, resistance hygrometry is influenced by changes in ambient conditions such as relative humidity, surface temperature, and convection currents. We have developed a ventilated capsule method that minimized these potential sources of measurement error and that allowed second-by-second, long-term, continuous measurements of evaporative water loss in sleeping infants. Air with a controlled reference humidity (dew-point temperature = 0 degree C) is delivered to a small, lightweight skin capsule and mixed with the vapor on the surface of the skin. The dew point of the resulting mixture is measured by using a chilled mirror dew-point hygrometer. The system indicates leaks, is mobile, and is accurate within 2%, as determined by gravimetric calibration. Examples from a recording of a 13-wk-old full-term infant obtained by using the system give evaporative water loss rates of approximately 0.02 mgH2O.cm-2.min-1 for normothermic baseline conditions and values up to 0.4 mgH2O.cm-2. min-1 when the subject was being warmed. The system is effective for clinical investigations that require dynamic measurements of water loss.

Conversion of percutaneous ureteral stent to indwelling pigtail stent over guidewire.

A ureteral stent placed percutaneously through a nephrostomy can be readily exchanged endoscopically for a ureteral indwelling pigtail stent over a percutaneous guide wire. Percutaneous antegrade stent placement can sometimes be accomplished when retrograde placement cannot. We report 10 successful conversions to indwelling stent in 11 cases. In 1 case the percutaneous guide wire could not be retrieved endoscopically because of a bleeding tumor in the bladder. No serious difficulties or complications were encountered. The percutaneous approach offers an alternative method of providing internal urinary diversion if retrograde ureteral indwelling stent placement has failed.

Fowl cholera: immunization of chickens with potassium thiocyanate (KSCN) extract of Pasteurella multocida serotype 3.

Potassium thiocyanate (KSCN) extract of Pasteurella multocida, serotype 3, was found to be immunogenic against a challenge infection of homologous as well as one heterologous strain tested (serotype 1). Ouchterlony's gel-diffusion analysis revealed the presence of two components in the KSCN-extracts of both serotypes 3 and 1, which were antigenically identical.

Light variability in the modern neonatal nursery: chronobiologic issues.

The role that nursery light variability may play in modulating infant biological rhythms is being studied in Stanford Medical Center's Neonatal Intensive Care (NICU) and Intermediate Care (IN) Nurseries. In this investigation, spatial and temporal variability in illuminance was determined at 20 sites within each nursery over a 5-day period. The analysis of 240 measurements at 30 min intervals from each site revealed marked variability in illumination with respect to both time and position in the nursery. These aperiodic lighting patterns differed greatly from the published characterization of NICUs as having 'constant' illumination. Light pulses of variable frequency, intensity, and duration were common at each of the 40 bedsites studied. Given the powerful impact of light on circadian rhythmicity and sleep in adults, the results from this study suggest that modern NICU lighting, while implemented to facilitate intensive care, may have adverse effects on infant development. Future studies on the influence of light on biological rhythmicity and sleep are essential to provide a framework for clinical and environmental interventions, which may play a significant role in improving developmental outcome in hospitalized preterm or term infants.

Latent bovine brucellosis.

Adult cattle in a herd suffering from widespread infection with Brucella abortus biotype 2 were slaughtered during the eradication campaign. A heifer calf fom that herd was moved to a fresh herd which remained apparently free from brucellosis until nine years later when the same animal produced a strongly positive serological reaction and Brucella abortus biotype 2 was isolated from its milk.