Reproductive outcomes in women opting for fertility preservation after fertility-sparing surgery for borderline ovarian tumors.

PURPOSE: What are the reproductive outcomes of women who had fertility preservation (FP) using either oocyte or embryo vitrification after fertility-sparing surgery (FSS) for a borderline ovarian tumor (BOT)? METHODS: A retrospective, single-center cohort study was conducted between January 2013 and December 2021. Patients with BOT who resorted to FP by vitrifying oocytes or embryos were included. Both clinical and reproductive parameters were reviewed. The primary outcome was live birth. RESULTS: In total, thirteen patients who performed 31 FP cycles were included. Of those, six patients achieved eight live births after a mean follow-up period of 79 months. Three further pregnancies are still ongoing. All pregnancies/live births were obtained without using their cryopreserved oocytes or embryos. CONCLUSION: Women who had FSS for BOT have favorable prospects of live offspring, even without the need to use their cryopreserved material. Fertility preservation in patients with BOT has to be considered as a tool to mitigate the risk of infertility that may arise in case of BOT recurrence requiring castrating surgery.

Progestin primed ovarian stimulation using dydrogesterone from day 7 of the cycle onwards in oocyte donation cycles: a longitudinal study.

RESEARCH QUESTION: Does a progestin-primed ovarian stimulation (PPOS) protocol with dydrogesterone from cycle day 7 yield similar outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol in the same oocyte donors? DESIGN: This retrospective longitudinal study included 128 cycles from 64 oocyte donors. All oocyte donors had the same type of gonadotrophin and daily dose in both stimulation cycles. The primary outcome was the number of cumulus-oocyte complexes (COC) retrieved. RESULTS: The number of COC retrieved (mean ± SD 19.7 ± 10.8 versus 19.2 ± 8.3; P = 0.5) and the number of metaphase II oocytes (15.5 ± 8.4 versus 16.2 ± 7.0; P = 0.19) were similar for the PPOS and GnRH antagonist protocols, respectively. The duration of stimulation (10.5 ± 1.5 days versus 10.8 ± 1.5 days; P = 0.14) and consumption of gonadotrophins (2271.9 ± 429.7 IU versus 2321.5 ± 403.4 IU; P = 0.2) were also comparable, without any cases of premature ovulation. Nevertheless, there was a significant difference in the total cost of medication per cycle: €898.3 ± 169.9 for the PPOS protocol versus €1196.4 ± 207.5 (P < 0.001) for the GnRH antagonist protocol. CONCLUSION: The number of oocytes retrieved and number of metaphase II oocytes were comparable in both stimulation protocols, with the advantage of significant cost reduction in favour of the PPOS protocol compared with the GnRH antagonist protocol. No cases of premature ovulation were observed, even when progestin was started later in the stimulation.

Clinical outcomes from ART in predicted hyperresponders: in vitro maturation of oocytes versus conventional ovarian stimulation for IVF/ICSI.

STUDY QUESTION: Do ongoing pregnancy rates (OPRs) differ in predicted hyperresponders undergoing ART after IVM of oocytes compared with conventional ovarian stimulation (OS) for IVF/ICSI? SUMMARY ANSWER: One cycle of IVM is non-inferior to one cycle of OS in women with serum anti-Müllerian hormone (AMH) levels ≥10 ng/ml. WHAT IS KNOWN ALREADY: Women with high antral follicle count and elevated serum AMH levels, indicating an increased functional ovarian reserve, are prone to hyperresponse during ART treatment. To avoid iatrogenic complications of OS, IVM has been proposed as a mild-approach alternative treatment in predicted hyperresponders, including women with polycystic ovary syndrome (PCOS) who are eligible for ART. To date, inferior pregnancy rates from IVM compared to OS have hampered the uptake of IVM by ART clinics. However, it is unclear whether the efficiency gap between IVM and OS may differ depending on the extent of AMH elevation. STUDY DESIGN, SIZE, DURATION: This study is a retrospective cohort analysis of clinical and laboratory data from the first completed highly purified hMG (HP-hMG) primed, non-hCG-triggered IVM or OS (FSH or HP-hMG stimulation in a GnRH antagonist protocol) cycle with ICSI in predicted hyperresponders ≤36 years of age at a tertiary referral university hospital. A total of 1707 cycles were included between January 2016 and June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Predicted hyperresponse was defined as a serum AMH level ≥3.25 ng/ml (Elecsys® AMH, Roche Diagnostics). The primary outcome was cumulative ongoing pregnancy rate assessed 10-11 weeks after embryo transfer (ET). The predefined non-inferiority limit was -10.0%. The analysis was adjusted for AMH strata. Time-to-pregnancy, defined as the number of ET cycles until ongoing pregnancy was achieved, was a secondary outcome. Statistical analysis was performed using a multivariable regression model controlling for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Data from 463 IVM cycles were compared with those from 1244 OS cycles. Women in the IVM group more often had a diagnosis of Rotterdam PCOS (434/463, 93.7%) compared to those undergoing OS (522/1193, 43.8%), were significantly younger (29.5 years versus 30.5 years, P ≤ 0.001), had a higher BMI (25.7 kg/m2 versus 25.1 kg/m2, P ≤ 0.01) and higher AMH (11.6 ng/ml versus 5.3 ng/ml, P ≤ 0.001). Although IVM cycles yielded more cumulus-oocyte complexes (COCs) (24.5 versus 15.0 COC, P ≤ 0.001), both groups had similar numbers of mature oocytes (metaphase II (MII)) (11.9 MII versus 10.6 MII, P = 0.9). In the entire cohort, non-adjusted cumulative OPR from IVM was significantly lower (198/463, 42.8%) compared to OS (794/1244, 63.8%), P ≤ 0.001. When analysing OPR across different serum AMH strata, cumulative OPR in both groups converged with increasing serum AMH, and OPR from IVM was non-inferior compared to OS from serum AMH levels >10 ng/ml onwards (113/221, 51.1% (IVM); 29/48, 60.4% (OS)). The number of ETs needed to reach an ongoing pregnancy was comparable in both the IVM and the OS group (1.6 versus 1.5 ET's, P = 0.44). Multivariable regression analysis adjusting for ART type, age, BMI, oocyte number, and PCOS phenotype showed that the number of COCs was the only parameter associated with OPR in predicted hyperresponders with a serum AMH >10 ng/ml. LIMITATIONS, REASONS FOR CAUTION: These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Among subfertile women who are eligible for ART, IVM, and OS resulted in comparable reproductive outcomes in a subset of women with a serum AMH ≥10 ng/ml. These findings should be corroborated by a randomised controlled trial (RCT) comparing both treatments in selected patients with elevated AMH. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. P.D. has been consultant to Merck Healthcare KGaA (Darmstadt, Germany) from April 2021 till June 2023 and is a Merck employee (Medical Director, Global Medical Affairs Fertility) with Merck Healthcare KGAaA (Darmstadt, Germany) since July 2023. He declares honoraria for lecturing from Merck KGaA, MSD, Organon, and Ferring. The remaining authors declared no conflict of interest pertaining to this study. TRIAL REGISTRATION NUMBER: N/A.

Does dual oocyte retrieval with continuous FSH administration increase the number of mature oocytes in low responders? An open-label randomized controlled trial.

STUDY QUESTION: Is there an increase in the total number of metaphase II (MII) oocytes between a conventional ovarian stimulation (OS) and a double uninterrupted stimulation? SUMMARY ANSWER: There is no increase in the total number of MII oocytes when comparing one conventional OS to a continuous stimulation with double oocyte aspiration. WHAT IS KNOWN ALREADY: Based on the concept of multiple follicular waves, the combination of two stimulations in the same ovarian cycle has gained interest in patients with a low ovarian reserve. This so-called dual stimulation approach is usually characterized by a discontinuation of FSH administration for ∼5 days and appears to have a favourable impact on the number of retrieved oocytes without affecting the embryo quality or ploidy status. The outcomes of dual uninterrupted OS have not yet been studied. STUDY DESIGN, SIZE, DURATION: This was an open-label randomized controlled trial (RCT) with superiority design, performed in a single tertiary centre. Subjects were randomized with a 1:1 allocation into two groups between October 2019 and September 2021. All patients underwent a conventional stimulation with recombinant FSH. When two or more follicles of 17 mm were present, the final inclusion criterion was assessed; randomization occurred only in the presence of ≤9 follicles of ≥11 mm. In Group A, ovulation was triggered with hCG, and oocyte retrieval (OR) was performed 34-36 h later, followed by a fresh single or double embryo transfer (SET or DET) on Day 3/5. In Group B, ovulation was triggered with GnRH agonist, followed by another OS, without discontinuation of the FSH administration. In the presence of one or more follicles of ≥17 mm, the second stimulation was completed with hCG. A freeze-all strategy (Day 3/5) was applied for both retrievals, followed by transfer of one or two embryos in an artificially prepared frozen-thawed cycle. In the absence of one or more follicles of ≥17 mm after 13 additional days of stimulation, the second cycle was cancelled. All ORs were executed by a senior fertility specialist who was blinded for the first treatment, and all follicles >10 mm were aspirated, according to routine clinical practice. The primary outcome was the total number of MII oocytes. Patients were followed up until all embryos were transferred, or until live birth was achieved. Other secondary outcomes included the number of cumulus-oocyte complexes (COCs), the number of good quality embryos (Day 3/5), the ongoing pregnancy rate, and gonadotropin consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients between 25 and 40 years old, with an anti-Müllerian hormone level of ≤1.5 ng/ml, antral follicle count of ≤6, or ≤5 oocytes after a previous stimulation, were included. At the start, 70 patients were eligible for participation in the trial, of whom 48 patients fulfilled the final inclusion criterium and were randomized. After drop-out of two patients, 23 patients were randomized to a single round of OS (Group A), and 23 patients were randomized to two uninterrupted rounds of OS (Group B). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar between both groups. The cumulative number of COCs and MII oocytes after completion of the second OR was similar in Group A and Group B [5.3 ± 2.7 versus 5.3 ± 3.0 (P = 0.95); 4.1 ± 2.4 versus 4.3 ± 2.7 (P = 0.77)]. Likewise, a comparable number of excellent and good quality embryos was available on Day 3 (3.0 ± 2.0 versus 2.7 ± 2.0; P = 0.63). In Group B, the cancellation rate due to insufficient response to the second round of stimulation was 39.1% (9/23). When focusing on the first stimulation in both groups, there were no significant differences regarding basal FSH, gonadotropin consumption, and the number of preovulatory follicles. After the first OR, the mean number of COC and MII oocytes was significantly higher in Group A (who had hCG triggering), compared to Group B (who had GnRH agonist triggering) [5.3 ± 2.7 versus 3.3 ± 2.2; difference 95% CI (0.54 to 3.45), P = 0.004 and 4.1 ± 2.4 versus 3.0 ± 2.2; difference 95% CI (-0.15 to 2.6), P = 0.05, respectively]. Likewise, the number of excellent and good quality embryos on Day 3 was significantly higher (3.0 ± 2.0 versus 1.9 ± 1.7; P = 0.02) in Group A. LIMITATIONS, REASONS FOR CAUTION: This study was powered to demonstrate superiority for the number of MII oocytes after dual stimulation. Investigating the impact of dual stimulation on pregnancy rates would have required a larger sample size. Furthermore, the heterogeneity in embryo vitrification and transfer policies precluded a correct comparison of embryologic outcomes between both groups. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT investigating the role of continuous stimulation with double aspiration in low responders. Our results show no statistically significant differences in the cumulative number of MII oocytes between one conventional stimulation with fresh ET and two consecutive stimulations with a freeze-only approach. Furthermore, the observed suboptimal oocyte yield after agonist ovulation triggering in low responders in the dual uninterrupted OS group is a reason for concern and further scrutiny, given that previous RCTs have shown similar outcomes in normal and high responders after hCG and GnRH agonist triggers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by a research grant from Organon. H.T. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, Cook, Goodlife, and Ferring. L.B. received fees for lectures from Merck & Organon and support for attending ESHRE 2023. M.D.V. reports fees for lectures from Ferring, Merck, Organon, IBSA, Gedeon Richter, and Cooper Surgical and support for attending ASRM 2023. S.M. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. C.B. was on the Advisory board and received consulting fees from Theramex and received honoraria for lectures and presentations from Abbott, Ferring, Gedeon-Richter, IBSA, and Merck. TRIAL REGISTRATION NUMBER: NCT03846544. TRIAL REGISTRATION DATE: 19 February 2019. DATE OF FIRST PATIENT'S ENROLMENT: 28 October 2019.

A 10-year follow-up of reproductive outcomes in women attempting motherhood after elective oocyte cryopreservation.

STUDY QUESTION: Which reproductive treatment outcomes are observed in women who underwent elective oocyte cryopreservation (EOC) and who returned to the clinic with a desire for a child? SUMMARY ANSWER: Whether to warm oocytes or to first use fresh own oocytes for ART depends on age upon returning, but both strategies result in favorable reproductive outcomes. WHAT IS KNOWN ALREADY: Most affluent countries have observed a trend toward postponement of childbearing, and EOC is increasingly used based on the assumption that oocytes cryopreserved at a younger age may extend a woman's reproductive lifespan and mitigate her age-related fertility decline. Although most follow-up studies after EOC have focused on women who requested oocyte warming, a substantial proportion of women who do not conceive naturally will embark on fertility treatment without using their cryopreserved oocytes. Reports on reproductive outcomes in past EOC users are scarce, and the lack of reproductive treatment algorithms in this group of women hampers counseling toward the most efficient clinical strategy. STUDY DESIGN, SIZE, DURATION: This retrospective observational single-center study encompasses 843 women who had elective oocyte vitrification between 2009 and 2019 at our fertility clinic. Women who underwent fertility preservation for medical or oncological reasons were excluded. This study describes the outcomes of the diverse reproductive treatment strategies performed until May 2022 in women returning to our clinic to attempt motherhood. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using descriptive statistics, patient characteristics and data of ovarian stimulation (OS) of EOC cycles were analyzed, as well as data related to OS and laboratory data of ART in women who pursued fertility treatment with and/or without using their cryopreserved oocytes. The primary outcome was live birth rate (LBR) per patient after oocyte warming and after ART using fresh oocytes. Secondary outcomes were return rate, utilization rate of the cryopreserved oocytes, laboratory outcomes upon return, and LBR per embryo transfer. A multivariable regression model was developed to identify factors associated with the decision to thaw oocytes as the primary strategy and factors associated with ongoing pregnancy upon return to the clinic. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1353 EOC cycles (mean ± SD, 1.6 ± 0.9 per patient) were performed. At the time of EOC, the mean age was 36.5 ± 2.8 years, mean anti-Müllerian hormone (AMH) was 2.3 ± 2.0 ng/ml, and 174 (20.6%) women had a partner. On average, 13.9 ± 9.2 mature oocytes were cryopreserved. Two hundred thirty-one (27.4%) women returned to the clinic, an average of 39.9 ± 23.4 months after EOC. Upon returning, their mean age was 40.4 ± 3.1 years, mean AMH was 1.5 ± 1.5 ng/ml, and 158/231 (68.3%) patients had a partner. As a primary approach, 110/231 (47.6%) past EOC users embarked on oocyte warming, 50/231 (21.6%) had intrauterine insemination, and 71/231 (30.7%) had ART using fresh own oocytes. Cumulative LBR (CLBR) was 45.9% (106/231) notwithstanding a miscarriage rate (MR) of 30.7% (51/166) in the entire cohort. In total, 141 women performed oocyte warming at some stage in their treatment trajectory. A subset of 90/231 (39.0%) patients exclusively had oocyte warming (41.6 ± 3.0 years, with 10.0 ± 5.2 oocytes warmed per patient). 52/231 (22.5%) patients exclusively had ART using fresh own oocytes (mean age of 39.0 ± 2.8 years, with 9.9 ± 7.4 mature oocytes retrieved per patient). CLBR was 37/90 (41.1%) in the oocyte warming-only group and 25/52 (48.1%) in the OS-only group. MR/transfer was 25.0% and 29.3% in the oocyte warming-only group and the OS-only group, respectively. LIMITATIONS, REASONS FOR CAUTION: Both sample size and the retrospective design are limitations of this study. The decision to embark on a specific reproductive treatment strategy was based on patient preference, after counseling on their treatment options. This precludes direct comparison of the efficiency of reproductive treatment options in past EOC users in this study. WIDER IMPLICATIONS OF THE FINDINGS: Reporting on clinical outcomes of women who underwent EOC and returned to the clinic to embark on divergent reproductive treatment strategies is mandatory to establish guidelines for best clinical practice in this growing patient population. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

To Test or Not? Xpert MTB/RIF as an Alternative to Smear Microscopy to Guide Line Probe Assay Testing for Drug-Resistant Tuberculosis.

Xpert MTB/RIF (Xpert) revolutionized tuberculosis (TB) diagnosis. Laboratory decision making on whether widely-used reflex drug susceptibility assays (MTBDRplus, first-line resistance; MTBDRsl, second-line) are conducted is based on smear status, with smear-negative specimens often excluded. We performed receiver operator characteristic (ROC) curve analyses using bacterial load information (smear microscopy grade, Xpert-generated semi-quantitation categories and minimum cycle threshold [CTmin] values) from Xpert rifampicin-resistant sputum for the prediction of downstream line probe assay results as "likely non-actionable" (no resistance or susceptible results generated). We evaluated actionable-to-non-actionable result ratios and pay-offs with missed resistance versus LPAs done universally. Smear-negatives were more likely than smear-positive specimens to generate a non-actionable MTBDRplus (23% [133/559] versus 4% [15/381]) or MTBDRsl (39% [220/559] versus 12% [47/381]) result. However, excluding smear-negatives would result in missed rapid diagnoses (e.g., only 49% [264/537] of LPA-diagnosable isoniazid resistance would be detected if smear-negatives were omitted). Testing smear-negatives with a semi-quantitation category ≥ "medium" had a high ratio of actionable-to-non-actionable results (12.8 or a 4-fold improvement versus testing all using MTBDRplus, 4.5 or 3-fold improvement for MTBDRsl), which would still capture 64% (168/264) and 77% (34/44) of LPA-detectable smear-negative resistance, respectively. Use of CTmins permitted optimization of this ratio with higher specificity for non-actionable results but decreased resistance detected. Xpert quantitative information permits identification of a smear-negative subset in whom the payoffs of the ratio of actionable-to-non-actionable LPA results with missed resistance may prove acceptable to laboratories, depending on context. Our findings permit the rational expansion of direct DST to certain smear-negative sputum specimens.

Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon ß-1a.

OBJECTIVE: Evaluate the effect of subcutaneous interferon ß-1a (sc IFN ß-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). METHODS: Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN ß-1a 44 µg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. RESULTS: In patients not converting to CDMS, sc IFN ß-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P < 0.001 and P = 0.005) and new T1 iso-intense lesions (P < 0.001 and P = 0.002) after 24 months; only sc IFN ß-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P < 0.001). PVVC findings in patients treated with sc IFN ß-1a suggested pseudo-atrophy that was ~ fivefold greater versus placebo in the first year of treatment (placebo 1.11%; qw 4.28%; tiw 6.76%; P < 001); similar findings were apparent for non-converting patients. CONCLUSIONS: In patients with an FCDE, treatment with sc IFN ß-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

Does the dose or type of gonadotropins affect the reproductive outcomes of poor responders undergoing modified natural cycle IVF (MNC-IVF)?

OBJECTIVE: Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing IVF in a modified natural cycle (MNC-IVF)? STUDY DESIGN: This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. All predicted poor responders (Poseidon groups 3 and 4) who underwent MNC-IVF in our center were included. Mild ovarian stimulation (rFSH/uFSH/hp-hMG) was started when a follicle with a mean diameter of 12-14 mm was observed on ultrasound scan; GnRH antagonist was added from the next day onwards. Mature oocytes were inseminated using ICSI. RESULTS: In total 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.28 (0.26) ng/ml, respectively. The daily dose of gonadotropins was either < 75 IU/d [11/1398 (0.8 %)] or 75 to < 100 IU/d [1303/1398 (93.2 %)] or ≥ 100 to 150 IU/d [84/1398 (6 %)]. Patients were stimulated with rFSH [251/1398 (18 %)], uFSH [45/1398 (3.2 %)] or hp-hMG [1102/1398 (78.8 %)]. Clinical pregnancy rate was 119/1398 (8.5 %). Live birth was achieved in 80/1398 (5.7 %) of cycles. There was no significant difference in rates of pregnancy and live birth across different types and doses of gonadotropins. The GEE multivariate regression analysis, adjusting for relevant confounders, showed that the type of treatment strategy (rFSH/uFSH/hp-hMG) and the daily dose of gonadotropins were not associated with live birth rates (LBR) (p value 0.08 and 0.8, respectively). CONCLUSIONS: The type and daily dose of gonadotropins do not affect the reproductive outcome of poor responders undergoing MNC-IVF.

Validation of Baveno VI and Expanded-Baveno VI Criteria for predicting gastroesophageal varices in patients with alcoholic and non-alcoholic fatty liver disease.

Background and aims: Baveno VI and Expanded-Baveno VI Criteria were validated to rule out high-risk esophageal varices (HRV) and to prevent unneeded endoscopies in compensated advanced chronic liver disease (cACLD) mainly related to viral hepatitis. We aim to assess these criteria to rule out low- and high- risk varices in patients with cACLD secondary to alcoholic liver disease (ALD) and non- alcoholic fatty liver disease (NAFLD). Methods: Data were collected retrospectively from 2016 to 2020. Inclusion criteria were: NAFLD and /or ALD related cACLD, a liver stiffness measurement (LSM) ≥ 10 kPa and an esophagogastroduodenoscopy (EGD) within 12 months. Exclusion criteria were: use of non cardioselective ß-blockers, hepatic decompensation, previous variceal bleeding, portal thrombosis, liver cancer, or liver transplant. Results: One hundred and ninety-four patients were included in this study. Eighty-one patients (42%) met Baveno VI criteria and 103 (53%) met Expanded-Baveno VI criteria. Baveno VI criteria yielded a high negative predictive value (NPV ≥ 95%) for detecting HRV and varices of any size. Expanded-Baveno VI criteria yielded a high NPV ≥ 95% only for detecting HRV: the miss rate for varices of any size was 8%. Expanded-Baveno VI criteria could avoid more endoscopies than the original Baveno VI criteria to rule out HRV (53% versus 42%). Conclusion: In this study, both criteria showed high NPV to rule out HRV but only original Baveno VI criteria yielded a satisfactory high NPV to rule out varices of any size. Expanded-Baveno VI criteria could avoid more endoscopies to exclude HRV.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

First live birth after fertility preservation using vitrification of oocytes in a woman with mosaic Turner syndrome.

PURPOSE: To report the case of a young woman diagnosed with Turner syndrome (TS) who achieved a live birth using her own oocytes that had been vitrified for fertility preservation. METHODS: A 25-year-old woman with mosaic (45,X/46,XX) TS was referred for fertility preservation (FP) counseling. Serum anti-Müllerian hormone (AMH) level was normal (6.4 µg/L). In view of the unpredictable rate of follicle loss in TS individuals, she requested FP and underwent two cycles of ovarian stimulation (OS) for oocyte cryopreservation (OoC) using a GnRH antagonist protocol and recombinant follicle stimulating hormone (rFSH), 200-250 IU daily for 8 resp. 12 days. RESULTS: In total, 29 metaphase II oocytes (MII) were vitrified after OS. After conceiving spontaneously and achieving a live birth, she returned to the clinic five years after OoC with a desire for pregnancy using in vitro fertilization (IVF) of her cryopreserved oocytes and preimplantation genetic testing (PGT-A). All 29 MII oocytes were thawed; 23 oocytes survived (79.3%) and were inseminated with partner sperm using intracytoplasmic sperm injection (ICSI). Thirteen oocytes were fertilized resulting in three good quality blastocysts which were vitrified after trophectoderm biopsy for PGT-A using array-CGH. Two blastocysts were found to be euploid. One was thawed and transferred to the uterus using a HRT priming protocol. An uneventful pregnancy occurred. The patient delivered a healthy baby girl weighing 3490 g at 40 weeks of gestation. CONCLUSIONS: We report the first live birth achieved using cryopreserved oocytes in a woman diagnosed with mosaic TS. Cryopreservation of oocytes after ovarian stimulation is a realistic option for FP in selected post menarche individuals with mosaic TS. Whether PGT-A may reduce the risk of pregnancy loss in TS has to be confirmed by further studies.

Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. CONCLUSIONS: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings.

Parameters of poor prognosis in preimplantation genetic testing for monogenic disorders.

STUDY QUESTION: What is the likelihood of success of a single cycle of preimplantation genetic testing for monogenic disorders (PGT-M), measured as the cumulative live birth rate (CLBR) and based on various patient demographics? SUMMARY ANSWER: For all women aged ≤40 years, the CLBR was at least 10% when the number of oocytes was ≥7 (range 10-30%) or was at least 5% when the number of oocytes was ≥3 (range 5-17%). WHAT IS KNOWN ALREADY: The number of oocytes is significantly associated with the number of embryos for genetic testing and the clinical outcome in PGT-M. Embryos diagnosed as affected or embryos that remain without diagnosis cannot be used for embryo transfer. The size of the group of embryos non-suitable for transfer varies between 25% and 81%, depending on the indication. Thus, PGT-M is more likely to be more severely impacted by suboptimal ovarian response, poor fertilization and suboptimal embryo development than conventional IVF/ICSI schemes without PGT. STUDY DESIGN, SIZE, DURATION: This was a single-centre retrospective comparative cohort study, of cycles between January 2011 and December 2015. A total number of 2265 PGT-M cycles were compared to 2833 conventional ICSI cycles. The principal aim of our study was the identification of the parameters of poor CLBR in couples undergoing PGT-M using multiplex short tandem repeat (STR) markers on blastomere biopsy DNA. The secondary aim was to compare the parameters of poor CLBR of the PGT-M population to those of couples undergoing ICSI without PGT. PARTICIPANTS/MATERIALS, SETTING, METHODS: The baseline characteristics of the PGT-M group were compared to the conventional ICSI group. A multiple regression analysis was applied to account for the following potential confounding factors: female age, number of previous ART cycles, number of oocytes/suitable embryos for transfer and dosage of gonadotrophins used for ovarian stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: The PGT-M group was younger (female age 32.0 vs 34.5 years), had a higher number of previous ART cycles (1.1 vs 0.9 cycles) and used more gonadotrophins (2367 vs 1984 IU). Per cycle, the PGT-M group had more retrieved oocytes (11.8 vs 8.3 oocytes), fewer suitable embryos for transfer (1.7 vs 2.8 embryos) and a lower CLBR (29.4% vs 35.0%). Multiple regression analysis showed that the CLBR in the PGT-M group was significantly influenced by female age, the number of previous ART cycles, the number of oocytes and the dose of ovarian stimulation. In both groups, the predicted CLBR increased with increasing numbers of oocytes and suitable embryos. At least two retrieved oocytes or one embryo per single PGT-M cycle could confer an estimated CLBR above 10%. By assessing female age and the number of retrieved oocytes together, it was shown that for all women aged ≤40 years, the predicted CLBR per single PGT-M cycle was ≥10% when the number of oocytes was ≥7 or was ≥5% when the number of oocytes was ≥3. LIMITATIONS, REASONS FOR CAUTION: Despite the large sample size, the findings are confined by limited confounder adjustment and the lack of specific PGT-M comparators. WIDER IMPLICATIONS OF THE FINDINGS: This study aimed to describe the likelihood of success of PGT-M treatment, measured as CLBR, based on various patient demographics. In a PGT-M program, couples need to be informed of the prognosis more specifically when it is futile. The table of predicted CLBRs presented in this study is a useful tool in counselling PGT-M couples for making reproductive choices. STUDY FUNDING/COMPETING INTEREST(S): No funding was required and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

How doctors actually (do not) involve families in decisions to continue or discontinue life-sustaining treatment in neonatal, pediatric, and adult intensive care: A qualitative study.

BACKGROUND: Intensive care doctors have to find the right balance between sharing crucial decisions with families of patients on the one hand and not overburdening them on the other hand. This requires a tailored approach instead of a model based approach. AIM: To explore how doctors involve families in the decision-making process regarding life-sustaining treatment on the neonatal, pediatric, and adult intensive care. DESIGN: Exploratory inductive thematic analysis of 101 audio-recorded conversations. SETTING/PARTICIPANTS: One hundred four family members (61% female, 39% male) and 71 doctors (60% female, 40% male) of 36 patients (53% female, 47% male) from the neonatal, pediatric, and adult intensive care of a large university medical center participated. RESULTS: We identified eight relevant and distinct communicative behaviors. Doctors' sequential communicative behaviors either reflected consistent approaches-a shared approach or a physician-driven approach-or reflected vacillating between both approaches. Doctors more often displayed a physician-driven or a vacillating approach than a shared approach, especially in the adult intensive care. Doctors did not verify whether their chosen approach matched the families' decision-making preferences. CONCLUSIONS: Even though tailoring doctors' communication to families' preferences is advocated, it does not seem to be integrated into actual practice. To allow for true tailoring, doctors' awareness regarding the impact of their communicative behaviors is key. Educational initiatives should focus especially on improving doctors' skills in tactfully exploring families' decision-making preferences and in mutually sharing knowledge, values, and treatment preferences.

Impact of ARTs on oncological outcomes in young breast cancer survivors.

STUDY QUESTION: What is the risk of recurrence in young breast cancer survivors who undergo ARTs following completion of anticancer treatment? SUMMARY ANSWER: ART in breast cancer survivors does not appear to have a negative impact on disease-free survival. WHAT IS KNOWN ALREADY: In healthy women, fertility treatment does not increase the risk of developing breast cancer. At the time of breast cancer diagnosis and before starting anticancer treatments, several studies have shown the safety of performing ART. However, the safety of ART in breast cancer survivors following completion of anticancer treatment remains under-investigated. In general, breast cancer survivors are counselled to avoid any hormonal treatment but there are limited data available on the effect of short exposure to high oestradiol levels during ART. The largest study in this regard included 25 breast cancer survivors exposed to ART and did not show a detrimental effect of ART on patient survival. Hence, taking into account that pregnancy after breast cancer does not affect cancer prognosis, defining the safety of ART in breast cancer survivors remains a priority. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective multicentric matched cohort study including a cohort of breast cancer survivors who underwent ART (exposed patients) between January 2006 and December 2016. Exposed patients who were eligible for the study were matched according to known breast cancer prognostic factors. Matched breast cancer survivors did not undergo ART (non-exposed patients) and were disease-free for a minimum time that was not less than the time elapsed between breast cancer diagnosis and first ART for the matched ART-exposed patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were retrieved from all survivors who had been diagnosed with breast cancer in eight participating centres at an age of ≤40 years, without metastasis, ongoing pregnancy, pre-existing neoplasia or ovarian failure. ART included ovarian stimulation for IVF/ICSI, clomiphene citrate treatment and hormone replacement therapy for embryo transfer. Data were collected from an oncological database for the selection of breast cancer patients in the non-exposed group. Exposed patients were matched (1:2) for germline BRCA status, tumour stage, anticancer treatment and age, whenever feasible. Matched groups were compared at baseline according to characteristics using conditional logistic regression. Kaplan-Meier curves were constructed to compare time to recurrence between groups, with the time of ART as starting point that has been adjusted in the non-exposed group. The analyses were performed using Stata IC/15.1. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 39 breast cancer patients in the ART group were eligible for the analysis and were matched with 73 controls. There was no statistical difference between the two groups for the presence of BRCA mutation, tumour characteristics, use of (neo)adjuvant chemotherapy and of adjuvant endocrine therapy. Exposed patients were younger than non-exposed patients (mean age 31.8 vs 34.3 years, respectively; P < 0.001). In the ART group, 89.7% were nulliparous at diagnosis compared to 46.6% of controls (P < 0.001). ART was performed at a mean age of 37.1 years old, after a median time of 4.1 years following breast cancer diagnosis (range: 1.5-12.5). Median anti-Müllerian hormone at the time of ART was 0.28 ng/ml (range: 0-4.4) and median serum oestradiol peak level was 696.5 pg/ml (range: 139.7-4130). Median follow-up time from first attempt of ART was 4.6 years (range: 2.4-12.5) in the ART group. Adjusted follow-up time for the non-exposed group was 6.9 years (range: 1.1-16.5 years) (P = 0.004). In the ART group, 59% of patients had a pregnancy after breast cancer compared to 26% in the non-exposed patients (P = 0.001). Breast cancer relapsed in 7.7% versus 20.5% women in the ART and non-exposed groups, respectively (hazard ratio 0.46, 95% CI 0.13-1.62, P = 0.23). Median time to relapse was 1.3 (range: 0.3-2.7) years versus 4.5 (range: 0.4-11.1) years after ART and adjusted time in the ART and non-exposed groups, respectively (P = 0.14). LIMITATIONS, REASONS FOR CAUTION: Although this is the first and largest multicentric study addressing the impact of ART on breast cancer recurrence to provide data on oestrogen exposure, only a small number of patients could be included. This reflects the reluctance of breast cancer survivors and/or oncologists to perform ART, and highlights the need for a prospective data registry to confirm the safety of this approach. This would offer the possibility for these patients, who are at a high risk of infertility, to fully benefit from ART. WIDER IMPLICATIONS OF THE FINDINGS: Although recent studies have proven that pregnancy after breast cancer has no detrimental impact on prognosis, counselling patients about the safety of ART remains challenging. Our study provides reassuring data on the use of ART in breast cancer survivors with favourable prognostic factors, for when natural conception fails. STUDY FUNDING/COMPETING INTEREST(S): M.C. and I.D. are funded by FNRS, Télévie-FNRS and Fonds Erasme. M.D.V. is a CooperSurgical scientific advisory board member and receives lecture fees for MSD, Gedeon-Richter and Ferring, outside the submitted work. M.L. has acted as a consultant for Roche and Novartis and has received honoraria from Theramex, Roche, Lilly, Pfizer, Novartis and Takeda, outside the submitted work. I.D. has acted as a consultant for ROCHE and has received speaker's fees from Novartis, outside the submitted work. E.d.A. has received honoraria and is a Roche/GNE, Novartis, SeaGen and Zodiac scientific advisory board member, has received travel grants from Roche/GNE and GSK/Novartis, and has received research grants from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier, outside the submitted work. A.D. is a recipient of a research grant from Ferring Pharmaceuticals and receives lecture and/or consultancy fees from Merck, Gedeon-Richter and Ferring Pharmaceuticals, outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Early pregnancy loss in patients with polycystic ovary syndrome after IVM versus standard ovarian stimulation for IVF/ICSI.

STUDY QUESTION: Is the incidence of early pregnancy loss (EPL) in patients with polycystic ovary syndrome (PCOS) higher after IVM of oocytes than after ovarian stimulation (OS) for IVF/ICSI? SUMMARY ANSWER: Women with PCOS who are pregnant after fresh embryo transfer have a higher probability of EPL following IVM, but after frozen embryo transfer (FET), no significant difference in the incidence of EPL was observed following IVM compared to OS. WHAT IS KNOWN ALREADY: There is conflicting evidence in the current literature with regard to the risk of EPL after IVM of oocytes when compared with OS. Because of the limited sample size in previous studies, the use of different IVM systems and the possible bias introduced by patient characteristics and treatment type, firm conclusions cannot be drawn. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study evaluating 800 women, with a diagnosis of infertility and PCOS as defined by Rotterdam criteria, who had a first positive pregnancy test after fresh or FET following IVM or OS between January 2010 and December 2017 in a tertiary care academic medical centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancies after non-hCG triggered IVM following a short course of highly purified human menopausal gonadotropin were compared with those after conventional OS. The primary outcome was EPL, defined as a spontaneous pregnancy loss before 10 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 329 patients with a positive pregnancy test after IVM and 471 patients with a positive pregnancy test after OS were included. Women who were pregnant after IVM were younger (28.6 ± 3.4 years vs 29.3 ± 3.6 years, P = 0.005) and had higher serum anti-Mullerian hormone levels (11.5 ± 8.1 ng/ml vs 7.2 ± 4.1 ng/ml, P < 0.001) compared to those who were pregnant after OS. The distribution of PCOS phenotypes was significantly different among women in the IVM group compared to those in the OS group and women who were pregnant after OS had previously suffered EPL more often (28% vs 17.6%, P = 0.003). EPL was significantly higher after fresh embryo transfer following IVM compared to OS (57/122 (46.7%) vs 53/305 (17.4%), P < 0.001), while the results were comparable after FET (63/207 (30.4%) vs 60/166 (36.1%), respectively, P = 0.24). In the multivariate logistic regression analysis evaluating fresh embryo transfer cycles, IVM was the only independent factor (adjusted odds ratio (aOR) 4.24, 95% CI 2.44-7.37, P < 0.001)) significantly associated with increased odds of EPL. On the other hand, when the same model was applied to FET cycles, the type of treatment (IVM vs OS) was not significantly associated with EPL (aOR 0.73, 95% CI 0.43-1.25, P = 0.25). LIMITATIONS, REASONS FOR CAUTION: The current data are limited by the retrospective nature of the study and the potential of bias due to unmeasured confounders. WIDER IMPLICATIONS OF THE FINDINGS: The increased risk of EPL after fresh embryo transfer following IVM may point towards inadequate endometrial development in IVM cycles. Adopting a freeze-all strategy after IVM seems more appropriate. Future studies are needed to ascertain the underlying cause of this observation. STUDY FUNDING/COMPETING INTEREST(S): The Clinical IVM research has been supported by research grants from Cook Medical and Besins Healthcare. All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Combining fertility preservation procedures to spread the eggs across different baskets: a feasibility study.

STUDY QUESTION: What is the reproductive potential following combinations of ovarian stimulation, IVM and ovarian tissue cryopreservation (OTC) in female patients seeking fertility preservation (FP)? SUMMARY ANSWER: In selected patients, combining different FP procedures is a feasible approach and reproductive outcomes after FP in patients who return to attempt pregnancy are promising. WHAT IS KNOWN ALREADY: FP is increasingly performed in fertility clinics but an algorithm to select the most suitable FP procedure according to patient characteristics and available timeframe is currently lacking. Vitrification of mature oocytes (OV) and OTC are most commonly performed, although in some clinical scenarios a combination of procedures including IVM, to spread the sources of gametes, may be considered in order to enhance reproductive options for the future. STUDY DESIGN, SIZE, DURATION: Retrospective, observational study in a university-based, tertiary fertility centre involving all female patients who underwent urgent medical FP between January 2012 and December 2018. Descriptive analysis of various FP procedures, either stand-alone or combined, was performed, and reproductive outcomes of patients who attempted pregnancy in the follow-up period were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 207 patients underwent medical FP. Patient-tailored strategies and procedures were selected after multidisciplinary discussion. When deemed feasible, FP procedures were combined to cryopreserve different types of reproductive tissue for future use. The main primary outcome measure was the number of mature oocytes. Live birth rates were evaluated in patients who returned for reproductive treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Among patients seeking FP, 95/207 (46%) had breast cancer, 43/207 (21%) had haematological malignancies and 31/207 (15%) had a gynaecological tumour. Mean ± SD age was 27.0 ± 8.3 years. Eighty-five (41.1%) patients underwent controlled ovarian stimulation (COS), resulting in 10.8 ± 7.1 metaphase II (MII) oocytes for vitrification. Eleven (5.3%) patients had multiple COS cycles. Transvaginal oocyte retrieval for IVM was performed in 17 (8.2%) patients, yielding 9.2 ± 10.1 MII oocytes. Thirty-four (16.4%) patients underwent OTC combined with IVM of oocytes retrieved from ovarian tissue 'ex vivo' (OTO-IVM), yielding 4.0 ± 4.3 MII oocytes in addition to ovarian fragments. Seventeen (8.2%) patients had OTC combined with OTO-IVM and transvaginal retrieval of oocytes for IVM from the contralateral ovary, resulting in 13.5 ± 9.7 MII oocytes. In 13 (6.3%) patients, OTC with OTO-IVM was followed by controlled stimulation of the contralateral ovary, yielding 11.3 ± 6.6 MII oocytes in total. During the timeframe of the study, 31/207 (15%) patients have returned to the fertility clinic with a desire for pregnancy. Of those, 12 (38.7%) patients had preserved ovarian function and underwent ART treatment with fresh oocytes, resulting in nine (75%) livebirth. The remaining 19 (61.3%) patients requested warming of their cryopreserved material because of ovarian insufficiency. Of those, eight (42.1%) patients had a livebirth, of whom three after OTO-IVM. To date, 5/207 patients (2.4%) achieved an ongoing pregnancy or livebirth after spontaneous conception. LIMITATIONS, REASONS FOR CAUTION: Our FP programme is based on a patient-tailored approach rather than based on an efficiency-driven algorithm. The data presented are descriptive, which precludes firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Combining different FP procedures is likely to enhance the reproductive fitness of patients undergoing gonadotoxic treatment but further follow-up studies are needed to confirm this. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study and the authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

To trigger or not to trigger ovulation in a natural cycle for frozen embryo transfer: a randomized controlled trial.

STUDY QUESTION: Is the clinical pregnancy rate (CPR) following a frozen embryo transfer (FET) in a natural cycle (NC) higher after spontaneous ovulation than after triggered ovulation [natural cycle frozen embryo transfer (NC-FET) versus modified NC-FET]? SUMMARY ANSWER: The CPR did not vary significantly between the two FET preparation protocols. WHAT IS KNOWN ALREADY: Although the use of FET is continuously increasing, the most optimal endometrial preparation protocol is still under debate. For transfer in the NC specifically, conflicting results have been reported in terms of the outcome following spontaneous or triggered ovulation. STUDY DESIGN, SIZE, DURATION: In a tertiary hospital setting, subjects were randomized with a 1:1 allocation into two groups between January 2014 and January 2019. Patients in group A underwent an NC-FET, while in group B, a modified NC-FET was performed with a subcutaneous hCG injection to trigger ovulation. In neither group was additional luteal phase support administered. All embryos were vitrified-warmed on Day 3 and transferred on Day 4 of embryonic development. The primary outcome was CPR at 7 weeks. All patients were followed further until 10 weeks of gestation when the ongoing pregnancy rate (OPR) was defined by the observation of foetal cardiac activity on ultrasound scan. Other secondary outcomes included biochemical pregnancy rate, early pregnancy loss and the number of visits, blood samples and ultrasonographic examinations prior to FET. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 260 patients (130 per study arm) were randomized, of whom 12 withdrew consent after study arm allocation. A total of 3 women conceived spontaneously before initiating the study cycle and 16 did not start for personal or medical reasons. Of the 229 actually commencing monitoring for the study FET cycle, 7 patients needed to be switched to a hormonal replacement treatment protocol due to the absence of follicular development, 12 had no embryo available for transfer after warming and 37 had a spontaneous LH surge before the ovulation trigger could be administered, although they were allocated to group B. Given the above, an intention-to-treat (ITT) analysis was performed taking into account 248 patients (125 in group A and 123 in group B), as well as a per protocol (PP) analysis on a subset of 173 patients (110 in group A and 63 in group B). MAIN RESULTS AND THE ROLE OF CHANCE: Demographic features were evenly distributed between the study groups, as were the relevant fresh and frozen ET cycle characteristics. According to the ITT analysis, the CPR and OPR in group A (33.6% and 27.2%, respectively) and group B (29.3% and 24.4%, respectively) did not vary significantly [relative risk (RR) 0.87, 95% CI (0.60;1.26), P = 0.46 and RR 0.90, 95% CI (0.59;1.37), P = 0.61, respectively]. Biochemical pregnancy rate and early pregnancy loss were also found to be not statistically significantly different between the groups. In contrast, more clinic visits and blood samplings for cycle monitoring were required in the NC-FET group (4.05 ± 1.39) compared with the modified NC-FET group (3.03 ± 1.16, P = <0.001), while the number of ultrasound scans performed were comparable (1.70 ± 0.88 in group A versus 1.62 ± 1.04 in group B). The additional PP analysis was in line with the ITT results: CPR in group A was 36.4% versus 38.1% in group B [RR 1.05, 95% CI (0.70;1.56), P = 0.82]. LIMITATIONS, REASONS FOR CAUTION: The results are limited by the high drop-out rate for the PP analysis in the modified NC-FET group as more than one-third of the subjects allocated to this group ovulated spontaneously before ovulation triggering. Nonetheless, this issue is inherent to routine clinical practice and is an important observation of an event that can only be avoided by performing a very extensive monitoring that limits the practical advantages associated with modified NC-FET. Furthermore, although this is the largest randomized controlled trial (RCT) investigating this specific research question so far, a higher sample size would allow smaller differences in clinical outcome to be detected, since currently they may be left undetected. WIDER IMPLICATIONS OF THE FINDINGS: This RCT adds new high-quality evidence to the existing controversial literature concerning the performance of NC-FET versus modified NC-FET. Based on our results showing no statistically significant differences in clinical outcomes between the protocols, the treatment choice may be made according to the patient's and treating physician's preferences. However, the modified NC-FET strategy reduces the need for hormonal monitoring and may therefore be considered a more patient-friendly and potentially cost-effective approach. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study. TRIAL REGISTRATION NUMBER: NCT02145819. TRIAL REGISTRATION DATE: 8 January 2014. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2014.

Smartphone-based remote assessment of upper extremity function for multiple sclerosis using the Draw a Shape Test.

OBJECTIVE: Smartphone devices may enable out-of-clinic assessments in chronic neurological diseases. We describe the Draw a Shape (DaS) Test, a smartphone-based and remotely administered test of Upper Extremity (UE) function developed for people with multiple sclerosis (PwMS). This work introduces DaS-related features that characterise UE function and impairment, and aims to demonstrate how multivariate modelling of these metrics can reliably predict the 9-Hole Peg Test (9HPT), a clinician-administered UE assessment in PwMS. APPROACH: The DaS Test instructed PwMS and healthy controls (HC) to trace predefined shapes on a smartphone screen. A total of 93 subjects (HC, n = 22; PwMS, n = 71) contributed both dominant and non-dominant handed DaS tests. PwMS subjects were characterised as those with normal (nPwMS, n = 50) and abnormal UE function (aPwMS, n = 21) with respect to their average 9HPT time (≤ or > 22.7 (s), respectively). L 1-regularization techniques, combined with linear least squares (OLS, IRLS), or non-linear support vector (SVR) or random forest (RFR) regression were investigated as functions to map relevant DaS features to 9HPT times. MAIN RESULTS: It was observed that average non-dominant handed 9HPT times were more accurately predicted by DaS features (r 2 = 0.41, [Formula: see text] 0.05; MAE: 2.08 ± 0.34 (s)) than average dominant handed 9HPTs (r 2 = 0.39, [Formula: see text] 0.05; MAE: 2.32 ± 0.43 (s)), using simple linear IRLS ([Formula: see text] 0.01). Moreover, it was found that the Mean absolute error (MAE) in predicted 9HPTs was comparable to the variability of actual 9HPT times within HC, nPwMS and aPwMS groups respectively. The 9HPT however exhibited large heteroscedasticity resulting in less stable predictions of longer 9HPT times. SIGNIFICANCE: This study demonstrates the potential of the smartphone-based DaS Test to reliably predict 9HPT times and remotely monitor UE function in PwMS.