The first clinical validation of whole-genome screening on standard trophectoderm biopsies of preimplantation embryos.

Objective: To validate the performance of our laboratory-developed whole-genome screening assay within clinical preimplantation genetic testing environments. Design: Perform a laboratory-developed whole-genome assay on both cell lines and trophectoderm biopsies, subsequently employing the next-generation sequencing procedure to reach a sequencing depth of 30X. Adhere to the Genome Analysis Toolkit best practices for accuracy, sensitivity, specificity, and precision calculations by comparing samples with references. Our assay was then applied to cell lines and biopsies harboring known pathogenic variants, aiming to ascertain these changes solely from the next-generation sequencing data, independent of parental genome information. Settings: Clinical laboratory. Patients: Coriell cell lines and research embryos with known chromosomal or genetic variants. Research trophectoderm biopsies from a couple that are heterozygous carriers for distinct variants in the same autosomal recessive gene (HOGA1). Intervention: Not applicable. Main Outcome Measures: Accuracy, sensitivity, specificity, and precision were assessed by comparing the samples to their references. For samples with known variants, we calculated our sensitivity to detecting established variants. For the research embryos, noncarrier, carrier, and compound heterozygous states of inherited HOGA1 variants were distinguished independently of parental samples. Results: Amplification of DNA from cell lines and embryos yielded success rates exceeding 99.9% and 98.2%, respectively, although maintaining an accuracy of >99.9% for aneuploidy assessment. The accuracy (99.99%), specificity (99.99%), sensitivity (98.0%), and precision (98.1%) of amplified genome in the bottle (reference NA12878) and embryo biopsies were comparable to results on genomic DNA, including mitochondrial heteroplasmy. Using our assay, we achieved >99.99% sensitivity when examining samples with known chromosomal and genetic variants. This encompassed pathogenic CFTR, BRCA1, and other variants, along with uniparental isodisomies and microdeletions such as DiGeorge syndrome. Our research study identified noncarrier, carrier, and compound heterozygous states within trophectoderm biopsies while simultaneously screening for 1,300 other severe monogenic diseases. Conclusion: To our knowledge, this is the first clinical validation of whole-genome embryo screening. In this study, we demonstrated high accuracy for aneuploidy calls (>99.9%) and genetic variants (99.99%), even in the absence of parental genomes. This assay demonstrates advancements in genomic screening and an extended scope for testing capabilities in the realm of preimplantation genetic testing.

Impact of artificial intelligence arrhythmia mapping on time to first ablation, procedure duration, and fluoroscopy use.

INTRODUCTION: Artificial intelligence (AI) ECG arrhythmia mapping provides arrhythmia source localization using 12-lead ECG data; whether this information impacts procedural efficiency is unknown. We performed a retrospective, case-control study to evaluate the hypothesis that AI ECG mapping may reduce time to ablation, procedural duration, and fluoroscopy. MATERIALS AND METHODS: Cases in which system output was used were retrospectively enrolled according to IRB-approved protocols at each site. Matched control cases were enrolled in reverse chronological order beginning on the last day for which the technology was unavailable. Controls were matched based upon physician, institution, arrhythmia, and a predetermined complexity rating. Procedural metrics, fluoroscopy data, and clinical outcomes were assessed from time-stamped medical records. RESULTS: The study group consisted of 28 patients (age 65 ± 11 years, 46% female, left atrial dimension 4.1 ± 0.9 cm, LVEF 50 ± 18%) and was similar to 28 controls. The most common arrhythmia types were atrial fibrillation (n = 10), premature ventricular complexes (n = 8), and ventricular tachycardia (n = 6). Use of the system was associated with a 19.0% reduction in time to ablation (133 ± 48 vs. 165 ± 49 min, p = 0.02), a 22.6% reduction in procedure duration (233 ± 51 vs. 301 ± 83 min, p < 0.001), and a 43.7% reduction in fluoroscopy (18.7 ± 13.3 vs. 33.2 ± 18.0 min, p < 0.001) versus controls. At 6 months follow-up, arrhythmia-free survival was 73.5% in the study group and 63.3% in the control group (p = 0.56). CONCLUSION: Use of forward-solution AI ECG mapping is associated with reductions in time to first ablation, procedure duration, and fluoroscopy without an adverse impact on procedure outcomes or complications.

Is Choosing Wisely Wise for Lobular Carcinoma in Patients Over 70 Years of Age? A National Cancer Database Analysis of Sentinel Node Practice Patterns.

BACKGROUND: Controversy continues in the treatment of breast cancer in women over 70 years of age. In 2016, the Society of Surgical Oncology recommended against routine use of sentinel lymph node biopsy (SLNBx) as part of the 'Choosing Wisely Campaign'. This study examines the oncologic safety of avoidance of routine SLNBx in patients over 70 years of age with invasive lobular carcinoma (ILC). METHODS: The National Cancer Database was used to identify women with invasive ductal carcinoma (IDC) and ILC diagnosed between 2012 and 2020. Clinical and pathological staging, axillary staging, surgery type, and lymph node positivity between patients with IDC or ILC were compared. RESULTS: Among women with T1 tumors, 85,949 (79.6%) patients with IDC and 12,761 (81.5%) patients with ILC underwent SLNBx (p < 0.001). Among patients who underwent SLNBx, those with IDC were more likely to have positive nodes (n = 7535, 8.8%) than those with ILC (n = 1041, 8.2%; p = 0.02). During the time interval of interest, for both IDC and ILC patients, the rate of axillary lymph node dissection decreased and rates of SLNBx or no axillary staging increased. On multivariate analysis, ILC histology was associated with use of SLNBx, but without nodal positivity. CONCLUSION: A trend de-escalation of axillary staging was identified in this study, however the majority of patients meeting the 'Choosing Wisely' criteria are still undergoing SLNBx. No increased risk of nodal positivity was identified among patients with ILC, suggesting that surgeons can continue to choose wisely and limit the use of SLNBx in women over 70 years of age with T1 ILC tumors.

The "rail sign": an ultrasound finding in placenta accreta spectrum indicating deep villous invasion and adverse outcomes.

BACKGROUND: Ultrasound has demonstrated a high accuracy in the prenatal diagnosis of placenta accreta spectrum. However, it is not known whether ultrasound findings can pinpoint the depths of villous invasion, recommend surgical strategies, and predict clinical outcomes. OBJECTIVE: We described an ultrasound descriptor for the placenta accreta spectrum and investigated whether it can predict the severity of villous invasion and clinical outcomes. STUDY DESIGN: The patients with placenta accreta spectrum in this retrospective cross-sectional study were diagnosed and managed in our hospital from 2002 to 2017. The placenta, with overlying myometrium and bladder, was mapped with color Doppler sonography while the patient's bladder was full. A "rail sign" was defined as 2 parallel neovascularizations depicted by color Doppler sonography over the uterovesical junction and bladder mucosa, with interconnecting bridging vessels perpendicular to both. The patients received serial ultrasound examinations and surgery at our hospital. An unpaired t test and Pearson chi-square test compared the pathology subtypes, surgical strategies, and clinical outcomes in patients with or without a rail sign. RESULTS: We enrolled 133 consecutive cases of placenta accreta spectrum confirmed either by surgical inspection or pathology examination. Patients with a rail sign had a significantly higher risk of an abnormally invasive placenta (placenta increta or placenta percreta) than those patients without a rail sign (83.3% [60 of 72] vs 27.9% [17 of 61]; odds ratio, 12.94; P<.001). In addition, patients with a rail sign had a higher probability of perioperative approaches, including preoperative vascular control (58.3% [42 of 72] vs 21.3% [13 of 61]; odds ratio, 5.17; P<.001) and uterine artery embolization (34.7% [25 of 72] vs 11.5% [7 of 61]; odds ratio, 4.1; P=.0002]. Furthermore, patients with a rail sign carried a higher risk of adverse clinical outcomes than patients without a rail sign, such as blood transfusion (80.6% [58 of 72] vs 36.1% [22 of 61]; odds ratio, 7.34; P<.001], admission to the intensive care unit (33.3% [24 of 72] vs 16.4% [10 of 61]; odds ratio, 2.55; P=.026), hysterectomy (75% [54 of 72] vs 24.6% [15 of 61]; odds ratio, 9.2; P<.001), and bladder invasion (16.7% [12 of 72] vs 4.9% [3 of 61]; odds ratio, 3.86; P=.033). Notably, the negative predictive value of bladder invasion was 95.1%, indicating a high confidence to reject bladder invasion while the rail sign was negative. When the rail sign was used as a screening test, the positive likelihood ratio of predicting deep villous invasion was 3.64 and correlated with an increased probability of 20% to 25%. Patients with a rail sign also had a greater blood loss (2944±2748 mL vs 1530±1895 mL; P<.001) and a longer hospital stay (11.9±10.9 days vs 8.6±7.1 days; P=.036) than patients without a rail sign. CONCLUSION: A "rail sign" depicted by color Doppler sonography correlates with deeper villous invasion, additional perioperative approaches, and more adverse outcomes.

Uncontrolled before-after study adding carbetocin in addition to oxytocin decreases blood loss for cesarean section in twin pregnancies.

PURPOSE: To evaluate the effectiveness of adding carbetocin to regular uterotonic agents for prevention of postpartum hemorrhage (PPH) after cesarean section for twin pregnancies. METHODS: This is a retrospective uncontrolled before-after study done in a tertiary center in Taiwan, 2010-2017. Women with twin pregnancies that underwent cesarean section were enrolled. The control group (n = 114) received oxytocin infusion and direct uterine injection. In addition to these, the study group (n = 127) received 100ug of intravenous carbetocin. Primary endpoint was the change in hemoglobin. Secondary endpoints included risk of PPH and undiagnosed PPH (Hb dropped more than 2 g/dL), blood loss, the need for additional uterotonic maneuvers, and blood transfusion. Hemodynamic changes were also investigated. RESULTS: After adjusting for confounding factors, the change in Hb (0.35 g/dL, 95% CI: -0.03∼0.74) and incidence of PPH (OR 0.30, 95% CI: 0.03∼3.28) were comparable in both groups. However, women with undiagnosed PPH decreased (OR 0.43, 95% CI:0.22∼0.85). Total blood loss in 24 h after delivery also decreased (-40.33 mL, 95%CI: -80.32∼ -0.34). The use of extra uterotonic medications and the need for blood transfusion did not differ. The systolic blood pressure 4 h after childbirth was higher in the carbetocin group (6.71, 95% CI: 2.27∼11.15). CONCLUSION: The use of carbetocin in addition to regular uterotonic agents decreased total blood loss and undiagnosed PPH. Also, systolic blood pressure 4 h after childbirth is higher in the carbetocin group. There was no significant difference in hemoglobin change and risk of PPH.

Monocyte Subsets With High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8.

Osteoclasts (OCs) are bone-resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type (WT) mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C- monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of preestablished transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of interferon regulatory factor 8 (IRF8), a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8-deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation. © 2020 American Society for Bone and Mineral Research (ASBMR).

Complication rates after chorionic villus sampling and midtrimester amniocentesis: A 7-year national registry study.

PURPOSE: To assess the complication rates following chorionic villus sampling (CVS) and midtrimester amniocentesis in Taiwan. METHODS: This is a national registry-based cohort study from Taiwan. We included all women with singleton pregnancies who received either CVS (n = 1409) or midtrimester amniocentesis (n = 250,566) during 2006-2012. We assessed preterm premature rupture of membranes (PPROM), intrauterine fetal demise (IUFD), infection and spontaneous abortion (SA) that occurred within fourteen days after the procedures. We also assessed the risks of preterm delivery and miscarriage before 24 gestational weeks after amniocentesis. These complications were collected from the Genetic Disease Database of the Ministry of Health and Welfare, Taiwan National Birth Certificate Registry, and the Taiwan National Health Insurance Database. Pearson χ2 tests were used to compare the distributions between groups. RESULTS: For patients who underwent midtrimester amniocentesis, the rates of PPROM, IUFD, infection and SA within fourteen days were 0.24%, 0.11%, 0.05%, and 0.05%, respectively. Women with a normal fetal karyotype had a preterm birth rate (<37 gestational weeks) of 9.38%. The miscarriage rate (<24 gestational weeks) was 0.68%, which was 0.22% higher than those who did not receive the invasive procedures (p < 0.0001). After CVS, the IUFD rate was 1.68%, and the SA rate within fourteen days was 0.77%. CONCLUSION: The use of our large cohort demonstrated that the procedure-related complication rates were comparable to recent review or meta-analysis. This dataset might facilitate counselling in women who consider invasive genetic diagnostic procedures.

Diagnosing Distensible Venous Malformations of the Orbit With Diffusion-weighted Magnetic Resonance Imaging.

PURPOSE: To compare the diffusion-weighted imaging of nonthrombosed distensible venous malformations of the orbit with that of other histologically-proven orbital tumors. DESIGN: Retrospective case-control study. METHODS: Patients with nonthrombosed distensible venous malformations of the orbit and patients with other histologically-proven orbital tumors were selected for chart review. The main outcome measure was the apparent diffusion coefficient of these lesions. RESULTS: Sixty-seven patients qualified for chart review; 9 patients had nonthrombosed distensible venous malformations and 58 patients had other histologically-proven tumors. Three of the 9 patients with nonthrombosed distensible venous malformations were initially misdiagnosed as having had solid orbital tumors. The mean apparent diffusion coefficient of distensible venous malformations was 2.80 ± 0.48 × 10-3 mm2/s, whereas the mean apparent diffusion coefficient of other histologically-proven tumors was 1.18 ± 0.39 × 10-3 mm2/s (P < .001). The mean apparent diffusion coefficient ranged from 2.42 to 3.94 × 10-3 mm2/s in the distensible venous malformation group, whereas other histologically-proven tumors ranged from 0.53 to 2.08 × 10-3 mm2/s. Therefore, in this single-institution series, a threshold value of 2.10 × 10-3 mm2/s was 100% sensitive and 100% specific for distensible venous malformations. CONCLUSION: Certain nonthrombosed distensible venous malformations can evade diagnostic suspicion and mimic solid orbital tumors on standard magnetic resonance imaging sequences. In this single-institution series, diffusion-weighted imaging effectively distinguished these nonthrombosed distensible venous malformations from other orbital tumors.

Cataract surgery complications in nonagenarians.

PURPOSE: To investigate whether nonagenarians relative to octogenarians are at increased risk of ocular complications from cataract surgery in the US Veterans Health Administration (VHA). DESIGN: A retrospective cohort study. PARTICIPANTS: A total of 554 nonagenarians and 11 407 octogenarians who received cataract surgery in the VHA. METHODS: Nonagenarians and octogenarians who received 1 cataract surgery without a second surgery within 90 days between October 1, 2005, and September 30, 2007, were identified using the National Patient Care Database (NPCD). Data collected include demographics, preoperative systemic and ocular comorbidities, intraoperative complications, and 90-day postoperative complications. The adjusted odds ratio (OR) of complications in nonagenarians using octogenarians as a reference group was calculated using logistic regression modeling. MAIN OUTCOME MEASURES: Intraoperative and postoperative ocular complications within 90 days of cataract surgery in nonagenarians versus octogenarians. RESULTS: The most common systemic comorbidity for both age groups was diabetes mellitus (DM), and the most common ocular comorbidity for both age groups was age-related macular degeneration (AMD). Octogenarians had a higher prevalence of most systemic comorbidities, and nonagenarians had a higher prevalence of most ocular comorbidities. The most common intraoperative and postoperative complications for both age groups were vitreous loss or posterior capsular tear and posterior capsular opacification. The risk of having any intraoperative or postoperative complication was 13.5% for octogenarians and 13.4% for nonagenarians (P = 0.9001). The OR of having any intraoperative or postoperative complication in nonagenarians with octogenarians as a reference group was 0.94 (95% confidence interval, 0.73-1.22). CONCLUSIONS: Nonagenarians relative to octogenarians are not at increased risk of ocular complications from cataract surgery in the VHA. Further studies are needed to evaluate other outcome parameters, such as visual function and quality of life, in nonagenarians undergoing cataract surgery.