Combined upper lid skin crease and endoscopic approach to frontal sinus mucocoeles.

PURPOSE: This case series describes the ophthalmic manifestations of frontal sinus mucoceles and reports the long-term surgical outcomes of a combined endoscopic and upper-lid skin crease drainage approach carried out jointly with otorhinolaryngology. METHODS: We present a retrospective case review of 18 orbits and 15 patients presenting with frontal sinus mucocoeles, all of whom underwent drainage via an adapted anterior orbitotomy approach between January 2015 and July 2023. Data collection included preoperative and postoperative examination findings (visual acuity, extraocular motility, lid retraction, and lagophthalmos), mucocoele recurrence, cosmetic satisfaction, and surgical complications. Patients were followed up for an average of 22 months. RESULTS: All patients underwent successful frontal mucocoele drainage via a modified anterior orbitotomy and simultaneous endonasal approach. At presentation, three (20%) had extraocular restriction leading to diplopia, and six (40%) had proptosis in the eye adjacent to the mucocoele. One patient presented acutely with no light perception in the affected eye due to compressive optic neuropathy. All patients who had reduced extraocular motility before surgery regained full motility post-operatively. Treatment was successful in all cases, and there was no documented mucocoele recurrence during follow-up. Satisfactory aesthetic outcomes were achieved in all cases. Reported complications included temporary forehead numbness and ptosis of the affected eyelid, which resolved without intervention. CONCLUSION: The modified anterior orbitotomy approach to frontal mucocoeles allows optimal frontal sinus access and mucocoele treatment while preserving cosmesis.

A multidisciplinary approach to frontal sinus mucocoeles using an upper lid skin crease incision combined with endoscopic drainage allows full access to the frontal sinus and treatment of the mucocoele while preserving cosmesis.

Safety of day-case endoscopic sinus surgery in England: An observational study using an administrative dataset.

INTRODUCTION: As elective surgical services recover from the COVID-19 pandemic a movement towards day-case surgery may reduce waiting lists. However, evidence is needed to show that day-case surgery is safe for endoscopic sinus surgery (ESS). The aim of this study was to investigate the safety of day-case ESS in England. DESIGN: Secondary analysis of administrative data. METHODS: We extracted data from the Hospital Episodes Statistics database for the 5 years from 1 April 2014 to 31 March 2019. Patients undergoing elective ESS procedures aged ≥17 years were included. Exclusion criteria included malignant neoplasm, complex systemic disease and trans-sphenoidal pituitary surgery. The primary outcome was readmission within 30 days post-discharge. Multilevel, multivariable logistic regression modelling was used to compare outcomes for those operated on as day-cases and those with an overnight stay after adjusting for demographic, frailty, comorbidity and procedural covariates. RESULTS: Data were available for 49 223 patients operated on across 129 NHS hospital trusts. In trusts operating on more than 50 patients in the study period, rates of day-case surgery varied from 20.6% to 100%. Nationally, rates of day-case surgery increased from 64.0% in the financial year 2014/2015 to 78.7% in 2018/2019. Day-case patients had lower rates of 30-day emergency readmission (odds ratio 0.71, 95% confidence interval 0.62 to 0.81). Outcomes for patients operated on in trusts with ≥80% day-case rates compared with patients operated on in trusts with <50% rates of day-case surgery were similar. CONCLUSIONS: Our data support the view that ESS can safely be performed as day-case surgery in most cases, although it will not be suitable for all patients. There appears to be scope to increase rates of day-case ESS in some hospital trusts in England.

Frontal sinus mucocele with orbital extension drained via a combined upper lid skin crease and endoscopic approach.

This case report discusses the ophthalmic complications of frontal sinus mucoceles and describes the favorable long-term surgical outcomes of a combined endoscopic and upper-lid skin crease drainage approach carried out jointly with otorhinolaryngology. A 47-year-old single mother presented to eye casualty with markedly swollen eyelids and visual acuity of 6/6 in the left eye, no perception of light in the right. Ophthalmic examination revealed right-sided hypoglobus and proptosis with exposure keratopathy inferiorly. There was complete ophthalmoplegia in the right eye and a hemorrhagic optic disc visible on fundoscopy. CT orbit with contrast confirmed a diagnosis of giant frontal mucocele with orbital extension. The patient underwent mucocele drainage via a modified anterior orbitotomy approach and FESS (Functional Endoscopic Sinus Surgery) drainage performed jointly with otorhinolaryngology. Two weeks post-operatively her proptosis was resolving and by three months she had regained full extraocular motility. As expected, vision was not restored in the right eye. At one year, the patient's upper lid skin crease scar was completely buried in the eyelid's natural contour, and repeat CT scanning confirmed no re-stenosis or mucocele recurrence. This case demonstrates, that a multidisciplinary approach to far-lateral frontal sinus mucoceles with orbital extension and ophthalmic complications which combines an upper lid skin crease incision with FESS drainage, allows adequate access to the frontal sinus while preserving cosmesis.

Birthweight and Chemotherapy Exposure in Women Diagnosed with Breast Cancer during Pregnancy.

OBJECTIVE: Breast cancer is one of the most frequently diagnosed cancers in pregnancy and is commonly treated with chemotherapy. To date, studies examining effects of chemotherapy during pregnancy on fetal growth have yielded conflicting results, and most are limited by small sample sizes or are nonspecific with respect to cytotoxic regimen or type of cancer treated. We sought to evaluate the effect of chemotherapy for breast cancer in pregnancy on birthweight and small for gestational age infants. STUDY DESIGN: This is a retrospective cohort study of 74 women diagnosed with pathologically confirmed breast cancer during pregnancy between 1997 and 2018 at one of three academic medical centers, who had a singleton birth with known birthweight. Forty-nine received chemotherapy and 25 did not receive chemotherapy. Linear regression modeling was used to compare birthweight (by gestational age and sex-specific z-score) by chemotherapy exposure. Subanalyses of specific chemotherapy regimen and duration of chemotherapy exposure were also performed. Placental, neonatal, and maternal outcomes were also analyzed by chemotherapy exposure. RESULTS: In the adjusted model, chemotherapy exposure was associated with lower birthweight (Δ z-score = -0.49, p = 0.03), but similar rates of small for gestational age (defined as birthweight <10th percentile for gestational age) infants (8.2 vs. 8.0%, p = 1.0; Fisher's exact test). Each additional week of chemotherapy (Δ z-score = -0.05, p = 0.03) was associated with decreased birthweight, although no association was found with specific chemotherapy regimen. Chemotherapy exposure was associated with lower median placental weight percentile by gestational age (9th vs. 75th, p < 0.05). Secondary maternal outcomes were similar between the group that did and did not receive chemotherapy. CONCLUSION: Chemotherapy for breast cancer in pregnancy in this cohort is associated with lower birthweight but no difference in the rate of small for gestational age infants. KEY POINTS: · Chemotherapy for breast cancer in pregnancy is associated with decreased birthweight but similar rates of small for gestational age infants.. · Birthweight did not differ according to chemotherapy regimen.. · There is no difference in the rate of small for gestational age infants..

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity.

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

Tracheostomy care and decannulation during the COVID-19 pandemic. A multidisciplinary clinical practice guideline.

PURPOSE: Traditional critical care dogma regarding the benefits of early tracheostomy during invasive ventilation has had to be revisited due to the risk of COVID-19 to patients and healthcare staff. Standard practises that have evolved to minimise the risks associated with tracheostomy must be comprehensively reviewed in light of the numerous potential episodes for aerosol generating procedures. We meet the urgent need for safe practise standards by presenting the experience of two major London teaching hospitals, and synthesise our findings into an evidence-based guideline for multidisciplinary care of the tracheostomy patient. METHODS: This is a narrative review presenting the extensive experience of over 120 patients with tracheostomy, with a pragmatic analysis of currently available evidence for safe tracheostomy care in COVID-19 patients. RESULTS: Tracheostomy care involves many potentially aerosol generating procedures which may pose a risk of viral transmission to staff and patients. We make a series of recommendations to ameliorate this risk through infection control strategies, equipment modification, and individualised decannulation protocols. In addition, we discuss the multidisciplinary collaboration that is absolutely fundamental to safe and effective practise. CONCLUSION: COVID-19 requires a radical rethink of many tenets of tracheostomy care, and controversy continues to exist regarding the optimal techniques to minimise risk to patients and healthcare workers. Safe practise requires a coordinated multidisciplinary team approach to infection control, weaning and decannulation, with integrated processes for continuous prospective data collection and audit.

Potential Effects of Regionalized Maternity Care on U.S. Hospitals.

OBJECTIVE: To examine the current patterns of care for women at high risk for delivery-related morbidity to inform discussions about the feasibility of this regionalized approach. METHODS: We performed a cross-sectional study and linked 2014 American Hospital Association survey and State Inpatient Database data from seven representative states. We used American Hospital Association-reported hospital characteristics and State Inpatient Database procedure codes to assign a level of maternal care to each hospital. We then assigned each patient to a minimum required level of maternal care (I-IV) based on maternal comorbidities captured in the State Inpatient Database. Our outcome was delivery at a hospital with an inappropriately low level of maternal care. Comorbidities associated with delivery at an inappropriate hospital were assessed using descriptive statistics. RESULTS: The analysis included 845,545 deliveries occurring at 556 hospitals. The majority of women had risk factors appropriate for delivery at level I or II hospitals (85.1% and 12.6%, respectively). A small fraction (2.4%) of women at high risk for maternal morbidity warranted delivery in level III or IV hospitals. The majority (97.6%) of women delivered at a hospital with an appropriate level of maternal care, with only 2.4% of women delivering at a hospital with an inappropriate level of maternal care. However, 43.4% of the 19,988 high-risk patients warranting delivery at level III or IV hospitals delivered at level I or II hospitals. Women with comorbidities likely to benefit from specialized care (eg, maternal cardiac disease, placenta previa with prior uterine surgery) had high rates of delivery at hospitals with an inappropriate level of maternal care (68.2% and 37.7%, respectively). CONCLUSION: Though only 2.41% of deliveries occurred at hospitals with an inappropriate level of maternal care, a substantial fraction of women at risk for maternal morbidity delivered at hospitals potentially unequipped with resources to manage their needs. Promoting triage of high-risk patients to hospitals optimized to provide risk-appropriate care may improve maternal outcomes with minimal effect on most deliveries.

Evaluation of a Quality Improvement Intervention to Increase Vaginal Birth for Twins.

OBJECTIVE: To evaluate whether there was an association between the systematic promotion of twin vaginal delivery and an increase in the rates of twin vaginal birth. METHODS: We conducted a retrospective cohort study. We implemented a quality improvement initiative promoting twin vaginal delivery at an academic tertiary care center in 2013. The program included a needs assessment, simulation of vaginal twin delivery, online educational material, and the expansion of a dedicated twin clinic. We analyzed rates of twin vaginal birth in pregnancies at or beyond 24 weeks of gestation without a contraindication to labor, prior uterine surgery, or a demise or lethal anomaly of either twin. Using linear regression, we calculated annual adjusted rates of twin vaginal birth from 2010 to 2015 and in the 3 years before and after our intervention. We performed an interrupted time-series analysis estimating rates of change before and after the intervention to account for the influence of secular trend. RESULTS: Of 1,574 patients delivering twins, 897 (57%) were included, with 479 in the 3 years before and 418 in the 3 years after the intervention. Adjusted rates of vaginal delivery increased from 32.1% (n=153) to 44.2% (n=185) before and after the intervention (P<.01), with a decrease in elective cesarean delivery from 54.6% (n=479) to 44.3% (n=185) (P<.01). Rates of breech extraction increased after the intervention (5.7% vs 9.3%, P=.04). However, there was no difference in the rate of change in twin vaginal birth in the time period before (1.35% annual increase, P=.76) or after (5.8% annual increase, P=.40) the intervention. CONCLUSIONS: Although we observed an increased rate of twin vaginal birth in the time period after our intervention, because the rates of increase before and after the intervention were not statistically different, the increase is not attributable to our intervention and is more properly attributed to secular trend.

When ultrasound anomalies are present: An estimation of the frequency of chromosome abnormalities not detected by cell-free DNA aneuploidy screens.

OBJECTIVES: This study characterizes cytogenetic abnormalities with ultrasound findings to refine counseling following negative cell-free DNA (cfDNA). METHODS: A retrospective cohort of pregnancies with chromosome abnormalities and ultrasound findings was examined to determine the residual risk following negative cfDNA. Cytogenetic data was categorized as cfDNA detectable for aneuploidies of chromosomes 13, 18, 21, X, or Y or non-cfDNA detectable for other chromosome abnormalities. Ultrasound reports were categorized as structural anomaly, nuchal translucency (NT) ≥3.0 mm, or other "soft markers". Results were compared using chi squared and Fishers exact tests. RESULTS: Of the 498 fetuses with cytogenetic abnormalities and ultrasound findings, 16.3% (81/498) had non-cfDNA detectable results. In the first, second, and third trimesters, 12.4% (32/259), 19.5% (42/215), and 29.2% (7/24) had non-cfDNA detectable results respectively. The first trimester non-cfDNA detectable results reduced to 7.7% (19/246) if triploidy was detectable by cfDNA testing. For isolated first trimester NT of 3.0-3.49 mm, 15.8% (6/38) had non-cfDNA detectable results, while for NT ≥3.5 mm, it was 12.3% (20/162). For cystic hygroma, 4.3% (4/94) had non-cfDNA detectable results. CONCLUSIONS: Counseling for residual risk following cfDNA in the presence of an ultrasound finding is impacted by gestational age, ultrasound finding, and cfDNA detection of triploidy.

Does Universal Insurance Mitigate Racial Differences in Minimally Invasive Hysterectomy?

STUDY OBJECTIVE: To determine if racial differences exist in receipt of minimally invasive hysterectomy (defined as total vaginal hysterectomy [TVH] and total laparoscopic hysterectomy [TLH]) compared with an open approach (total abdominal hysterectomy [TAH]) within a universally insured patient population. DESIGN: Retrospective data analysis (Canadian Task Force classification II-2). SETTING: The 2006-2010 national TRICARE (universal insurance coverage to US Armed Services members and their dependents) longitudinal claims data. PATIENTS: Women aged 18 years and above who underwent hysterectomy stratified into 4 racial groups: white, African American, Asian, and "other." INTERVENTION: Receipt of hysterectomy (TAH, TVH, or TLH). MEASUREMENTS AND MAIN RESULTS: We used risk-adjusted multinomial logistic regression models to determine the relative risk ratios of receipt of TVH and TLH compared with TAH in each racial group compared with referent category of white patients for benign conditions. Among 33 015 patients identified, 60.82% (n = 20 079) were white, 26.11% (n = 8621) African American, 4.63% (n = 1529) Asian, and 8.44% (n = 2786) other. Most hysterectomies (83.9%) were for benign indications. Nearly 42% of hysterectomies (n = 13 917) were TAH, 27% (n = 8937) were TVH, and 30% (n = 10 161) were TLH. Overall, 36.37% of white patients received TAH compared with 53.40% of African American patients and 51.01% of Asian patients (p < .001). On multinomial logistic regression analyses, African American patients were significantly less likely than white patients to receive TVH (relative risk ratio [RRR], .63; 95% confidence interval [CI], .58-.69) or TLH (RRR, .65; 95% CI, .60-.71) compared with TAH. Similarly, Asian patients were less likely than white patients to receive TVH (RRR, .71; 95% CI, .60-.84) or TLH (RRR, .69; 95% CI, .58-.83) compared with TAH. Analyses by benign indications for surgery showed similar trends. CONCLUSION: We demonstrate that racial minority patients are less likely to receive a minimally invasive surgical approach compared with an open abdominal approach despite universal insurance coverage. Further work is warranted to better understand factors other than insurance access that may contribute to racial differences in surgical approach to hysterectomies.

Disparities in receipt of a laparoscopic operation for ectopic pregnancy among TRICARE beneficiaries.

BACKGROUND: Racial disparities in receipt of a laparoscopic operation for ectopic pregnancy are attributed to inequalities in access to care. This study sought to determine if racial disparities in laparoscopic operation for ectopic pregnancy exist among a universally insured population. METHODS: Using 2006-2010 TRICARE (insurance for members of the United States Armed Services and their dependents) data, patients who received a laparoscopic operation or laparotomy for ectopic pregnancy were stratified into direct/military or purchased/civilian system of care. Odds of receipt of a laparoscopic operation in each racial group were compared adjusting for patient demographics, system of care, and severity of ectopic pregnancy. RESULTS: Among 3,041 patients in the study sample, 1,878 (61.7%) received laparotomy and 1,163 (38.2%) received a laparoscopic operation within 30 days of diagnosis. Overall, 42.4% of white women received a laparoscopic operation compared with 33.1% of Asian women and 34.9% of black women (P < .001). On multivariable analysis, black women had a 33% lesser odds of receiving a laparoscopic operation (odds ratio: 0.67; confidence interval: 0.55-0.83) compared with white women. These disparities were absent within direct care (odds ratio: 0.93; confidence interval: 0.71-1.21) but were present within purchased care (odds ratio: 0.54; confidence interval: 0.40-0.73). CONCLUSION: Racial minority patients are less likely to receive a laparoscopic operation for ectopic pregnancy despite universal insurance coverage within civilian/purchased care. Further work is warranted to better understand the factors other than insurance access that may contribute to racial disparities in selection of operative approach.

A multi-state analysis of postpartum readmissions in the United States.

BACKGROUND: Readmission rates are used as a quality metric in medical and surgical specialties; however, little is known about obstetrics readmissions. OBJECTIVE: Our goals for this study were to describe the trends in postpartum readmissions over time; to characterize the common indications and associated diagnoses for readmissions; and to determine maternal, delivery, and hospital characteristics that may be associated with readmission. STUDY DESIGN: Postpartum readmissions occurring within the first 6 weeks after delivery in California, Florida, and New York were identified between 2004 and 2011 in State Inpatient Databases. Of the 5,949,739 eligible deliveries identified, 114,748 women were readmitted over the 8-year period. We calculated the rates of readmissions and their indications by state and over time. The characteristics of the readmission stay, including day readmitted, length of readmission, and charge for readmission, were compared among the diagnoses. Odds ratios were calculated using a multivariate logistic regression to determine the predictors of readmission. RESULTS: The readmission rate increased from 1.72% in 2004 to 2.16% in 2011. Readmitted patients were more likely to be publicly insured (54.3% vs 42.0%, P < .001), to be black (18.7% vs 13.5%, P < .001), to have comorbidities such as hypertension (15.3% vs 2.4%, P < 0.001) and diabetes (13.1% vs 6.8%, P < .001), and to have had a cesarean delivery (37.2% vs 32.9%, P < .001). The most common indications for readmission were infection (15.5%), hypertension (9.3%), and psychiatric illness (7.7%). Patients were readmitted, on average, 7 days after discharge, but readmission day varied by diagnosis: day 3 for hypertension, day 5 for infection, and day 9 for psychiatric disease. Maternal comorbidities were the strongest predictors of postpartum readmissions: psychiatric disease, substance use, seizure disorder, hypertension, and tobacco use. CONCLUSION: Postpartum readmission rates have risen over the last 8 years. Understanding the risk factors, etiologies, and cause-specific timing for postpartum readmissions may aid in the development of new quality metrics in obstetrics and targeted strategies to curb the rising rate of postpartum readmissions in the United States.

What is the role of the 11- to 14-week ultrasound in women with negative cell-free DNA screening for aneuploidy?

OBJECTIVE: This study aimed to examine the role of the 11- to 14-week ultrasound in women with negative cell-free DNA screening. METHODS: A retrospective cohort study of women at increased risk for aneuploidy based on age or medical history and negative cell-free DNA screening between March 2012 and March 2014 was conducted. Patients were included if they had an 11- to 14-week ultrasound and obstetrical care at our center(s). Primary outcome was an unexpected finding at ultrasound. Imaging findings were compared with obstetrical outcome by medical record review. RESULTS: Study group was composed of 1739 patients. An unexpected finding was identified in 60/1739 (3.5%). An abnormal fetal finding occurred in 37 living fetuses (2.1%); 33 had a nuchal translucency (NT) ≥ 3 mm, including four 'isolated' cystic hygroma and three with a structural abnormality. Four fetuses had a structural anomaly without a thick NT. Karyotype confirmed euploidy in 98.7% of available cases. Pregnancy termination was chosen by 63.6% of those with cystic hygroma or anomaly at the 11- to 14-week scan. Unexpected multiples were identified in 13 (0.7%) women and a fetal demise in 10 (0.6%). CONCLUSION: Unexpected findings at the 11- to 14-week scan occur in 3.5% of patients with negative cell-free DNA. Recognition provides options for comprehensive testing, consultation, and management.

How Accurate Is the Dating of Scheduled 39-Week Deliveries?

OBJECTIVE: We assessed the impact of a policy preventing scheduled repeat cesarean deliveries at less than 39 weeks, accounting for potential inaccuracies in pregnancy dating. STUDY DESIGN: We analyzed a cohort of repeat cesarean deliveries before and after the policy change and used chi-square testing to compare the proportion of deliveries at less than 39 weeks. We assessed whether the reduction in early-term deliveries was different if the gestational age was based on the documented estimated date of delivery (EDD) as compared with best obstetric dating. RESULTS: Our cohort consisted of 213 women; 112 before the policy change and 101 after. Using the EDD assigned at delivery, there was a 12.1% absolute decrease in scheduled deliveries at less than 39 weeks (25.0-12.9%; p = 0.025). However, using the EDD by best obstetric dating, there was no significant change (32.1-25.7%; p = 0.305). Of the 85 discrepant EDDs, providers were more likely to assign an earlier EDD (63.5%; p = 0.013). CONCLUSION: Our institution's policy change led to a 12.1% absolute reduction in documented, scheduled early-term deliveries, however only a 6.4% absolute decline using best obstetric dating. Policy initiatives to reduce early-term deliveries should consider the source and accuracy of the assigned pregnancy dating.

Angiogenic markers in pregnancies conceived through in vitro fertilization.

OBJECTIVE: Pregnancies that have been conceived through in vitro fertilization (IVF) have been associated with higher rates of preeclampsia and other complications that are associated with placental dysfunction. We evaluated whether IVF pregnancies, when compared with those conceived spontaneously, would be associated with alterations in serum angiogenic markers. STUDY DESIGN: This was a retrospective cohort study from 3 US academic institutions (2006-2008). Women with singleton pregnancies who conceived via IVF or spontaneously were included. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 4 time points throughout gestation. Pregnancy outcomes that included diagnosis of preeclampsia or other obstetric complications were ascertained from the medical record. The relationship among IVF status, PlGF, and sFlt-1 were modeled over gestation and stratified by clinical pregnancy outcome. RESULTS: Of the included 2392 singleton pregnancies, 4.5% (108 pregnancies) were conceived though IVF. IVF pregnancies were significantly more likely to be complicated by preeclampsia (15.7% vs 7.7%). IVF pregnancies had significantly higher levels of sFlt-1 at 18, 26, and 35 weeks of gestation (P = .04, P = .004, P < .0001, respectively) and lower levels of PlGF at 18 and 35 weeks of gestation (P = .007 and .0006, respectively). These differences persisted even after being controlled for maternal comorbidities or obstetric outcomes such as preeclampsia. CONCLUSION: Pregnancies conceived via IVF were found to have an increased antiangiogenic profile (elevated sFlt-1 and decreased PlGF) at multiple time points throughout gestation when compared with spontaneously conceived pregnancies. Alterations in the angiogenic profile persisted even after we controlled for maternal comorbidities of clinically evident disorders of abnormal placentation such as preeclampsia. The increased antiangiogenic profile suggests fundamentally aberrant placentation related to in vitro fertilization, which may warrant closer fetal surveillance in these pregnancies.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Eliminating first trimester markers: will replacing PAPP-A and ßhCG miss women at risk for small for gestational age?

OBJECTIVE: Placental analytes are traditionally used for aneuploidy screening, although may be replaced by cell-free fetal DNA. Abnormal analytes also identify women at risk for small for gestational age (SGA). We sought to quantify the proportion of women at risk for SGA by low pregnancy-associated plasma protein-A (PAPP-A) or ßhCG who would not otherwise be identified by maternal risk factors. METHODS: We studied first-trimester PAPPA-A and ßhCG from 658 euploid singleton pregnancies from a prospective longitudinal cohort. Analytes were standardized for gestational age in multiples of the median (MoM). SGA was defined as birthweight z-score ≤-1.28. Maternal risk factors included chronic hypertension, pre-gestational diabetes and age ≥40. RESULTS: Mean GA was 38.8 ± 1.9 weeks; 6.8% had a SGA infant. Low PAPP-A and ßhCG were identified in 48 (7.4%) and 9 (1.4%) of pregnancies, respectively, of whom 18.9% were SGA (OR 3.0, 95% CI 1.4-6.3). 88% did not have risk factors for SGA. Among women with no risk factors, low PAPP-A was a significant predictor of SGA (OR 3.3, 95% CI 1.5-7.4). CONCLUSION: Most women with abnormal analytes did not have risk factors for SGA. Eliminating PAPP-A and ßhCG may present missed opportunities to identify women at risk for SGA.

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.