Objective The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix. Study Design Women with prior spontaneous preterm birth less than 34 weeks ...were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm. Results Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks ( P = .09). In planned analyses, birth less than 24 weeks ( P = .03) and perinatal mortality ( P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks ( P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum. Conclusion In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed “funneling”). To date, we do not understand ...why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility. Objective To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility. Study Design Using institutional review board–approved protocols, nonpregnant women <50 years old undergoing hysterectomy for benign indications were consented. Cervical tissue from the internal and external os were immunostained for smooth muscle cell markers (α-smooth muscle actin, smooth muscle protein 22 calponin) and contraction-associated proteins (connexin 43, cyclooxygenase-2, oxytocin receptor). To evaluate cervical smooth muscle cell morphology throughout the entire cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 μmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate. Results Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10% cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10–5 mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10–4 mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine –4% ± 20%, P = .003), and 10–3 mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine –15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10–5 mol/L. Conclusion Our findings suggest a new paradigm for cervical tissue morphology–one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Influenza immunisation during pregnancy is recommended but not widely implemented in some low-income regions. We assessed the safety and efficacy in mothers and infants of ...year-round maternal influenza immunisation in Nepal, where influenza viruses circulate throughout the year. Methods In this phase 4, randomised, placebo-controlled trial, we enrolled two consecutive sequential annual cohorts of pregnant women from the Sarlahi district in southern Nepal. We randomised mothers 1:1 to receive seasonally recommended trivalent inactivated influenza vaccine or saline placebo in blocks of eight, stratified by gestational age at enrolment (17–25 weeks vs 26–34 weeks). Women were eligible if they were married, 15–40 years of age, 17–34 weeks' gestation at enrolment, and had not previously received any influenza vaccine that season. We collected serum samples before and after immunisation, and cord blood from a subset of women and infants. Staff masked to allocation made home visits every week from enrolment to 6 months after delivery. Midnasal swabs for respiratory virus PCR testing were collected during maternal acute febrile respiratory infections, and from infants with any respiratory symptom. We assessed vaccine immunogenicity, safety, and three primary outcomes: the incidence of maternal influenza-like illness in pregnancy and 0–180 days postpartum, the incidence of low birthweight (<2500 g), and the incidence of laboratory-confirmed infant influenza disease from 0 to 180 days. This trial is registered with ClinicalTrials.gov , number NCT01034254. Findings From April 25, 2011, to Sept 9, 2013, we enrolled 3693 women in two cohorts of 2090 (1041 assigned to placebo and 1049 to vaccine) and 1603 (805 assigned to placebo and 798 to vaccine), with 3646 liveborn infants (cohort 1, 999 in placebo group and 1010 in vaccine group; cohort 2, 805 in placebo group and 798 in vaccine group). Immunisation reduced maternal febrile influenza-like illness with an overall efficacy of 19% (95% CI 1 to 34) in the combined cohorts; 9% efficacy (−16 to 29) in the first cohort, and 36% efficacy (9 to 55) in the second cohort. For laboratory-confirmed influenza infections in infants aged 0–6 months, immunisation had an overall efficacy for the combined cohorts of 30% (95% CI 5 to 48); in the first cohort, the efficacy was 16% (−19 to 41), and in the second cohort it was 60% (26 to 88). Maternal immunisation reduced the rates of low birthweight by 15% (95% CI 3–25) in both cohorts combined. The rate of small for gestational age infants was not modified by immunisation. The number of adverse events was similar regardless of immunisation status. Miscarriage occurred in three (0·2%) participants in the placebo group versus five (0·3%) in the vaccine group, stillbirth occurred in 31 (1·7%) versus 33 (1·8%), and congenital defects occurred in 18 (1·0%) versus 20 (1·1%). Five women died in the placebo group and three died in the vaccine group. The number of infant deaths at age 0–6 months was similar in each group (50 in the placebo group and 61 in the vaccine group). No serious adverse events were associated with receipt of immunisation. Interpretation Year-round maternal influenza immunisation significantly reduced maternal influenza-like illness, influenza in infants, and low birthweight over the entire course of the study, indicating the strategy could be useful in subtropical regions. Funding Bill & Melinda Gates Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably ...detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). Study Design This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). Results MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. Conclusion High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This study evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs).
We analyzed 165 patients with FPAs who were treated at a single institution with proton ...therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy(RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as ≥ 3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported.
With a median follow-up time of 4.3 years (range, 0.5-20.6 years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone-secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors.
Proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect.
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External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we ...present 5-year results of a prospective trial.
From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months).
Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval CI, 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537).
Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Analysis of the replication history of transitional B cells in patients with CVIDs showed that decreased numbers of transitional B cells in a subgroup reflect decreased BM maturation rather than ...impaired proliferation in the periphery.5 In the only study of BM biopsy specimens to date, the finding that 9 of 25 patients with CVIDs showed a partial arrest in early B-cell developmental stages supported this hypothesis.6 However in that study BM was taken to exclude malignant lymphoma and other serious causes of cytopenias; the changes seen in B-cell subpopulations in that study could be caused by immune dysregulation, inflammation in patients with severe clinical phenotypes or treatment for these complications. The methodology has been shown previously to be consistent in children7,11 and now in adults. Because early B-cell maturation is considered antigen independent and given that there was no clinical or blood count evidence of any immune deficiency in the healthy subjects providing these samples, these findings provide pilot data for comparisons of mechanisms of antibody failure in other adult BM samples.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective To assess the relationship between robotic surgical simulation performance and the real-life surgical skill of attending surgeons. We hypothesized that simulation performance would not ...correlate with real-life robotic surgical skill in attending surgeons. Design In 2013, Birkmeyer et al. demonstrated an association between laparoscopic surgical performance as determined by expert review of video clips and surgical outcomes. Using that model of expert review, we studied the relationship between robotic simulator performance and real-life surgical skill. Ten attending robotic surgeons performed 4 tasks on the da Vinci Skills Simulator (Camera Targeting 1, Ring Walk 3, Suture Sponge 3, and Energy Dissection 3). Two video clips of a robotic-assisted operation were then recorded for each surgeon. Three expert robotic surgeons reviewed the recordings and rated surgical technique using the Global Evaluative Assessment of Robotic Skills. Setting University of Virginia; Charlottesville, VA; tertiary hospital Participants All attending surgeons who perform robotic-assisted surgery at our institution were enrolled and completed the study. Results The surgeons had a median of 7.25 years of robotic surgical experience with a median of 91 cases (ranging: 20-346 cases) in the last 4 years. Median scores for each simulator task were 87.5%, 39.0%, 77.5%, and 81.5%. Using Pearson’s correlation, scores for each of the individual tasks correlated poorly with expert review of intraoperative performance. There was also no correlation ( r = −0.0304) between overall simulation score (mean: 70.7 ± 9.6%) and expert video ratings (mean: 3.66 ± 0.32 points). Conclusions There was no correlation between attending surgeons’ simulator performance and expert ratings of intraoperative videos based on the Global Evaluative Assessment of Robotic Skills scale. Although novice surgeons may put considerable effort into training on robotic simulators, performance on a simulator may not correlate with attending robotic surgical performance. Development of simulation exercises that guide novice surgeons toward expert performance is needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective The objective of the study was to evaluate the indications for late preterm birth and compare outcomes by gestational age among late preterm (34-36 weeks) and term (≥ 37 weeks) neonates at ...our institution. Study Design This was a retrospective analysis of delivery indications and short-term neonatal outcomes in women who delivered at the University Hospital between January 1, 2005 and Dec. 31, 2006. Data were analyzed using χ2 , Student's t -test, analysis of variance, and post hoc Tukey tests. Results One hundred forty-nine late preterm (n = 49 for 34, n = 50 for 35, n = 50 for 36 weeks) and 150 term infants (n = 50 for 37, n = 50 for 38, n = 50 for 39 weeks or longer) were evaluated. Differences among groups (ie, 34 vs 35 vs 36 vs 37, etc) as well as combinations of differences between 2 groups (ie, 34-36 weeks vs ≥ 37 or ≥ 38 weeks) were analyzed. Spontaneous labor and/or rupture of membranes were the most common indications for late preterm delivery (92%). Compared with term, late preterm infants had longer hospital stays (5 days vs 2.4 days; P < .001) and higher rates of neonatal intensive care unit (NICU) admissions (56% vs 4%; P < .001), feeding problems (36% vs 5%; P < .001), hyperbilirubinemia (25% vs 3%; P < .001), and respiratory complications (20% vs 5%; P < .001). Neonatal complications were minimal at 38 weeks or longer. Conclusion Rates of neonatal intensive care unit admission, length of stay, and neonatal morbidities are significantly higher in late preterm as compared with term births.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK