Development of a Maternal Equity Safety Bundle to Eliminate Racial Inequities in Massachusetts.

OBJECTIVE: The PNQIN (Perinatal-Neonatal Quality Improvement Network of Massachusetts) sought to adapt the Reduction of Peripartum Racial and Ethnic Disparities Conceptual Framework and Maternal Safety Consensus Bundle by selecting and defining measures to create a bundle to address maternal health inequities in Massachusetts. This study describes the process of developing consensus-based measures to implement the PNQIN Maternal Equity Bundle across Massachusetts hospitals participating in the Alliance for Innovation on Maternal Health Initiative. METHODS: Our team used a mixed-methods approach to create the PNQIN Maternal Equity Bundle through consensus including a literature review, expert interviews, and a modified Delphi process to compile, define, and select measures to drive maternal equity-focused action. Stakeholders were identified by purposive and snowball sampling and included obstetrician-gynecologists, midwives, nurses, epidemiologists, and racial equity scholars. Dedoose 9.0 was used to complete an inductive analysis of interview transcripts. A modified Delphi method was used to reach consensus on recommendations and measures for the PNQIN Maternal Equity Bundle. RESULTS: Twenty-five interviews were completed. Seven themes emerged, including the need for 1) data stratification by race, ethnicity and language; 2) performance of a readiness assessment; 3) culture shift toward equity; 4) inclusion of antiracism and bias training; 5) addressing challenges of nonacademic hospitals; 6) a life-course approach; and 7) selection of timing of implementation. Twenty initial quality measures (structure, process, and outcome) were identified through expert interviews. Group consensus supported 10 measures to be incorporated into the bundle. CONCLUSION: Structure, process, and outcome quality measures were selected and defined for a maternal equity safety bundle that seeks to create an equity-focused infrastructure and equity-specific actions at birthing facilities. Implementation of an equity-focused safety bundle at birthing facilities may close racial gaps in maternal outcomes.

A Case Report of Rotational Thromboelastometry-Assisted Decision Analysis for Two Pregnant Patients With Platelet Storage Pool Disorder.

Platelet storage pool disorders (PSPDs) constitute a diverse group of hematologic abnormalities, which share the common feature of a deficiency in the ability of platelets to aggregate. Parturients with PSPD can present management challenges to their care team when they present for childbirth, especially with regard to neuraxial anesthesia. We report a series of 2 deliveries from unrelated patients affected by PSPD. In particular, we highlight the utility of rotational thromboelastometry (ROTEM) and the need for a multidisciplinary approach to the care of patients with this hematologic abnormality.

Gestational weight gain and patterns of breastfeeding among patients with class III obesity.

BACKGROUND: Maternal obesity is associated with delayed lactogenesis and shorter duration of breastfeeding compared to patients with a normal BMI. RESEARCH AIM/QUESTION: We investigated the impact of excessive gestational weight gain, defined as greater than the Institute of Medicine guidelines (>9.1 kg), on the initiation and duration of breastfeeding in patients with class III obesity. METHODS: Retrospective cohort of patients with body mass index ≥40 in first trimester, delivering a singleton term infant at a tertiary care center between July 2013 and December 2017. Primary outcome was exclusive breastfeeding at discharge and at postpartum visit. Secondary outcomes included any breastfeeding at discharge and postpartum visit, and cessation of breastfeeding by the postpartum visit. Descriptive statistics were used to compare those whose gestational weight gain exceeded (eIOM) versus met (mIOM) Institute of Medicine guidelines. Regression models were performed to adjust for baseline confounding factors. RESULTS: Of 294 women included, 117(39.8%) were in the eIOM group. These women were more likely to be primigravida, have a higher delivery BMI, greater delivery blood loss, and have a neonate admitted to the intensive care unit. Exclusive breastfeeding at discharge was not different between eIOM and mIOM (66.7% vs 70.9%, p = .44), nor did eIOM impact likelihood of exclusive breastfeeding at postpartum visit (40.1% vs 34.2%, p = .31). When controlling for confounding factors, breastfeeding at discharge (aOR 1.54 95% CI [0.68-3.49]) or postpartum visit (aOR 0.67[0.31-1.47]) did not differ between eIOM compared to mIOM. CONCLUSIONS: Among women with class III obesity, excessive gestational weight gain did not impact the rate of exclusive breastfeeding at discharge or postpartum visit.

Maternal weight gain and neonatal outcomes in women with class III obesity.

OBJECTIVE: Obesity in the USA continues to be a prominent medical and public health concern. Due to increasing rates of maternal obesity, the current Institute of Medicine (IOM) guidelines recommend 11-20 pounds of total weight gain during pregnancy in women with a BMI ≥30 kg/m2. The impact of maternal obesity on adverse perinatal outcomes has been well documented however, there is minimal data on the effect of gestational weight gain on neonatal outcomes. In this study, we assessed the association between gestational weight gain (GWG) and neonatal outcomes at term in women with class III obesity. STUDY DESIGN: A retrospective cohort of women delivering at a tertiary care institution between July 2013 and December 2017 with a first-trimester baseline BMI ≥40 kg/m2 was studied. Pregnancies complicated by multiple gestations, preterm delivery, fetal anomalies, intrauterine fetal demise or with missing data were excluded. The primary outcome was a composite of adverse neonatal outcomes including 5 min Apgar <7, neonatal intubation, grade 3 or 4 intraventricular hemorrhage (IVH), confirmed neonatal sepsis or Neonatal Intensive Care Unit (NICU) admission. Secondary outcomes included individual components of composite and NICU admission for >7 days. Demographic, pregnancy complications & delivery characteristics of women who gained more than IOM guidelines (>20 lbs.) were compared to women who gained at or less than IOM guidelines (≤20 lbs.) using bivariate statistics. Stepwise backward regression was used to estimate the odds of outcomes as appropriate. RESULTS: Of 374 women included, 144 (39.5%) gained more than guidelines. Women who gained above IOM recommendations were less likely to be multiparous and use tobacco. Additional demographic, obstetric and delivery characteristics, including BMI at the entry to care, did not differ. The neonatal composite occurred in 30 (8.0%) of all neonates; corresponding to 11.1% of women who gained more than IOM recommendations and 6.1% of those who gained at or below recommendations (p = .12, OR = 1.71, 95%CI 0.74-3.96). Additionally, neonates born to women gaining more than IOM recommendations were more likely to be admitted to the NICU (10.4 vs. 4.3%, p = .03) and have a NICU length of stay >7 days (6.9 vs. 2.2%, p = .03). When adjusted for mode of delivery, delivery BMI, tobacco use, and chorioamnionitis, women who gained more were not more likely to have an adverse neonatal outcome (1.54, 95%CI 0.62-3.80), they were 3.6 times more likely to have a neonate admitted to the NICU for more than 7 days (95%CI 1.00-13.42). CONCLUSIONS: In women with class III obesity, excess gestational weight gain was associated with increased odds of NICU stay >7 days, with trends toward increased NICU admission risk, further emphasizing the importance of appropriate weight gain counseling in this population at risk.

The impact of excessive gestational weight gain timing on neonatal outcomes in women with class III obesity.

OBJECTIVE: This study evaluated the influence of early gestational weight gain (GWG) on neonatal outcomes among women with class III obesity. STUDY DESIGN: Retrospective cohort of women with class III obesity who gained more than the Institute of Medicine (IOM) guidelines (>20lbs). Women gaining ≥75% of total gestational weight prior to 28 weeks (EWG) were compared to women gaining <75% of their total weight prior to 28 weeks (SWG). The primary outcome was a neonatal composite morbidity and mortality. Secondary outcomes included individual components of composite and LGA. RESULTS: Of 144 women identified, 42 (29.2%) had EWG and 102 (70.8%) had SWG. Though 11% of the total population had composite neonatal morbidity, this did not differ between groups (p = .4). LGA was nearly twice as common in the SWG group (41% vs 26%, p = .13). EWG was associated with decreased risk of LGA (AOR 0.25 95% CI 0.08, 0.78) and lower median birth weight (AOR -312 g 95% CI -534.7, -90.2). CONCLUSION: Though adverse neonatal outcomes were common in this population, timing of gestational weight gain was not correlated. Increased rates of LGA and higher median birth weight in the SWG group suggests excessive GWG continuing in the third trimester of pregnancy may be of import for neonatal size.

Investigating Decreased Rates of Nulliparous Cesarean Deliveries during the COVID-19 Pandemic.

OBJECTIVE: Preventing the first cesarean delivery (CD) is important as CD rates continue to rise. During the novel coronavirus disease 2019 (COVID-19) pandemic, quality improvement metrics at our hospital identified lower rates of CD. We sought to investigate this change and identify factors that may have contributed to the decrease. STUDY DESIGN: We compared nulliparous singleton deliveries at a large academic hospital during the COVID-19 pandemic (April through July 2020 during a statewide "stay-at-home" order) to those in the same months 1 year prior to the pandemic (April through July 2019). The primary outcome, mode of delivery, was obtained from the electronic medical record system, along with indication for CD. RESULTS: The cohort included 1,913 deliveries: 892 in 2019 and 1,021 in 2020. Patient characteristics (age, body mass index, race, ethnicity, and insurance type) did not differ between the groups. Median gestational age at delivery was the same in both groups. The CD rate decreased significantly during the COVID-19 pandemic compared with prior (28.9 vs. 33.6%; p = 0.03). There was a significant increase in the rate of labor induction (45.7 vs. 40.6%; p = 0.02), but no difference in the proportion of inductions that were elective (19.5 vs. 20.7%; p = 0.66). The rate of CD in labor was unchanged (15.9 vs. 16.3%; p = 0.82); however, more women attempted a trial of labor (87.0 vs. 82.6%; p = 0.01). Thus, the proportion of CD without a trial of labor decreased (25.1 vs. 33.0%; p = 0.04). CONCLUSION: There was a statistically significant decrease in CD during the COVID-19 pandemic at our hospital, driven by a decrease in CD without a trial of labor. The increased rate of attempted trial of labor suggests the presence of patient-level factors that warrant further investigation as potential targets for decreasing CD rates. Additionally, in a diverse and medically complex population, increased rates of labor induction were not associated with increased rates of CD. KEY POINTS: · Primary CD rate fell during COVID-19 pandemic.. · Decrease was driven by more women attempting labor.. · Higher rate of induction without rise in CD rate was found..

Identified themes of interactive visualizations overlayed onto EHR data: an example of improving birth center operating room efficiency.

OBJECTIVE: While electronic health record (EHR) systems store copious amounts of patient data, aggregating those data across patients can be challenging. Visual analytic tools that integrate with EHR systems allow clinicians to gain better insight and understanding into clinical care and management. We report on our experience building Tableau-based visualizations and integrating them into our EHR system. MATERIALS AND METHODS: Visual analytic tools were created as part of 12 clinician-initiated quality improvement projects. We built the visual analytic tools in Tableau and linked it within our EPIC environment. We identified 5 visual themes that spanned the various projects. To illustrate these themes, we choose 1 exemplary project which aimed to improve obstetric operating room efficiency. RESULTS: Across our 12 projects, we identified 5 visual themes that are integral to project success: scheduling & optimization (in 11/12 projects); provider assessment (10/12); executive assessment (8/12); patient outcomes (7/12); and control and goal charts (2/12). DISCUSSION: Many visualizations share common themes. Identification of these themes has allowed our internal team to be more efficient and directed in developing visualizations for future projects. CONCLUSION: Organizing visual analytics into themes can allow informatics teams to more efficiently provide visual products to clinical collaborators.

Gestational Weight Gain and Postpartum Depression in Women with Class III Obesity.

OBJECTIVE: We investigated the association between gestational weight gain (GWG) and postpartum depression (PPD) in women with class III obesity. STUDY DESIGN: This is a retrospective cohort of women with body mass index (BMI) ≥ 40 kg/m2 at entry to care, first prenatal visit ≤14 weeks gestation, with singleton, nonanomalous pregnancies who delivered at term from July 2013 to December 2017. Women missing data regarding PPD were excluded. Primary outcome was PPD; classified as Edinburgh Postnatal Depression Scale (EPDS) score >13/30 or provider's report of depression. Participants were classified, according to Institute of Medicine GWG guidelines (11-20 pounds), as either less than 11 pounds (LT11) or at/more than 11 pounds (GT11). Bivariate statistics compared demographics and pregnancy characteristics. Logistic regression used to estimate odds of primary outcome. RESULTS: Of 275 women, 96 (34.9%) gained LT11 and 179 (65.1%) gained GT11 during pregnancy. The rate of PPD was 8.7% (n = 24), 9 (9.4%) in the LT11 group and 15 (8.4%) in the GT11 group (p = 0.82, odds ratio: 1.13, 95% confidence interval [CI]: 0.48, 2.69). When controlling for entry BMI and multiparity, adjusted odds of PPD was 1.07 (95% CI: 0.44, 2.63). No correlation was found between GWG and EPDS. CONCLUSION: A relationship between GWG and PPD in class III obese women was not found in this cohort.

Antibiotic Prophylaxis for Cesarean Delivery: A Survey of Anesthesiologists.

BACKGROUND: The most common complication after cesarean delivery is surgical site infection. Antibiotic prophylaxis reduces infectious morbidity and current anesthetic quality metrics include preincision antibiotic prophylaxis. Recently, studies suggest reductions in infectious morbidity with the addition of azithromycin for unscheduled cesarean delivery. Larger doses of cefazolin are recommended for morbidly obese women, but evidence is conflicting. The aim of this study was to survey anesthesiologists to assess current practice for antibiotic prophylaxis for cesarean delivery. METHODS: We invited a random sample of 10,000 current members of the American Society of Anesthesiologists to complete an online survey about their current practice of antibiotic prophylaxis for cesarean delivery in November 2017. The survey included questions similar to a previous survey on this topic in 2012. RESULTS: The response rate was 12.2% (n = 1223). Most respondents had at least 15 years of experience (684, 55.9%), work at a nonteaching or community hospital (729, 59.6%), with >500 cesarean deliveries annually (619, 50.6%), and administer obstetric anesthesia several times a week (690, 56.4%). Routine preincision antibiotic prophylaxis was reported by 1162 (95.0%) of the 1223 respondents, a substantial improvement versus the 63.5% reported in the previous study in 2012. For intrapartum cesarean deliveries, 141 (11.5%) administer azithromycin for unscheduled cesarean deliveries. Those who use cefazolin, 509 (42.5%) administer 3 g for morbidly obese women. CONCLUSION: Adherence to preincision antibiotic prophylaxis for cesarean delivery is very high, a significant improvement within 5 years. A minority of anesthesiologists utilize azithromycin for intrapartum cesarean deliveries. The dose of cefazolin for morbidly obese women varies widely.

Pharmacologic Treatment of Diabetes in Pregnancy.

IMPORTANCE: Diabetes affects 6% to 9% of pregnancies, with gestational diabetes mellitus accounting for more than 90% of cases. Pregestational and gestational diabetes are associated with significant maternal and fetal risks; therefore, screening and treatment during pregnancy are recommended. Recommendations regarding the preferred treatment of diabetes in pregnancy have recently changed, with slight differences between American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommendations. OBJECTIVE: Our review discusses the diagnosis, management, and treatment of pregestational and gestational diabetes with the oral hypoglycemic agents metformin and glyburide as well as insulin. We also review the evidence for the safety and efficacy of these medications in pregnancy. EVIDENCE ACQUISITION: Articles were obtained from PubMed, the ACOG Practice Bulletin on Gestational Diabetes Mellitus, and the SMFM statement on the pharmacological treatment of gestational diabetes. RESULTS: Insulin does not cross the placenta and has an established safety profile in pregnancy and is therefore considered a first-line treatment for gestational diabetes. Metformin and glyburide have also been shown to be relatively safe in pregnancy but with more limited long-term data. Regarding maternal and fetal outcomes, metformin is superior to glyburide and similar to insulin. CONCLUSIONS AND RELEVANCE: Insulin is the preferred pharmacologic treatment according to ACOG. However, SMFM has stated that outcomes with metformin are similar, and it may also be considered as first-line therapy. Both agree that the available data show that metformin is safer and superior to glyburide, and glyburide is no longer recommended as a first-line therapy for the treatment of gestational diabetes.

Tocolysis: A Review of the Literature.

IMPORTANCE: Preterm delivery represents an important cause of infant morbidity and mortality. Various tocolytics have been studied with the objective of stopping preterm labor, increasing gestational age at delivery, and preventing complications related to preterm birth. OBJECTIVE: This review aims to summarize the major classes of tocolytics and review the evidence regarding use of each. EVIDENCE ACQUISITION: A PubMed search of the following terms was performed to gather relevant data: "tocolytic," "preterm labor," "preterm delivery," "PPROM," "magnesium," "indomethacin," "nifedipine," and "betamimetics." RESULTS: The benefits and risks of nonsteroid anti-inflammatory drugs, calcium channel blockers, magnesium, and betamimetics are reviewed. Calcium channel blockers afford superior outcomes in terms of prolonging gestation and decreasing neonatal morbidity and mortality with the fewest adverse effects. CONCLUSIONS AND RELEVANCE: Tocolytics, particularly calcium channel blockers, may provide benefit to pregnant women and their infants. Their use should be tailored to the particular clinical circumstances of the patient and used in conjunction with other management strategies (e.g., administration of corticosteroids for fetal lung maturation or magnesium for neuroprotection and transfer to a tertiary medical center). Further research and professional guidelines are needed on optimal use of these agents.

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.

The influence of noninvasive prenatal testing on gestational age at time of abortion for aneuploidy.

OBJECTIVE: The objective of this study is to compare the gestational age at termination for trisomy 13, 18, or 21 (aneuploidy) before and after the introduction of noninvasive prenatal testing (NIPT). METHODS: A retrospective cohort of women undergoing termination for aneuploidy at two academic institutions and one private clinic. We compared two time periods: before and after the introduction of NIPT (2006-2011 and 2012-2014, respectively). Maternal demographics and clinical characteristics were abstracted from the medical record. Nonparametric statistical methods were used to compare the two cohorts. RESULTS: Our cohort included 93 women: 41 prior to NIPT and 52 post-NIPT. Maternal age (38 post-NIPT vs 37 pre-NIPT; p = 0.17) did not differ between the time periods. Women in the post-NIPT were less likely to undergo diagnostic testing (82.7% vs 97.6%; p < 0.01) before proceeding to abortion after a positive screening result. In the post-NIPT period, there was a significant decrease in the gestational age at time of invasive testing (13.0 vs 15.7 weeks; p < 0.01) and women were more likely to undergo chorionic villous sampling (CVS) (59.6% vs 41.5%; p < 0.01). There was a significant decrease in the gestational age at termination (14.2 vs 17.2; p < 0.01). Women in the post-NIPT group were less likely to have terminations after 16 weeks (25.0% vs 61.0%; p < 0.01), 18 weeks (7.7% vs 39.0%; p < 0.01), or 20 weeks (3.9% vs 12.2%; p = 0.23). CONCLUSION: With the introduction of NIPT, the median gestational age at diagnosis and termination for women with Trisomy 13, 18, or 21 was 3 weeks earlier. Women were four times less likely to have a termination after 18 weeks and three times less likely to have a termination after 20 weeks. © 2017 John Wiley & Sons, Ltd.

Patient choice and clinical outcomes following positive noninvasive prenatal screening for aneuploidy with cell-free DNA (cfDNA).

OBJECTIVE: Evaluate patient choices and outcomes following positive cfDNA. METHOD: Retrospective cohort study of women with positive cfDNA through two academic centers between March 2012 and December 2014. Patients were screened based on ACOG indications. Medical records reviewed for counseling, ultrasound findings, diagnostic testing, karyotype and outcome. RESULTS: CfDNA was positive in 114 women; 105 singletons and 9 twin pairs. CfDNA was positive for autosomal trisomy (21, 18, 13) in 96 (84.2%) and sex chromosome aneuploidy in 18 (15.8%). Certified genetic counselors performed 95% of post-cfDNA counseling. Prenatal diagnostic testing was pursued by 71/114 (62%). Karyotype was available in 91/105 (86.7%) singletons and confirmed aneuploidy in 75/91 (82.4%); the PPV of cfDNA with any ultrasound finding was 93.6% versus 58.6% without a finding. An abnormal sonographic finding was seen in 4/16 (25%) singletons with false positive cfDNA. Fetal termination occurred in 53/79 (67%) singletons and 3/5 (60%) twins with prenatal abnormal or unknown karyotype for autosomal trisomy. Eleven fetuses (11/56, 19.6%) were terminated for suspected autosomal trisomy without karyotype confirmation. CONCLUSION: Patient choices following positive cfDNA are varied. Ultrasound modifies the PPV of cfDNA. Termination rates for aneuploidy are not higher than historical controls. Recommendation for karyotype confirmation prior to termination is not universally followed. © 2016 John Wiley & Sons, Ltd.

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.

Single bone intramedullary fixation of the ulna in pediatric both bone forearm fractures: analysis of short-term clinical and radiographic results.

BACKGROUND: Although single bone intramedullary (IM) fixation has been advocated in the treatment of unstable diaphyseal forearm fractures, some reports have questioned the ability of single bone fixation to maintain adequate reduction. The purpose of this investigation is to report the radiographic and early clinical results of single bone IM fixation for diaphyseal forearm fractures and to identify factors leading to loss of reduction of the radius after ulnar fixation. METHODS: A retrospective analysis of 38 children who underwent single bone IM fixation of the ulna for both bone forearm fractures was performed. Mean age was 9 years (range: 4-14 y). Preoperative, postoperative, and final follow-up radiographs were examined for radiographic alignment. Patient data (including age, fracture type, delay to fixation, open vs. percutaneous reduction and fixation, and time to implant removal) was collected to identify predictors for loss of reduction of the radius. Loss of reduction of the radius was defined as 10 degrees or greater change of angulation in either the frontal or lateral plane from initial postoperative radiographs to final follow-up. Multivariate analysis was used to determine associations between patient factors and loss of reduction. RESULTS: All patients went on to bony union with restoration of forearm rotation. Twenty-five patients (66%) healed with <10 degrees of angulation of the radius, whereas 11 patients (29%) had between 10 and 20 degrees of angulation at final follow-up. Two patients demonstrated greater than 20 degrees of radial angulation requiring additional surgical care. There was no statistically significant association between any patient factors and loss of radial reduction, though there was a trend for increased radial angulation in patients who had sustained open fractures. CONCLUSIONS: Single-bone IM fixation of the ulna is a safe and efficacious option for the treatment of unstable diaphyseal forearm fractures in children. Owing to the increased risk of loss of radial reduction, however, consideration should be made for IM fixation of both bones in older children and cases of open fractures. LEVEL OF EVIDENCE: IV, therapeutic.

Total synthesis and evaluation of C26-hydroxyepothilone D derivatives for photoaffinity labeling of beta-tubulin.

Three photoaffinity labeled derivatives of epothilone D were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. The key step for the asymmetric synthesis of (S,E)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (R)-Me-CBS-oxazaborolidine. For the synthesis of (5S)-5,7-di[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric Noyori reduction of a beta-ketoester was employed. The C26 hydroxyepothilone D derivative was constructed following a well-established total synthesis strategy and the photoaffinity labels were attached to the C26 hydroxyl group. The photoaffinity analogues were tested in a tubulin assembly assay and for cytotoxicity against MCF-7 and HCT-116 cancer cell lines. The 3- and 4-azidobenzoic acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrated significantly reduced cellular cytotoxicity compared to epothilone B. The benzophenone analogue was inactive in both assays. Docking and scoring studies were conducted that suggested that the azide analogues can bind to the epothilone binding site, but that the benzophenone analogue undergoes a sterically driven ligand rearrangement that interrupts all hydrogen bonding and therefore protein binding. Photoaffinity labeling studies with the 3-azidobenzoic acid derivative did not identify any covalently labeled peptide fragments, suggesting that the phenylazido side chain was predominantly solvent-exposed in the bound conformation.

(3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a novel neuroprotective agent.

Compounds that interact with microtubules, such as paclitaxel, have been shown to possess protective properties against beta-amyloid (Abeta) induced neurodegeneration associated with Alzheimer's disease. In this work, the novel agent (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol was investigated for effectiveness in protecting neurons against several toxic stimuli and its interaction with the microtubule network. Exposure of neuronal cultures to Abeta peptide in the presence of 5 nM (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol resulted in a 50% increase in survival. Neuronal cultures treated with other toxic stimuli such as staurosporine, thapsigargin, paraquat, and H(2)O(2) showed significantly enhanced survival in the presence of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol. Microtubule binding and tubulin assembly studies revealed differences compared to paclitaxel but confirmed the interaction of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol with microtubules. Furthermore, in vitro studies using bovine brain microvessel endothelial cells experiments suggest that (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol can readily cross the blood-brain barrier in a passive manner.

Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the beta-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1-C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.