Toughening Self-Healing Elastomers with Chain Mobility.

Enhancing fracture toughness and self-healing within soft elastomers is crucial to prolonging the operational lifetimes of soft devices. Herein, it is revealed that tuning the polymer chain mobilities of carboxylated-functionalized polyurethane through incorporating plasticizers or thermal treatment can enhance these properties. Self-healing is promoted as polymer chains gain greater mobility toward the broken interface to reassociate their bonds. Raising the temperature from 80 to 120 °C, the recovered work of fracture is increased from 2.86 to 123.7 MJ m-3. Improved fracture toughness is realized through two effects. First, strong carboxyl hydrogen bonds dissipate large energies when broken. Second, chain mobilities enable the redistribution of localized stress concentrations to allow crack blunting, enlarging the size of dissipation zones. At optimal conditions of plasticizers (3 wt.%) or temperature (40 °C) to promote chain mobilities, fracture toughness improves from 16.3 to 19.9 and 25.6 kJ m-2, respectively. Insights of fracture properties at healed soft interfaces are revealed through double cantilever beam tests. These measurements indicate that fracture mechanics play a critical role in delaying complete failure at partial self-healing. By imparting optimal polymer chain mobilities within tough and self-healing elastomers, effective prevention against damage and better recovery are realized.

First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

The birth center model of care: Staffing, business characteristics, and core clinical outcomes.

OBJECTIVES: Interest in expanding access to the birth center model is growing. The purpose of this research is to describe birth center staffing models and business characteristics and explore relationships to perinatal outcomes. METHODS: This descriptive analysis includes a convenience sample of all 84 birth center sites that participated in the AABC Site Survey and AABC Perinatal Data Registry between 2012 and 2020. Selected independent variables include staffing model (CNM/CM or CPM/LM), legal entity status, birth volume/year, and hours of midwifery call/week. Perinatal outcomes include rates of induction of labor, cesarean birth, exclusive breastfeeding, birthweight in pounds, low APGAR scores, and neonatal intensive care admission. RESULTS: The birth center model of care is demonstrated to be safe and effective, across a variety of staffing and business models. Outcomes for both CNM/CM and CPM/LM models of care exceed national benchmarks for perinatal quality with low induction, cesarean, NICU admission, and high rates of breastfeeding. Within the sample of medically low-risk multiparas, variations in clinical outcomes were correlated with business characteristics of the birth center, specifically annual birth volume. Increased induction of labor and cesarean birth, with decreased success breastfeeding, were present within practices characterized as high volume (>200 births/year). The research demonstrates decreased access to the birth center model of care for Black and Hispanic populations. CONCLUSIONS FOR PRACTICE: Between 2012 and 2020, 84 birth centers across the United States engaged in 90,580 episodes of perinatal care. Continued policy development is necessary to provide risk-appropriate care for populations of healthy, medically low-risk consumers.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

BACKGROUND: Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS: In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS: A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS: Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations.

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.

VBAC calculator 2.0: Recent evidence.

Following criticism for the use of race as a biological predictor of vaginal birth after cesarean (VBAC), an updated version of the Society for Maternal-Fetal Medicine (SMFM) VBAC calculator has been published. The variable "African American" or "Hispanic" (yes/no), which produced systematically lower chances of VBAC for nonwhites has been replaced with "chronic hypertension requiring treatment" (yes/no). Although there are no published external validation studies to date, developers report accuracy (area under the curve and calibration) nearly identical to the original calculator and it is published online for immediate use. This review examines the history of the calculator, measures of its validity, and recent studies measuring its performance among Hispanics, Blacks, Asians, and others with lower range scores. Underprediction of successful VBAC is evident in the original calculator, especially as predicted VBAC decreases. These studies raise a concern about the use of calculator scores in clinical management, that is, discouraging or restricting access to labor after cesarean (LAC) for parents with lower calculator scores. This raises special concern for minority populations who experience increased cesarean-related morbidity, face obstacles accessing LAC care, and who may benefit disproportionately from increased LAC uptake. Although calculator developers have discouraged using calculator scores to restrict access to LAC, such uses are documented. It is not clear what effect the removal of race will have on calculator performance, and further study is required before calculator scores are used in counseling. This includes studies that include large numbers of low scoring and minority patients.

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

Barriers to labor after cesarean: A survey of United States midwives.

INTRODUCTION: Despite calls for increased vaginal birth after cesarean (VBAC), <14% of candidates have VBAC. Requirements for documentation of scar type, and prohibitions on induction or augmentation of labor are not supported by evidence but may be widespread. The purpose of this study was to document midwives' perceptions of barriers to labor after cesarean (LAC) and their effects on midwives' ability to accommodate patient desires for LAC. METHODS: Midwives certified by the American Midwifery Certification Board (AMCB) were surveyed in 2019. Multiple option and open-ended text responses were analyzed using quantitative statistics and thematic content analysis. Select barriers to LAC, ability to accommodate LAC, and supportiveness of collaborators among midwives offering LAC were explored. RESULTS: Responses from 1398 midwives were analyzed. Eighty-four percent felt able to accommodate LAC "most of the time," and 39% reported one or more barriers to LAC. Barriers decreased ability to accommodate LAC by as much as 80%. Analysis of text responses revealed specific themes. CONCLUSIONS: Thirty-nine percent of midwives reported their practice was limited by one or more barriers that were inconsistent with professional guidelines. Imposition of barriers was driven primarily by collaborating physicians, and superceded supportive practices of midwives, nurses, and system administrators. Affected midwives were significantly less able to accommodate patient requests for LAC than those not affected. Midwives also reported pride in providing VBAC care, restrictions specific to midwifery scope of practice, and variation in physician support for LAC within practices affecting their ability to provide care.

Recovery of microbial community profile information hidden in chimeric sequence reads.

The next frontier in the field of microbiome studies is identification of all microbes present in the microbiome and accurate determination of their abundance such that microbiome profiles can serve as reliable assessments of health or disease status. PCR-based 16S rRNA gene sequencing and metagenome shotgun sequencing technologies are the prevailing approaches used in microbiome analyses. Each poses a number of technical challenges associated with PCR amplification, sample availability, and cost of processing and analysis. In general, results from these two approaches rarely agree completely with each other. Here, we compare these methods utilizing a set of vaginal swab and lavage specimens from a cohort of 42 pregnant women collected for a pilot study exploring the effect of the vaginal microbiome on preterm birth. We generated the microbial community profiles from the sequencing reads of the V3V4 and V4V5 regions of the 16S rRNA gene in the vaginal swab and lavage samples. For a subset of the vaginal samples from 12 subjects, we also performed metagenomic shotgun sequencing analysis and compared the results obtained from the PCR-based sequencing methods. Our findings suggest that sample composition and complexity, particularly at the species level, are major factors that must be considered when analyzing and interpreting microbiome data. Our approach to sequence analysis includes consideration of chimeric reads, by using our chimera-counting BlastBin program, and enables recovery of microbial content information generated during PCR-based sequencing methods, such that the microbial profiles more closely resemble those obtained from metagenomic read-based approaches.

Validation of Risk-Adapted Venous Thromboembolism Prediction in Multiple Myeloma Patients.

Multiple myeloma (MM) is associated with an increased risk of venous thrombosis (VTE). In the United Kingdom Medical Research Council (MRC) XI study of patients treated with immunomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thromboprophylaxis at the time of thrombosis. In order to effectively prevent VTE events in MM patients, a better understanding of patient and disease risk factors that might predict thrombosis is required. We performed a retrospective cohort analysis of over 300 newly diagnosed MM patients at a tertiary referral centre to determine the VTE rate, predictive factors for VTE, value of the Khorana score for MM VTE events and long-term mortality outcomes. Fifty-four percent of the patients were receiving thromboprophylaxis at the time of the VTE event. The mortality odds ratio was 3.3 (95% CI, 2.4-4.5) in patients who developed VTE in comparison to age-matched controls with MM. A younger age at diagnosis and higher white cell count (WCC) were found to be predictive of VTE events. Our data suggest that standard thromboprophylaxis may not be effective in preventing VTE events in myeloma patients, and alternative strategies, which could include higher-intensity thromboprophylaxis in young patients with a high WCC, are necessary.

Biclonal lymphoproliferative disorders: another association with NOTCH1-mutated chronic lymphocytic leukaemias.

INTRODUCTION: Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. METHODS: We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. RESULTS: Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. CONCLUSION: In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

Calculators Estimating the Likelihood of Vaginal Birth After Cesarean: Uses and Perceptions.

INTRODUCTION: A calculator estimating likelihood of vaginal birth after cesarean (VBAC) has been promoted by the Society for Maternal-Fetal Medicine, but little is known about how it is used and perceived in practice. Cutoffs for prohibiting labor after cesarean are discouraged by the calculator's developers, but such uses may be widespread. The purpose of this study was to determine how calculators predicting VBAC are used and perceived in midwifery practices. METHODS: Certified nurse-midwives and certified midwives currently providing care for labor after cesarean were surveyed between January 17, 2019, and February 7, 2019. Quantitative and text data were collected regarding the uses and perceptions of calculators among midwives and their colleagues. We compared these findings with midwives' perceptions of their ability to accommodate patient wishes for labor after cesarean. We used descriptive content analysis to evaluate themes occurring in text responses. RESULTS: There were 1305 valid responses. A requirement to use calculator scores for patient counseling was reported by 527 (40.4%) of responding midwives. Over 1 in 5 midwives reported that scores were used to discourage or prohibit labor after cesarean. Almost half reported some or strong disagreement with physician colleagues regarding calculator use. Interprofessional agreement and disagreement centered on how scores are used to direct clinical care or restrict patient options. Calculator scores were used in more than twice as many midwives' practices to discourage rather than encourage labor after cesarean. Descriptive analysis of text revealed 4 themes regarding calculators: inconsistent use, information counseling, informed consent, and influence patient management or options. DISCUSSION: Calculators predicting likelihood of VBAC success are widely used in midwifery settings and are more often used to discourage than to encourage labor after cesarean. Midwives reported both directive and nondirective counseling based on calculator scores.

Reasons Why Pregnant Women Participate in Ultrasound Research Involving Transvaginal Scans.

OBJECTIVES: The aim of this study was to explore the motivations of pregnant women in participating in an ultrasound study and the acceptability of vaginal ultrasound examinations. METHODS: A prospective sample of 270 women were asked one question: "Can you tell me what motivated you to participate in the study?" The data were then analyzed through a qualitative thematic analysis with an inductive approach. In addition to the thematic analysis, quantification of the data was performed to enhance the qualitative result. RESULTS: Through the thematic analysis, 5 themes emerged from the responses of the participants: altruism, research, personal experience, personal benefit, and finding out. All responses were relatively short, and some responses included more than one theme. CONCLUSIONS: Vaginal ultrasound examinations were acceptable to the participants, and pregnant women had many motivations to participate. Regardless of race, ethnicity, or insurance status, the women in our study were altruistic and curious about our research.

Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.