Risk of preterm birth in the subsequent pregnancy following caesarean section at full cervical dilatation compared with mid-cavity instrumental delivery.

BACKGROUND: Expediting delivery in the second stage of labour often involves a choice between a caesarean section at full dilatation or mid-cavity instrumental delivery. Accumulating evidence suggests that the mode of delivery may influence the risk of preterm birth in the subsequent pregnancy. AIMS: To directly compare first birth caesarean section at full dilatation with mid-cavity instrumental delivery for the risk of preterm birth in the subsequent pregnancy (second birth). A further aim was to identify predictive factors associated with these index modes of delivery. MATERIALS AND METHODS: This is a retrospective cohort study involving three maternity hospitals in western Sydney over the period of 2006-2017. Inclusion criteria were nulliparous women with a singleton term cephalic first birth delivered by caesarean section at full dilatation or mid-cavity instrumental delivery, and whose second birth also occurred under our care. Data were analysed separately for first and second births. RESULTS: There were 425 caesarean section at full dilatation and 874 mid-cavity instrumental cases which met inclusion criteria. The risk of preterm birth in the second birth was 5.7% compared to 3.2%, respectively (risk ratio 1.76; 95% CI 1.04-3.00; P = 0.035). After excluding causes of preterm birth not related to previous mode of delivery, the risk of spontaneous preterm birth was 4.3% compared to 2.0%, respectively (risk ratio 2.18; 1.14-4.19; P = 0.019). CONCLUSION: Caesarean section at full dilatation is associated with a significantly higher rate of preterm birth in the subsequent pregnancy compared to a mid-cavity instrumental delivery. This should be considered in second-stage mid-cavity decision-making.

Phase 1 trial of olaparib and oral cyclophosphamide in BRCA breast cancer, recurrent BRCA ovarian cancer, non-BRCA triple-negative breast cancer, and non-BRCA ovarian cancer.

BACKGROUND: We conducted a Phase 1 study to evaluate safety and activity of olaparib tablets and oral cyclophosphamide. METHODS: Patients had metastatic breast cancer (BC) or recurrent high-grade serous ovarian cancer (HGSOC), performance status 0-2, and ≤3 lines of prior therapy. Patients were treated using a dose escalation strategy with cohort expansion once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1): olaparib 300 mg bid, cyclophosphamide 50 mg on days 1, 3, and 5, weekly. DL2: olaparib 300 mg bid, cyclophosphamide 50 mg, days 1-5 weekly. RESULTS: Of 32 patients, 23 had HGSOC (germline BRCA mutation [gBRCAm] 70%) and 9 had BC (gBRCAm 67%). Four were treated at DL1 and 28 at DL2, the MTD. Haematological adverse events (AEs) were most common: grade 3/4 AEs: lymphopenia 75%, anaemia 31%, neutropenia 37%, thrombocytopenia 47%. Two permanently discontinued treatment due to haematological AEs. In BC, no objective response was reported. Unconfirmed objective response was 48% and 64% for all HGSOC and gBRCAm subset, respectively. CA125 responses were 70% (all HGSOC) and 92% (gBRCAm). CONCLUSIONS: In HGSOC and BC, olaparib 300 mg bid and cyclophosphamide 50 mg on days 1-5 weekly were tolerable and active, particularly in gBRCAm, and is worthy of further investigation.

Foley catheter silicone versus latex for term outpatient induction of labour: A randomised trial.

BACKGROUND: Both silicone and latex single-balloon Foley catheters are available for cervical ripening but no literature exists to compare them. Local experience suggested more frequent insertion-related accidental rupture of the membranes (acROM) with silicone. AIMS: To compare the performance of silicone versus latex catheters with respect to acROM and other outcomes. MATERIALS AND METHODS: Women undergoing outpatient Foley catheter cervical ripening were randomised to a silicone or latex catheter. Data were collected on the primary outcome, acROM, and secondary outcomes including catheter insertion failure, unplanned hospital admission and patient-reported discomfort, together with intrapartum fever and antibiotics for suspected chorioamnionitis along with general obstetric and neonatal outcomes. RESULTS: Among 534 recruited women, acROM was significantly more common with a silicone compared to a latex catheter at 7.2% (19/265) versus 1.5% (4/269) (relative risk (RR) 4.8; 95% CI 1.7-14.0). Insertion failure was significantly less common with silicone than latex at 2.6% (7/265) versus 9.3% (25/269) (RR 0.3; 95% CI 0.1-0.6). However, when the alternative catheter was subsequently tried, the final failure rates were 1.9% silicone (5/265) versus 2.6% latex (7/269). Insertion-related hospital admission was higher with silicone at 9.4% (25/265) than latex at 4.8% (13/269) (RR 2.1; 95% CI 1.1-4.1). All other obstetric outcomes were similar between the groups. CONCLUSION: When used for cervical ripening, a silicone Foley catheter is associated with a higher rate of acROM than a latex catheter but a lower rate of insertion failure. It may, therefore, be reasonable to attempt insertion with a latex catheter initially and manage insertion failures with a silicone catheter.

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial.

BACKGROUND: In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. METHODS: In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6-12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. FINDINGS: The adjusted average mean change from baseline over the first 12 months in TOI was -2·90 (95% CI -4·13 to -1·67) with olaparib and -2·87 (-4·64 to -1·10) with placebo (estimated difference -0·03; 95% CI -2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98-8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70-8·96) were significantly longer with olaparib than with placebo. INTERPRETATION: Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. FUNDING: AstraZeneca.

Health-related quality of life associated with regorafenib treatment in refractory advanced gastric adenocarcinoma.

BACKGROUND: The INTEGRATE phase II multinational randomized controlled trial demonstrated the activity of regorafenib on progression-free survival (PFS) in patients with refractory advanced gastric adenocarcinoma. We sought to evaluate whether these PFS gains had the potential to be offset by quality of life (QoL) impacts from treatment side effects and to thereby determine the appropriateness of continuing development to phase III. METHODS: QoL was assessed in INTEGRATE at baseline and at each 4 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30, STO22, and EQ-5D questionnaires. The patient disease and treatment assessment (PTDATA) form was also provided to English-speaking participants. Randomized groups were compared on the QLQ-C30, STO22, and EQ-5D scales using a repeated-measures model; the frequency of troublesome symptoms and side effects measured by the PTDATA form; and deterioration-free survival (DFS). The prognostic value of baseline QoL information was also evaluated. RESULTS: Of the 147 eligible randomized patients, 142 consented to participate in the QoL substudy, 136 completed a baseline QoL assessment, and 95 completed at least one post-baseline QoL assessment. The DFS rate was significantly improved with regorafenib, and there was no compelling statistical evidence that regorafenib had a broad negative effect across the spectrum of QoL indices evaluated. Fatigue, anxiety, appetite loss, and pain were among the issues most commonly reported for both randomized groups. Baseline levels of pain, appetite, constipation, and physical functioning were prognostic factors for survival. CONCLUSIONS: Regorafenib improved DFS without an excessively negative effect on QoL. Progressing development to the phase III setting is warranted.

Evaluating the role of magnetic resonance imaging post-neoadjuvant therapy for breast cancer in the NEONAB trial.

BACKGROUND: Magnetic resonance imaging (MRI) accuracy after neoadjuvant systemic therapy (NST) for breast cancer varies according to hormone receptor (HR), human epidermal growth factor receptor type-2 (HER2) subtype and Ki-67 proliferation index. Whether MRI accuracy varies by genomic signatures is unknown. We examined the accuracy of MRI in the NEONAB trial (Clinicaltrials.gov #: NCT01830244). AIM: To examine the accuracy of MRI to predict pathological response to neoadjuvant therapy for breast cancer in the NEONAB trial. METHODS: Patients with stages II-III breast cancer received sequential epirubicin, cyclophosphamide and nab-paclitaxel and trastuzumab if they were HER2+. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the utility of preoperative MRI to predict pathological complete response (pCR). Bland-Altman plots were used to assess agreement between MRI and pathological assessment of residual disease. RESULTS: MRI correctly predicted pCR in 64.1% of the cohort. Sensitivity and specificity were 52% and 78%, respectively; PPV 73% and NPV 58%. MRI predicted pCR most accurately in HER2-positive patients; sensitivity 58%, specificity 100%, PPV 100% and NPV 38%. MRI had higher PPV and NPV in tumours with Ki-67 ≥ 15% than tumours with Ki-67 < 15%, 75% versus 50% and 57.5% versus 50%, respectively. In this study, MRI underestimated residual tumour size by 1.65 mm (limits of agreement: 43.07-39.77 mm). CONCLUSIONS: MRI appears more accurate for predicting pCR in HER2+ disease than other subtypes and in cancers with Ki-67 ≥ 15% compared to those with Ki-67 < 15%. Accuracy of MRI in our HR+, RS ≥ 25 cohort is comparable to previous reports of unselected HR+ disease. MRI post-NST should be interpreted in conjunction with HER2 status and Ki-67 index of the primary.

Smartphone use in dermatology for clinical photography and consultation: Current practice and the law.

BACKGROUND: Smartphones are rapidly changing the way doctors capture and communicate clinical information, particularly in highly visual specialties such as dermatology. An understanding of how and why smartphones are currently used in clinical practice is critical in order to evaluate professional and legal risks, and to formulate policies that enable safe use of mobile technologies for the maximal benefit of practitioners and patients. METHODS: Australian dermatologists and dermatology trainees were surveyed on their current practices relating to clinical smartphone use. RESULTS: Of the 105 respondents, 101 provided useable results. The data show clinical smartphone use is common and frequent, with more than 50% of respondents sending and receiving images on their smartphones at least weekly. Clinical photographs were usually sent via multimedia message or email and were commonly stored on smartphones (46%). Security measures adopted to protect data were limited. There was inadequate documentation of consent for transmission of photographs and advice provided. Only 22% of respondents were aware of clear policies in their workplace regarding smartphone use, and a majority desired further education on digital image management. CONCLUSIONS: Given the frequency of use and the degree of importance placed on the ability to send and receive clinical images, clinical smartphone use will persist and will likely increase over time. Current practices are insufficient to comply with professional and legal obligations, and increase practitioners' vulnerability to civil and disciplinary proceedings. Further education, realistic policies and adequate software resources are critical to ensure protection of patients, practitioners and the reputation of the dermatological profession.

The Great Divide: Country of birth as a risk factor for obstetric anal sphincter injuries.

BACKGROUND: Obstetric anal sphincter injuries (OASIS) can complicate up to 6% of births and are a major contributor to preventable maternal morbidity. Asian women have a risk of third and fourth degree perineal tears up to four times greater than women of other ethnicities in the same community, but the lack of differentiation of Asian women into regional groups has limited insight into the reasons behind their increased risk. AIMS: To investigate risk of OASIS associated with country of birth. METHODS: This was a retrospective cohort study of all women with a singleton, nulliparous pregnancy who delivered vaginally by spontaneous vaginal birth or an instrumental delivery between 1 January 2009 and 31 December 2015. The demographics of women who experienced OASIS were compared with those women who had minor perineal trauma. RESULTS: From January 2009 to December 2015 there were 10 750 singleton, nulliparous and natural vaginal birth (NVB), forceps or vacuum deliveries. Of these deliveries, 581 (5.4%) werehad third degree tears and 36 (0.3%) fourth degree tears. Women born in South Asia were at a much higher risk of OASIS than other groups, including women born in other Asian countries, compared to the Australian/New Zealand cohort. One in every 10 nulliparous South Asian women having a singleton vaginal or instrumental delivery will sustain an OASIS. CONCLUSIONS: Our study further confirms the role of Asian ethnicity in the risk of OASIS, and is the second to confirm that South Asian women are at a dramatically increased risk.

Point-of-care measurement of fetal blood lactate - Time to trust a new device.

BACKGROUND: Point-of-care lactate devices are used worldwide for intrapartum decision making. Current practice is often based on Lactate Pro (Arkray) but its imminent product discontinuation necessitates determination of an optimal replacement device. AIMS: To evaluate the performance of Lactate Pro and two other point-of-care devices, Lactate Pro 2 (Arkray) and StatStrip (Nova Biomedical), and to derive scalp lactate cut-offs equivalent to the current intervention trigger of >4.8 mmol/L. MATERIALS AND METHODS: Paired umbilical cord arterial and venous blood samples from 109 births were tested on the three point-of-care products (two devices each), cross-compared with the reference method blood gas analyser. RESULTS: All brands deviate from the blood gas analyser, with Lactate Pro and StatStrip results consistently lower and Lactate Pro 2 consistently higher. Standard deviation from the blood gas analyser was smallest for StatStrip (0.78 mmol/L, cord artery), and largest for Lactate Pro 2 (1.03 mmol/L, cord artery). Within-brand variation exists and is similar for all brands (mean absolute difference on cord artery 0.23-0.30 mmol/L). Equivalent values to the 4.8 mmol/L intervention threshold based on Lactate Pro are 4.9-5.0 mmol/L for StatStrip and 5.3-5.9 mmol/L for Lactate Pro 2, calculated by receiver-operating characteristic analysis. CONCLUSIONS: StatStrip appears superior to Lactate Pro 2 to replace the original Lactate Pro. Using StatStrip, the 4.8 mmol/L intervention threshold equivalent was 4.9-5.0 mmol/L. The variation in accuracy of point-of-care lactate devices may exceed the small increments (eg <4.2 mmol/L vs >4.8 mmol/L) that guide obstetric decisions.

Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer: a phase III, randomised, multicentre trial (Ovaresist).

BACKGROUND: Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. METHODS: Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). RESULTS: Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. CONCLUSIONS: Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.

Safety and efficacy of single-agent bevacizumab-containing therapy in elderly patients with platinum-resistant recurrent ovarian cancer: Subgroup analysis of the randomised phase III AURELIA trial.

BACKGROUND: The AURELIA trial demonstrated significantly improved progression-free survival (PFS) with bevacizumab added to chemotherapy for platinum-resistant ovarian cancer (PROC). METHODS: Patients with PROC were randomised to receive investigator-selected single-agent chemotherapy alone or with bevacizumab. Post-hoc exploratory analyses assessed efficacy, safety and patient-reported outcomes according to age <65 versus ≥65years. RESULTS: In the 133 patients (37%) aged ≥65years, baseline hypertension was more frequent and ascites was less common than in patients <65years. The magnitude of PFS benefit from bevacizumab was similar in patients ≥65 versus <65years (hazard ratio 0.44 [95% CI, 0.31-0.64] versus 0.49 [95% CI, 0.37-0.64], respectively, treatment-age interaction p=0.58), with similar improvements in response rates. Grade≥3 hypertension was more common with bevacizumab than chemotherapy alone in both subgroups, and more common in older than younger patients irrespective of treatment. However, there was no excess of other adverse events of specific interest for bevacizumab, including venous thromboembolic events, in older patients. More patients receiving bevacizumab in the younger but not the older subgroup showed improved gastrointestinal/abdominal symptoms. CONCLUSION: In exploratory analyses, PFS and response rate improvement with bevacizumab were consistent in older and younger patients. Grade≥3 hypertension was more common in elderly bevacizumab-treated patients; careful monitoring is recommended. Overall, bevacizumab-containing therapy was well tolerated in a selected population aged ≥65years, suggesting a favourable benefit:risk profile. However, geriatric assessments are needed to improve selection of elderly patients potentially gaining symptom and quality of life improvements from bevacizumab-containing therapy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.govNCT00976911.

Validating self-report and proxy reports of the Dexamethasone Symptom Questionnaire -Chronic for the evaluation of longer-term corticosteroid toxicity.

PURPOSE: In brain tumours, brain metastases or advanced cancer; treatment with corticosteroids, side effects can add to symptoms. These are best assessed by patients, complementing clinical assessment. We assessed the feasibility and validity of the Dexamethasone Symptom Questionnaire-Chronic (DSQ-Chronic), patient and caregiver versions. METHODS: A longitudinal cohort study was conducted, collecting clinician-rated toxicity, performance status, dexamethasone dose and DSQ-Chronic (patient and caregiver versions) at baseline, then 2, 4 and 8 weeks later. Patients had a primary malignant brain tumour, brain metastases, or advanced cancer; Karnofsky Performance Status ≥40 and predicted survival ≥8 weeks. Analysis included questionnaire completion rates, frequency and severity of dexamethasone-attributable side effects, agreement between patient and caregiver ratings, comparison with clinician-rated toxicity and correlation with performance status. RESULTS: Sixty-six patients were recruited (mean age 60 years), with their caregivers. Completion of questionnaires was over 90% for the dyad at baseline but dropped over time, with caregiver completion rates higher at all timepoints. Agreement between patients and proxies was fair to moderate, and while proxies systematically overestimated symptom severity on DSQ-chronic total scores, the bias was less than 10 points. Patient and clinician agreement was higher for more objective symptoms. CONCLUSION: The DSQ-Chronic is feasible when the patient is relatively well. As capacity to complete the DSQ-Chronic diminishes, caregivers can be proxy-raters. Clinicians capture corticosteroid toxicities, which may not be obvious to the patient. The DSQ-Chronic, patient and caregiver versions, are useful tools to be used with clinician assessment.

Single-Legged Triple-Hop Propulsion Strategies in Females With and Those Without a History of Anterior Cruciate Ligament Reconstruction.

CONTEXT: The single-legged triple hop is a commonly used functional task after anterior cruciate ligament reconstruction (ACLR). Recently, researchers have suggested that individuals may use a compensatory propulsion strategy to mask underlying quadriceps dysfunction and achieve symmetric hop performance. OBJECTIVE: To evaluate the performance and propulsion strategies used by females with and those without ACLR during a single-legged triple hop. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 38 females, 19 with ACLR (age = 19.21 ± 1.81 years, height = 1.64 ± 0.70 m, mass = 63.79 ± 7.59 kg) and 19 without ACLR (control group; age = 21.11 ± 3.28 years, height = 1.67 ± 0.73 m, mass = 67.28 ± 9.25 kg). MAIN OUTCOME MEASURE(S): Hop distance and limb symmetry index (LSI) were assessed during a single-legged triple hop for distance. Propulsion strategies were evaluated during the first and second hops of the single-legged triple hop. Separate 2-way analysis-of-variance models were used to examine the influence of ACLR, joint, and their interaction on mechanical joint work, moment impulse, and the relative joint contributions to total work and moment impulse in females with and those without a history of ACLR. RESULTS: Despite achieving a mean LSI of approximately 96%, the ACLR group produced less total work in the reconstructed than the uninvolved limb during single-legged triple-hop propulsion (first hop: t18 = -3.73, P = .002; second hop: t18 = -2.55, P = .02). During the first and second hops, the reconstructed knee generated 19.3% (t18 = -2.33, P = .03) and 27.3% (t18 = -4.47, P < .001) less work than the uninvolved knee. No differences were identified between the involved and uninvolved limbs of the ACLR group in moment impulse (first hop: t18 = -0.44, P = .67; second hop: t18 = -0.32; P = .76). Irrespective of limb or group, the ankle was the largest contributor to both work and moment during both the first and second hops (P < .001). CONCLUSIONS: Clinicians should exercise caution when using a single-legged triple hop as a surrogate for restored lower extremity function in females post-ACLR. This recommendation is driven by the compelling findings that knee-joint deficits persisted in the reconstructed limb despite an LSI of approximately 96% and, regardless of previous injury status, single-legged triple-hop propulsion was predominantly driven by the ankle.

Single-Legged Triple-Hop Propulsion Strategies in Females With and Those Without a History of Anterior Cruciate Ligament Reconstruction.

CONTEXT: The single-legged triple hop is a commonly used functional task after anterior cruciate ligament reconstruction (ACLR). Recently, researchers have suggested that individuals may use a compensatory propulsion strategy to mask underlying quadriceps dysfunction and achieve symmetric hop performance. OBJECTIVE: To evaluate the performance and propulsion strategies used by females with and those without ACLR during a single-legged triple hop. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 38 females, 19 with ACLR (age = 19.21 ± 1.81 years, height = 1.64 ± 0.70 m, mass = 63.79 ± 7.59 kg) and 19 without ACLR (control group; age = 21.11 ± 3.28 years, height = 1.67 ± 0.73 m, mass = 67.28 ± 9.25 kg). MAIN OUTCOME MEASURE(S): Hop distance and limb symmetry index (LSI) were assessed during a single-legged triple hop for distance. Propulsion strategies were evaluated during the first and second hops of the single-legged triple hop. Separate 2-way analysis-of-variance models were used to examine the influence of ACLR, joint, and their interaction on mechanical joint work, moment impulse, and the relative joint contributions to total work and moment impulse in females with and those without a history of ACLR. RESULTS: Despite achieving a mean LSI of approximately 96%, the ACLR group produced less total work in the reconstructed than the uninvolved limb during single-legged triple-hop propulsion (first hop: t18 = -3.73, P = .002; second hop: t18 = -2.55, P = .02). During the first and second hops, the reconstructed knee generated 19.3% (t18 = -2.33, P = .03) and 27.3% (t18 = -4.47, P < .001) less work than the uninvolved knee. No differences were identified between the involved and uninvolved limbs of the ACLR group in moment impulse (first hop: t18 = -0.44, P = .67; second hop: t18 = -0.32; P = .76). Irrespective of limb or group, the ankle was the largest contributor to both work and moment during both the first and second hops (P < .001). CONCLUSIONS: Clinicians should exercise caution when using a single-legged triple hop as a surrogate for restored lower extremity function in females post-ACLR. This recommendation is driven by the compelling findings that knee-joint deficits persisted in the reconstructed limb despite an LSI of approximately 96% and, regardless of previous injury status, single-legged triple-hop propulsion was predominantly driven by the ankle.

Comparison of the effect of caseload midwifery program and standard midwifery-led care on primiparous birth outcomes: A retrospective cohort matching study.

BACKGROUND: The effectiveness of continuity of care during the perinatal period is well documented, but implementing continuity of care model to practice requires evaluation. AIM: To evaluate the effect of a caseload midwifery program (CMP) on birth outcomes and rates of perinatal interventions at a metropolitan tertiary hospital in Australia, compared with standard midwifery-led care (SMC). METHODS: This was a retrospective, matched-cohort study. We extracted the data of 1000 nulliparous women from records of 19,001 women who gave birth at the hospital from 2011 to 2014. We used basic statistical tests to compare baseline demographic data, and logistic regression to calculate odds ratios, to evaluate maternal and neonatal outcomes. RESULTS: Adjusted regression analysis for the primary outcome showed that compared with women who received SMC, women who received care through CMP had an increased rate of normal vaginal birth (69% vs. 50%, OR = 1.79, 95%, CI = 1.38-2.32). Assessment of secondary outcomes showed that the women in CMP group had decreased rates of instrumental birth (15% vs. 26%, OR = 0.48, 95% CI = 0.35-0.66), episiotomy (23% vs. 40%, OR = 0.43, 95% CI = 0.33-0.57), epidural analgesia (33% vs. 43%, OR = 0.64, 95% CI = 0.50-0.83) and amniotomy (35% vs. 50%, OR = 0.56, 95% CI = 0.43-0.72). The CMP group also had greater rates of water immersion (54% vs. 22%, OR = 4.18, 95% CI = 3.17-5.5), physiological 3rd stage (7% vs. 1%, OR = 11.71, 95% CI = 3.56-38.43) and 2nd degree tear (34% vs. 24%, OR = 1.60, 95% CI = 1.21-2.11). There were no significant differences between the two groups for rates of other secondary outcomes including Caesarean section, cervical ripening procedures, third- and fourth-degree tears, postpartum haemorrhage and neonatal outcomes. CONCLUSION: CMP care is associated with increased rate of normal vaginal birth which supports wider implementation of the model. In addition, using routinely collected data and a cohort matching design can be an effective approach to evaluate maternal and neonatal outcomes.

Data maturity and follow-up in time-to-event analyses.

We propose methods to determine the minimum number of subjects remaining at risk after which Kaplan-Meier survival plots for time-to-event outcomes should be curtailed, as, once the number remaining at risk drops below this minimum, the survival estimates are no longer meaningful in the context of the investigation. The size of the decrease of the Kaplan-Meier survival estimate S(t) at time t if one extra event should occur is considered in two ways. In the first approach, the investigator sets a maximum acceptable absolute decrease in S(t) should one extra event occur. In the second, a minimum acceptable number of subjects still at risk is calculated by comparing the size of the decrease in S(t) if an extra event should occur with the variability of the survival estimate had all subjects been followed to that time (confidence interval approach). We recommend calculating both limits for the number still at risk and then making an informed choice in the context of the particular investigation. We explore further how the amount of information actually available can assist in considering issues of data maturity for studies whose outcome of interest is a survival percentage at a particular time point. We illustrate the approaches with a number of published studies having differing sample sizes and censoring issues. In particular, one study was the subject of some controversy regarding how far in time the Kaplan-Meier plot should be extended. The proposed methods allow for limits to be calculated simply using the output provided by most statistical packages.

Immunogenicity and Safety of Monovalent Acellular Pertussis Vaccine at Birth: A Randomized Clinical Trial.

Importance: An alternative option to maternal vaccination to prevent severe pertussis in infants is vaccination at birth. Data are needed on the immunogenicity and safety of a birth dose of monovalent acellular pertussis (aP) vaccine. Objective: To compare IgG antibody responses to vaccine antigens at 6, 10, 24, and 32 weeks of age between newborn infants receiving the aP vaccine and hepatitis B vaccine (HBV) or HBV alone. Design, Setting, and Participants: A randomized clinical trial was conducted at 4 sites in Australia (Sydney, Melbourne, Adelaide, and Perth) between June 11, 2010, and March 14, 2013, among 440 healthy term (>36 weeks' gestation) infants aged less than 5 days at recruitment. Statistical analysis was performed from March 1, 2015, to June 2, 2016. Intervention: Newborns received HBV and, after stratification by maternal receipt of adult-formulated aP-containing vaccine (tetanus toxoid, reduced diphtheria toxoid, and pertussis antigen content [Tdap]) prior to pregnancy, were block randomized to receive the aP vaccine (without diphtheria or tetanus) within 5 days of birth or not. At 6, 16, and 24 weeks, infants received a hexavalent vaccine with pediatric-formulated diphtheria, tetanus and pertussis antigens (DTaP), Haemophilus influenzae type b (Hib), HBV, and polio vaccine, as well as the 10-valent pneumococcal conjugate vaccine. Main Outcomes and Measures: Detectable (>5 enzyme-linked immunosorbent assay units per milliliter) and geometric mean concentrations of IgG antibody to pertussis toxin (PT), pertactin, and filamentous hemagglutinin at 6, 10, and 24 weeks stratified by maternal Tdap history, and antibody at 32 weeks to HBV, Hib, polio, diphtheria, tetanus, and pneumococcal serotypes. The primary outcome was detectable IgG to both PT and pertactin at 10 weeks. Results: A total of 440 infants (207 girls and 233 boys; median gestation, 39.2 weeks) were randomized to receive the aP vaccine plus HBV (n = 221) or HBV only (control group; n = 219). At 10 weeks, 192 of 206 infants who received the aP vaccine (93.2%) had detectable antibodies to both PT and pertactin vs 98 of 193 infants in the control group (50.8%) (P < .001), with the geometric mean concentration for PT IgG 4-fold higher among the group that received the aP vaccine. At age 32 weeks, all infants (n = 181 with sera available for testing) who received the aP vaccine at birth had detectable PT IgG and significantly lower IgG geometric mean concentrations for Hib, hepatitis B, diphtheria, and tetanus antibodies. Local and systemic adverse events were similar between both groups at all time points. Conclusions and Relevance: The monovalent aP vaccine is immunogenic and safe in neonates and, if licensed and available, would be valuable for newborns whose mothers did not receive the Tdap vaccine during pregnancy. Trial Registration: http://anzctr.org.au Identifier: ACTRN12609000905268.

Validation of the accuracy of postpartum haemorrhage data in the ObstetriX database: A retrospective cohort study.

BACKGROUND: Data related to postpartum haemorrhage (PPH) are important clinical parameters which can be applied to all places of birth, and their recording can be missed by busy clinicians providing critical care to women. We compared the accuracy of electronic ObstetriX records to the paper-based medical records of the women who sustained PPH. METHODS: In this retrospective cohort study over a period of one month, 363 electronic records were compared to the paper-based medical records. The volume of blood loss for each patient and interventions for PPH were compared across birth unit, operating theatre and postpartum ward. The kappa statistic for agreement between the two types of recording methods was calculated. RESULTS: There was substantial agreement between the ObstetriX records and medical records for the volume of blood loss at birth (kappa = 0.74), but poor agreement between records for the cumulative total volume of blood loss (kappa = 0.18). More women who experienced PPH and delivered in the operating theatre had errors in their ObstetriX records compared to women who had PPH with births in the birth unit (50% vs 16%; n = 73, P = 0.005). Interventions for PPH were found to be poorly recorded in ObstetriX, with 84% (n = 64/76) of women who experienced PPH having none of the interventions they received recorded. CONCLUSIONS: The ObstetriX database was not a generally reliable source of data relating to PPH. However, some data were recorded reliably, in particular, the volume of blood loss at birth.

VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trials.

BACKGROUND: Untreated advanced hepatocellular carcinoma (HCC) has an overall poor prognosis. Currently there are 2 ongoing prospective randomized controlled trials that are evaluating the efficacy and safety of sorafenib and selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres in patients with advanced HCC. The SorAfenib versus Radioembolisation in Advanced Hepatocellular carcinoma (SARAH; 459 patients) trial is being performed in Europe and the SIRt VErsus SorafeNIB (SIRveNIB; 360 patients) trial in the Asia Pacific region. Prospectively combining the results, these trials will not only allow for increased precision to estimate efficacy (in terms of survival), but will also provide increased statistical power for subgroup analyses. OBJECTIVE: To ensure the prospectivity and transparency of the meta-analysis. METHODS: The sirVEnib and SARAH merge PROject (VESPRO) is an individual, patient-data prospective meta-analysis of the SIRveNIB and SARAH randomized trials. The VESPRO protocol includes prespecified hypotheses, inclusion criteria, and outcome measures. The primary outcome measure is overall survival and secondary outcomes include tumor response rate, progression-free survival, progression in the liver as first event, and disease control in the liver. Pooling of toxicity results will allow for robust safety profiles to be established for both therapies, and provides increased statistical power to investigate treatment effects in key subgroups. Analyses will be performed in the intent-to-treat population stratified by trial. RESULTS: Both studies are expected to demonstrate a survival benefit for SIRT together with a better toxicity profile compared with sorafenib. It is also anticipated that liver progression as the first event would be longer in the intervention compared with the control. CONCLUSIONS: As the results of the 2 trials are not yet known, the methodological strength is enhanced, as biases inherent in conventional meta-analyses are avoided. This has the effect of providing this meta-analysis with the advantages of a single, large,randomized study of 819 patients. It is anticipated that the SARAH and SIRveNIB trial results will be published separately and together with the combined meta-analysis results from VESPRO. The combined dataset will allow the effect of the interventions to be explored with improved reliability/precision with respect to prespecified patient and intervention-level characteristics. TRIAL REGISTRATION: Australian New Zealand Trials Registry: ACTRN12617000030370.

Development and validation of prognostic nomograms for metastatic gastrointestinal stromal tumour treated with imatinib.

PURPOSE: Metastatic gastrointestinal stromal tumour (GIST) is generally an incurable disease with variable response to imatinib. We aimed to develop prognostic nomograms to predict overall survival (OS) and progression-free survival (PFS) for patients treated with imatinib. METHODS: Nomograms were developed in a training cohort (n=330) of patients treated in a randomised trial (EORTC-ISG-AGITG 62005 phase III study) using Cox regression models, and validated in patients (n=236) treated in routine clinical care from six referral centres. Nomogram performance was assessed by calculating the c statistic. A classification based on the nomograms' scores was generated to group patients according to risk. RESULTS: Nomogram risk factors for OS and PFS were size of the largest metastasis, tumour genotype, primary tumour mitotic count, haemoglobin and blood neutrophil count at commencement of imatinib. The nomograms predicted survival with a c statistic of 0.75 (training) and 0.62 (validation) for OS, and 0.69 (training) and 0.62 (validation) for PFS. When tested in the validation cohort, the nomograms discriminated well the high and intermediate risk from low risk patients (hazard ratio [HR] for OS 3.83, 95% confidence interval [CI] 1.71-8.56; and 2.48, 95% CI 1.12-5.50; for PFS 2.84, 95% CI 1.66-4.87; and 1.45, 95% CI 0.87-2.41, respectively). CONCLUSION: The nomograms predicted the risk of GIST progression and death with good discrimination of risk groups, and may be of value for patient counselling and risk stratification.