Search

Background: A major challenge for primary care is to set priorities and balance demands with available resources. The registered nurses in this study are practice nurses working in primary care offices, playing a large role in initial assessments. The overall objective of this research is to investigate practices of communication and decision-making during nurses’ initial assessment of patients’ health problems in primary care, examine working mechanisms in good practices and develop feasible solutions. Methods: Project PINPOINT aims for a prospective multicenter study using various methods for data collection and analysis. A purposive sample of 150 patient‒nurse consultations, including 30 nurses and 150 patients, will be recruited at primary care centers in three different geographic areas of southwest Sweden. The study will report on outcomes of communication practices in relation to patient-reported expectations and experiences, communication processes and patient involvement, assessment and decision-making, related priorities and value conflicts with data from patient questionnaires, audio-recorded real-time communication, and reflective interviews with nurses. Discussion: This research will contribute to the knowledge needed for the guidance of first-line decision-making processes to best meet patient and public health needs. This knowledge is necessary for the development of assessments and decisions to be better aligned to patients and to set priorities. Insights from this research can empower patients and service providers and help understand and enhance feasible person-centered communication strategies tailored to patients’ level of health literacy. More specifically, this research will contribute to knowledge that can strengthen nurses’ communication, assessments, and clinical decision-making in primary care. In the long term, this will contribute to how the competencies of practice nurses and other professionals are organized and carried out to make the

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology. Significance Statement Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems fo, QC 20221017

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Background and Aim: Percutaneous cholecystostomy tube (PC) drainage of the gall bladder (GB) has long been the preferred alternative to laparoscopic cholecystectomy in patients who are deemed too high risk or not appropriate for surgical intervention. Although PC has proven effective in resolving acute sepsis, reintervention for tube dysfunction is required in up to 28% of cases. Recently, endoscopic ultrasound (EUS)-guided transluminal drainage using a novel lumen-apposing metal stent (LAMS) with an electrocautery-enhanced delivery system has gained favor as another means of providing GB drainage. A meta-analysis of the overseas literature demonstrated a technical success rate of 95.2% and a procedure mortality rate of 0.02%. This multicenter study aimed to evaluate the efficacy and safety of EUS-guided GB drainage using LAMS (Hot AXIOS; Boston Scientific) in an Australian cohort. Method(s): Patients in whom a LAMS was used for GB drainage across eight tertiary Australian hospitals from October 2016 to June 2020 were retrospectively identified. Patient and procedural data were collected from the electronic medical records of each respective hospital. Primary outcome measures were technical success, defined as successful initial deployment of the LAMS, and clinical success, defined as resolution of symptoms at 72 h after the procedure. Secondary outcomes included adverse events and 30-day mortality. Result(s): A total of 37 patients (median age, 76 years [range, 39-94]; 26 [70%] male) across the eight hospitals had attempted EUS-guided GB drainage. Indications for proceeding to cholecystostomy drainage, as opposed to surgical management, included advanced age and comorbidities (n = 18), incurable malignancy (n = 13), poor functional state (n = 4), and clinically significant portal hypertension (n = 2). Visible GB calculi were seen in 24 patients (65%), with the remaining patients having acalculous cholecystitis, largely due to malignant obstruction. Most patients (9

Background: On-site workstation based computed tomography derived fractional flow reserve (CT-FFR) is an emerging method to assess the vessel specific ischaemia in coronary artery disease (CAD). The impact of coronary calcification on its diagnostic performance is unknown. Purpose(s): To evaluate the impact of coronary calcification on the diagnostic performance of reduced-order CT-FFR at detecting vessel specific ischaemia. Method(s): This is a retrospective pooled analysis of 141 patients with suspected CAD enrolled from 3 global centres who underwent CTcoronary angiography (CTA), onsite CT-FFR and invasive FFR. Coronary calcification was assessed by Agatston score (AS). The diagnostic performance of CT-FFR (<=0.8) and CTA (>=50%) in evaluation of vessel specific ischaemia (FFR <= 0.8) was assessed across AS quartiles (Q1-4). A comparison of diagnostic performance of the low to mid AS (Q1 to Q3) versus high AS (Q4) was performed. Result(s): Mean age and median AS was 65.8 +/- 9.9 and 327.3 (interquartile range = 78.5 - 798.1). Diagnostic accuracy, sensitivity and specificity of CT-FFR for low-mid AS (0-798) and high AS (799-4019) were 77.4% vs 82.9%; 78.9% vs 94.7%; 68.8% vs 76.5% respectively with no statistical difference between the two groups. The AUC for ischaemia of CT-FFR in low to mid AS was comparable with AUC in the high AS (0.76 [95% CI: 0.66-0.86] vs 0.84 [0.69-0.99]; P = 0.397). The AUC for ischemia for CT-FFR in both low to mid AS and high AS was significantly higher than for CTA (0.76 [0.66-0.86] vs 0.57 [0.50-0.64]; P = 0.003 and 0.84 [0.69-0.99] vs 0.48 [0.38-0.57]; P < 0.001 respectively). Conclusion(s): On-site workstation CT-FFR demonstrated consistently high diagnostic performance in patients with high AS. Its diagnostic performance was superior when compared with significant stenosis assessment on CTA across all spectrum of Agatston scores.

INTRODUCTION: Bronchopulmonary dysplasia (BPD), an important sequela of preterm birth, is associated with long-term abnormalities of lung function and adverse neurodevelopmental outcomes. Inflammation, inhibition of secondary septation and vascular maldevelopment play key roles in the pathogenesis of BPD. Human amnion epithelial cells (hAECs), stem-like cells, derived from placental tissues are able to modulate the inflammatory milieu and, in preclinical studies of BPD-like injury, restore lung architecture and function. Allogeneic hAECs may present a new preventative and reparative therapy for BPD. METHODS AND ANALYSIS: In this two centre, phase Icell dose escalation study we will evaluate the safety of intravenous hAEC infusions in preterm infants at high risk of severe BPD. Twenty-four infants born at less than 29 weeks' gestation will each receive intravenous hAECs beginning day 14 of life. We will escalate the dose of cells contained in a single intravenous hAEC infusion in increments from 2million cells/kg to 10million cells/kg. Further dose escalation will be achieved with repeat infusions given at 5day intervals to a maximum total dose of 30million cells/kg (three infusions). Safety is the primary outcome. Infants will be followed-up until 2 years corrected age. Additional outcome measures include a description of infants' cytokine profile following hAEC infusion, respiratory outcomes including BPD and pulmonary hypertension and other neonatal morbidities including neurodevelopmental assessment at 2 years. ETHICS AND DISSEMINATION: This study was approved on the June12th, 2018 by the Human Research Ethics Committee of Monash Health and Monash University. Recruitment commenced in August 2018 and is expected to take 18 months. Accordingly, follow-up will be completed mid-2022. The findings of this study will be disseminated via peer-reviewed journals and at conferences. PROTOCOL VERSION: 5, 21 May 2018. TRIAL REGISTRATION NUMBER: ACTRN12618000920291; Pre-resul

OBJECTIVES: The onset of many illnesses is confounded with age and sex. Increasing age is a risk factor for the development of many illnesses, and sexual dimorphism influences brain anatomy, function, and cognition. Here, we examine frequency-specific connectivity in resting-state networks in a large sample (n = 406) of healthy aged adults. METHOD(S): We quantify frequency-specific connectivity in three resting-state networks known to be implicated in age-related decline: the default mode, dorsal attention, and salience networks, using multiband functional magnetic resonance imaging. Frequency-specific connectivity was quantified in four bands: low (0.015-0.027 Hz), moderately low (0.027-0.073 Hz), moderately high (0.073-0.198 Hz), and high (0.198-0.5 Hz) frequency bands, using mean intensity and spatial extent. Differences in connectivity between the sexes in each of the three networks were examined. RESULT(S): Each network showed the largest intensity and spatial extent at low frequencies and smallest extent at high frequencies. Males showed greater connectivity than females in the salience network. Females showed greater connectivity than males in the default mode network. DISCUSSION: Results in this healthy aged cohort are compatible with those obtained in young samples, suggesting that frequency-specific connectivity, and differences between the sexes, are maintained into older age. Our results indicate that sex should be considered as an influencing factor in studies of resting-state connectivity.Copyright © The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Objective: To determine current clinical practices for managing behavioural emergencies within Victorian public hospital EDs. Method(s): A multi-centre retrospective study involving all patients who attended ED in 2016 at the Alfred, Ballarat, Dandenong, Geelong and Royal Melbourne Hospitals. The primary outcome was the rate of patient presentations with at least one restrictive intervention. Secondary outcomes included the rate of security calls for unarmed threats (Code Grey), legal status under the Mental Health Act at both the time of ED arrival and the restrictive intervention, and intervention details. For each site, data on 100 patients who had a restrictive intervention were randomly extracted for indication and methods of restraint. Result(s): In 2016, 327 454 patients presented to the five EDs; the Code Grey rate was 1.49% (95% CI 1.45-1.54). Within the Code Grey population, 942 had at least one restrictive intervention (24.3%, 95% CI 23.0-25.7). Details were extracted on 494 patients. The majority (62.8%, 95% CI 58.4-67.1) were restrained under a Duty of Care. Physical restraint was used for 165 (33.4%, 95% CI 29.3-37.8) patients, 296 were mechanically restrained (59.9%, 95% CI 55.4-64.3), median mechanical restraint time 180 min (IQR 75-360), and 388 chemically restrained (78.5%, 95% CI 74.6-82.0). Conclusion(s): Restrictive interventions in the ED largely occurred under a Duty of Care. Care of patients managed under legislation that covers assessment and treatment of mental illness has a strong clinical governance framework and focus on minimising restrictive interventions. However, this is not applied to the majority of patients who experience restraint in Victorian EDs.Copyright © 2019 Australasian College for Emergency Medicine

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p <.001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p <.001) in year 2, and a 19% reduction in nonvertebral fracture (p =.120) and 40% reduction in hip fracture (p =.041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data s

Background: On-site workstation based computed tomography derived fractional flow reserve (CT-FFR) is an emerging method to assess the vessel specific ischaemia in coronary artery disease (CAD). The impact of coronary calcification on its diagnostic performance is unknown. Purpose(s): To evaluate the impact of coronary calcification on the diagnostic performance of reduced-order CT-FFR at detecting vessel specific ischaemia. Method(s): This is a retrospective pooled analysis of 141 patients with suspected CAD enrolled from 3 global centres who underwent CTcoronary angiography (CTA), onsite CT-FFR and invasive FFR. Coronary calcification was assessed by Agatston score (AS). The diagnostic performance of CT-FFR (<=0.8) and CTA (>=50%) in evaluation of vessel specific ischaemia (FFR <= 0.8) was assessed across AS quartiles (Q1-4). A comparison of diagnostic performance of the low to mid AS (Q1 to Q3) versus high AS (Q4) was performed. Result(s): Mean age and median AS was 65.8 +/- 9.9 and 327.3 (interquartile range = 78.5 - 798.1). Diagnostic accuracy, sensitivity and specificity of CT-FFR for low-mid AS (0-798) and high AS (799-4019) were 77.4% vs 82.9%; 78.9% vs 94.7%; 68.8% vs 76.5% respectively with no statistical difference between the two groups. The AUC for ischaemia of CT-FFR in low to mid AS was comparable with AUC in the high AS (0.76 [95% CI: 0.66-0.86] vs 0.84 [0.69-0.99]; P = 0.397). The AUC for ischemia for CT-FFR in both low to mid AS and high AS was significantly higher than for CTA (0.76 [0.66-0.86] vs 0.57 [0.50-0.64]; P = 0.003 and 0.84 [0.69-0.99] vs 0.48 [0.38-0.57]; P < 0.001 respectively). Conclusion(s): On-site workstation CT-FFR demonstrated consistently high diagnostic performance in patients with high AS. Its diagnostic performance was superior when compared with significant stenosis assessment on CTA across all spectrum of Agatston scores.

INTRODUCTION: Bronchopulmonary dysplasia (BPD), an important sequela of preterm birth, is associated with long-term abnormalities of lung function and adverse neurodevelopmental outcomes. Inflammation, inhibition of secondary septation and vascular maldevelopment play key roles in the pathogenesis of BPD. Human amnion epithelial cells (hAECs), stem-like cells, derived from placental tissues are able to modulate the inflammatory milieu and, in preclinical studies of BPD-like injury, restore lung architecture and function. Allogeneic hAECs may present a new preventative and reparative therapy for BPD. METHODS AND ANALYSIS: In this two centre, phase Icell dose escalation study we will evaluate the safety of intravenous hAEC infusions in preterm infants at high risk of severe BPD. Twenty-four infants born at less than 29 weeks' gestation will each receive intravenous hAECs beginning day 14 of life. We will escalate the dose of cells contained in a single intravenous hAEC infusion in increments from 2million cells/kg to 10million cells/kg. Further dose escalation will be achieved with repeat infusions given at 5day intervals to a maximum total dose of 30million cells/kg (three infusions). Safety is the primary outcome. Infants will be followed-up until 2 years corrected age. Additional outcome measures include a description of infants' cytokine profile following hAEC infusion, respiratory outcomes including BPD and pulmonary hypertension and other neonatal morbidities including neurodevelopmental assessment at 2 years. ETHICS AND DISSEMINATION: This study was approved on the June12th, 2018 by the Human Research Ethics Committee of Monash Health and Monash University. Recruitment commenced in August 2018 and is expected to take 18 months. Accordingly, follow-up will be completed mid-2022. The findings of this study will be disseminated via peer-reviewed journals and at conferences. PROTOCOL VERSION: 5, 21 May 2018. TRIAL REGISTRATION NUMBER: ACTRN12618000920291; Pre-resul

OBJECTIVES: The onset of many illnesses is confounded with age and sex. Increasing age is a risk factor for the development of many illnesses, and sexual dimorphism influences brain anatomy, function, and cognition. Here, we examine frequency-specific connectivity in resting-state networks in a large sample (n = 406) of healthy aged adults. METHOD(S): We quantify frequency-specific connectivity in three resting-state networks known to be implicated in age-related decline: the default mode, dorsal attention, and salience networks, using multiband functional magnetic resonance imaging. Frequency-specific connectivity was quantified in four bands: low (0.015-0.027 Hz), moderately low (0.027-0.073 Hz), moderately high (0.073-0.198 Hz), and high (0.198-0.5 Hz) frequency bands, using mean intensity and spatial extent. Differences in connectivity between the sexes in each of the three networks were examined. RESULT(S): Each network showed the largest intensity and spatial extent at low frequencies and smallest extent at high frequencies. Males showed greater connectivity than females in the salience network. Females showed greater connectivity than males in the default mode network. DISCUSSION: Results in this healthy aged cohort are compatible with those obtained in young samples, suggesting that frequency-specific connectivity, and differences between the sexes, are maintained into older age. Our results indicate that sex should be considered as an influencing factor in studies of resting-state connectivity.Copyright © The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Objective: To determine current clinical practices for managing behavioural emergencies within Victorian public hospital EDs. Method(s): A multi-centre retrospective study involving all patients who attended ED in 2016 at the Alfred, Ballarat, Dandenong, Geelong and Royal Melbourne Hospitals. The primary outcome was the rate of patient presentations with at least one restrictive intervention. Secondary outcomes included the rate of security calls for unarmed threats (Code Grey), legal status under the Mental Health Act at both the time of ED arrival and the restrictive intervention, and intervention details. For each site, data on 100 patients who had a restrictive intervention were randomly extracted for indication and methods of restraint. Result(s): In 2016, 327 454 patients presented to the five EDs; the Code Grey rate was 1.49% (95% CI 1.45-1.54). Within the Code Grey population, 942 had at least one restrictive intervention (24.3%, 95% CI 23.0-25.7). Details were extracted on 494 patients. The majority (62.8%, 95% CI 58.4-67.1) were restrained under a Duty of Care. Physical restraint was used for 165 (33.4%, 95% CI 29.3-37.8) patients, 296 were mechanically restrained (59.9%, 95% CI 55.4-64.3), median mechanical restraint time 180 min (IQR 75-360), and 388 chemically restrained (78.5%, 95% CI 74.6-82.0). Conclusion(s): Restrictive interventions in the ED largely occurred under a Duty of Care. Care of patients managed under legislation that covers assessment and treatment of mental illness has a strong clinical governance framework and focus on minimising restrictive interventions. However, this is not applied to the majority of patients who experience restraint in Victorian EDs.Copyright © 2019 Australasian College for Emergency Medicine

Objective: Asthma exacerbations are common presentations to ED. Key guideline recommendations for management include administration of inhaled bronchodilators, systemic corticosteroids and titrated oxygen therapy. Our aim was to compare management and outcomes between patients treated for asthma in Europe (EUR) and South East Asia/Australasia (SEA) and compliance with international guidelines. Method(s): In each region, prospective, interrupted time series studies were performed including adult (age >18 years) patients presenting to ED with the main complaint of dyspnoea during three 72 h periods. This was a planned sub-study that included those with an ED primary diagnosis of asthma. Data was collected on demographics, clinical features, treatment in ED, diagnosis, disposition and in-hospital outcome. The results of interest were differences in treatment and outcome between EUR and SEA cohorts. Result(s): Five hundred and eighty-four patients were identified from 112 EDs (66 EUR and 46 SEA). The cohorts had similar demographics and co-morbidity patterns, with 89% of the cohort having a previous diagnosis of asthma. There were no significant differences in treatment between EUR and SEA patients - inhaled beta-agonists were administered in 86% of cases, systemic corticosteroids in 66%, oxygen therapy in 44% and antibiotics in 20%. Two thirds of patients were discharged home from the ED. Conclusion(s): The data suggests that compliance with guideline-recommended therapy in both regions, particularly corticosteroid administration, is sub-optimal. It also suggests over-use of antibiotics.Copyright © 2019 Australasian College for Emergency Medicine

Objective: To characterize the clinical cognitive phenotypes and severity of cognitive burden according to disease subtype in children with primary central nervous system vasculitis (cPACNS). Method(s): This retrospective multicenter inflammatory brain disease database study examined the neuropsychological outcomes of 80 children (44 male; mean age - 7.89 years, SD = 4.17) consecutively diagnosed with primary CNS vasculitis between 1992 and 2016. Twenty-one children had small-vessel disease (AN=cPACNS), and 59 had large-vessel disease (including 49 nonprogressive [APNP-cPACNS] and 10 progressive [APP-cPACNS]). Neuroimaging revealed MRI abnormalities in 100% and 90% of children with large-and small-vessel vasculitis, respectively. The primary outcomes were Full Scale IQ (FSIQ) and the index scores from the Wechsler Intelligence Scale for Children-III (WISC-III, WISC-IV, and WISC-V). Analyses explored the effect of disease subtype. Result(s): Intellectual functioning was assessed on average 2.82 years after symptom onset. Children with small-vessel CNS vasculitis had significantly lower FSIQ scores than did those with large-vessel CNS vasculitis (Ms - 81.90 vs. 94.82; p - .04). Intellectual disability (FSIQ - 70) was more frequent in children with small-vessel disease (24% vs. 5%). All groups displayed lower Working Memory and Processing Speed index scores relative to Verbal Comprehension and Perceptual Reasoning index scores. Group differences in FSIQ remained significant after controlling for the presence of seizures. Conclusion(s): Children with small-vessel CNS vasculitis are more likely to demonstrate deficits in intellectual functioning than are those with large-vessel disease, and children with both types of CNS vasculitis demonstrate relatively poor working memory and processing speed.Copyright © 2019 American Psychological Association.

Objective: To determine the effectiveness of personalized embryo transfer (pET) versus frozen embryo transfer (FET) or fresh embryo transfer (ET) in infertile patients undergoing IVF at their first appointment. In pET, embryo transfer is performed within the optimal window of implantation identified by the endometrial receptivity analysis (ERA). Design(s): Multicenter randomized clinical trial. Participants aged <= 37 years scheduled for IVF with elective blastocyst transfer at the first appointment were randomized to undergo pET, FET or ET. Material(s) and Method(s): Setting: 16 reproductive medicine centers in Europe, America and Asia with a common reference genetic laboratory. Patient(s): We recruited 569 women, and 458 were randomly assigned to pET (N=148), FET (N=154), or ET (N=156) groups. Intervention(s): The ERA test was performed using hormone replacement therapy guiding embryo transfer in the pET arm. Blastocyst vitrification was performed in the pET and FET arms. Blastocyst transfer in all groups. Main outcome measure(s): The primary outcome was live birth. Secondary outcomes were pregnancy and implantation rates as well as clinical miscarriage, biochemical pregnancy, and obstetric and neonatal outcomes. We performed intention-to-treat and per protocol analyses. Result(s): In the per protocol analysis, live birth rates at the first embryo transfer were 45 of 80 (56.2%) in the pET group, 39 of 92 (42.4%) in the FET group, and 43 of 94 (45.7%) in the ET group (pET versus FET relative risk [RR] 1.35, 95% confidence interval (CI) 0.97- 1.86; p=0.09; pET versus ET [RR] 1.26, 95% (CI) 0.91-1.74; p=0.17). Cumulative live birth rates after 12 months were 57 of 80 (71.2%) in the pET group, 51 of 92 (55.4%) in the FET group, and 46 of 94 (48.9%) in the ET group (pET versus FET [RR] 1.47, 95% (CI)1.01-2.13; p=0.04; PET versus ET [RR]1.71, 95% (CI) 1.17-2.49; p=0.003). Pregnancy rates at the first embryo transfer in the pET, FET and ET were 72.5%, 54.3% and 58.5% res

Background: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Aim(s): This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. Material(s) and Method(s): International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Result(s): Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. Conclusion(s): This review provides the best available evidence informing recommendations (along with clinical expertise and cons

Objective: Asthma exacerbations are common presentations to ED. Key guideline recommendations for management include administration of inhaled bronchodilators, systemic corticosteroids and titrated oxygen therapy. Our aim was to compare management and outcomes between patients treated for asthma in Europe (EUR) and South East Asia/Australasia (SEA) and compliance with international guidelines. Method(s): In each region, prospective, interrupted time series studies were performed including adult (age >18 years) patients presenting to ED with the main complaint of dyspnoea during three 72 h periods. This was a planned sub-study that included those with an ED primary diagnosis of asthma. Data was collected on demographics, clinical features, treatment in ED, diagnosis, disposition and in-hospital outcome. The results of interest were differences in treatment and outcome between EUR and SEA cohorts. Result(s): Five hundred and eighty-four patients were identified from 112 EDs (66 EUR and 46 SEA). The cohorts had similar demographics and co-morbidity patterns, with 89% of the cohort having a previous diagnosis of asthma. There were no significant differences in treatment between EUR and SEA patients - inhaled beta-agonists were administered in 86% of cases, systemic corticosteroids in 66%, oxygen therapy in 44% and antibiotics in 20%. Two thirds of patients were discharged home from the ED. Conclusion(s): The data suggests that compliance with guideline-recommended therapy in both regions, particularly corticosteroid administration, is sub-optimal. It also suggests over-use of antibiotics.Copyright © 2019 Australasian College for Emergency Medicine

Aim: To evaluate the trend in presentation and postoperative outcomes of infants with hypertrophic pyloric stenosis (HPS) over the last decade. Method(s): This was a multicentre retrospective study in two tertiary paediatric centres between 2005 and 2015 inclusive. Participants included 626 infants who underwent a pyloromyotomy for HPS. We collected data on presentation features (age, weight, clinical signs, blood gas results, ultrasound findings) and postoperative outcomes (length of stay (LOS), complications, time to first postoperative feed). Result(s): No trend was identified during the study period with regards to age, weight, biochemical findings (pH, chloride, base excess) or pre-operative ultrasound measurements. There was a downtrend in the number of palpated tumours over time, with a mean of 36% of tumours clinically palpated. Pyloric wall thickness had a moderate association with LOS in patients admitted for >8 days (correlation = 0.4752) but had a weak negative association with shorter lengths of stay (<=8 day, correlation = -0.094). Overall, median time to first feed was 7.80 h and improved yearly during the study period (hazard ratio = 1.07). Conclusion(s): Patients presenting with HPS are not being identified at an earlier age or with fewer biochemical derangements, in contrast to our initial perceptions. Subsequently, biochemical derangements can still play an important role in the diagnosis of HPS, and attention needs to be given to fluid management and electrolyte correction in all patients with HPS.Copyright © 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Background: On-site workstation based computed tomography derived fractional flow reserve (CT-FFR) is an emerging method to assess vessel specific ischaemia in coronary artery disease (CAD). Global data on its diagnostic performance when compared with CT coronary angiography (CTA) is limited. Purpose(s): To evaluate the on-site multicentre diagnostic performance of reduced-order CT-FFR at detecting vessel specific ischaemia. Method(s): This is a retrospective pooled analysis of 141 patients (204 vessels) with suspected CAD enrolled from 3 global centres who underwent CTA, onsite CT-FFR and invasive FFR. On-site CT-FFR was performed using a reduced order model on a standard desktop computer with dedicated software. The per vessel diagnostic performance of CT-FFR (<=0.8) for vessel specific ischemia (FFR<=0.8) was compared with CTA (>=50% stenosis). Result(s): Mean age was 65.8+/-9.9, 70.7% were male. FFR significant stenosis was present in 34.3% (70/204) of vessels. Pearson correlation of CT-FFR for invasive FFR was 0.52, P<0.001. Bland Altman analysis demonstrated a mean difference of 0.06+/-0.15 (95% limits of agreement -0.22 to 0.35). Per vessel diagnostic accuracy, sensitivity and specificity of CT-FFR and CTA were 79.9% vs 53.5%; 78.6% vs 85.7%; 80.6% vs 35.9% respectively. Diagnostic performance as assessed by area under the receiver operator curve (AUC) for CT FFR was superior to CTA (0.82 [95% CI 0.76-0.88] vs 0.61 [0.55-0.67]; P<0.001). Conclusion(s): On-site workstation CT-FFR demonstrated high per vessel diagnostic performance and was superior when compared with CTA in assessment of vessel specific ischaemia as assessed by invasive FFR in a multicentre setting.

Objective: To characterize the clinical cognitive phenotypes and severity of cognitive burden according to disease subtype in children with primary central nervous system vasculitis (cPACNS). Method(s): This retrospective multicenter inflammatory brain disease database study examined the neuropsychological outcomes of 80 children (44 male; mean age - 7.89 years, SD = 4.17) consecutively diagnosed with primary CNS vasculitis between 1992 and 2016. Twenty-one children had small-vessel disease (AN=cPACNS), and 59 had large-vessel disease (including 49 nonprogressive [APNP-cPACNS] and 10 progressive [APP-cPACNS]). Neuroimaging revealed MRI abnormalities in 100% and 90% of children with large-and small-vessel vasculitis, respectively. The primary outcomes were Full Scale IQ (FSIQ) and the index scores from the Wechsler Intelligence Scale for Children-III (WISC-III, WISC-IV, and WISC-V). Analyses explored the effect of disease subtype. Result(s): Intellectual functioning was assessed on average 2.82 years after symptom onset. Children with small-vessel CNS vasculitis had significantly lower FSIQ scores than did those with large-vessel CNS vasculitis (Ms - 81.90 vs. 94.82; p - .04). Intellectual disability (FSIQ - 70) was more frequent in children with small-vessel disease (24% vs. 5%). All groups displayed lower Working Memory and Processing Speed index scores relative to Verbal Comprehension and Perceptual Reasoning index scores. Group differences in FSIQ remained significant after controlling for the presence of seizures. Conclusion(s): Children with small-vessel CNS vasculitis are more likely to demonstrate deficits in intellectual functioning than are those with large-vessel disease, and children with both types of CNS vasculitis demonstrate relatively poor working memory and processing speed.Copyright © 2019 American Psychological Association.

Objective: To determine the effectiveness of personalized embryo transfer (pET) versus frozen embryo transfer (FET) or fresh embryo transfer (ET) in infertile patients undergoing IVF at their first appointment. In pET, embryo transfer is performed within the optimal window of implantation identified by the endometrial receptivity analysis (ERA). Design(s): Multicenter randomized clinical trial. Participants aged <= 37 years scheduled for IVF with elective blastocyst transfer at the first appointment were randomized to undergo pET, FET or ET. Material(s) and Method(s): Setting: 16 reproductive medicine centers in Europe, America and Asia with a common reference genetic laboratory. Patient(s): We recruited 569 women, and 458 were randomly assigned to pET (N=148), FET (N=154), or ET (N=156) groups. Intervention(s): The ERA test was performed using hormone replacement therapy guiding embryo transfer in the pET arm. Blastocyst vitrification was performed in the pET and FET arms. Blastocyst transfer in all groups. Main outcome measure(s): The primary outcome was live birth. Secondary outcomes were pregnancy and implantation rates as well as clinical miscarriage, biochemical pregnancy, and obstetric and neonatal outcomes. We performed intention-to-treat and per protocol analyses. Result(s): In the per protocol analysis, live birth rates at the first embryo transfer were 45 of 80 (56.2%) in the pET group, 39 of 92 (42.4%) in the FET group, and 43 of 94 (45.7%) in the ET group (pET versus FET relative risk [RR] 1.35, 95% confidence interval (CI) 0.97- 1.86; p=0.09; pET versus ET [RR] 1.26, 95% (CI) 0.91-1.74; p=0.17). Cumulative live birth rates after 12 months were 57 of 80 (71.2%) in the pET group, 51 of 92 (55.4%) in the FET group, and 46 of 94 (48.9%) in the ET group (pET versus FET [RR] 1.47, 95% (CI)1.01-2.13; p=0.04; PET versus ET [RR]1.71, 95% (CI) 1.17-2.49; p=0.003). Pregnancy rates at the first embryo transfer in the pET, FET and ET were 72.5%, 54.3% and 58.5% res

Background: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Aim(s): This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. Material(s) and Method(s): International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Result(s): Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. Conclusion(s): This review provides the best available evidence informing recommendations (along with clinical expertise and cons

Background: On-site workstation based computed tomography derived fractional flow reserve (CT-FFR) is an emerging method to assess vessel specific ischaemia in coronary artery disease (CAD). Global data on its diagnostic performance when compared with CT coronary angiography (CTA) is limited. Purpose(s): To evaluate the on-site multicentre diagnostic performance of reduced-order CT-FFR at detecting vessel specific ischaemia. Method(s): This is a retrospective pooled analysis of 141 patients (204 vessels) with suspected CAD enrolled from 3 global centres who underwent CTA, onsite CT-FFR and invasive FFR. On-site CT-FFR was performed using a reduced order model on a standard desktop computer with dedicated software. The per vessel diagnostic performance of CT-FFR (<=0.8) for vessel specific ischemia (FFR<=0.8) was compared with CTA (>=50% stenosis). Result(s): Mean age was 65.8+/-9.9, 70.7% were male. FFR significant stenosis was present in 34.3% (70/204) of vessels. Pearson correlation of CT-FFR for invasive FFR was 0.52, P<0.001. Bland Altman analysis demonstrated a mean difference of 0.06+/-0.15 (95% limits of agreement -0.22 to 0.35). Per vessel diagnostic accuracy, sensitivity and specificity of CT-FFR and CTA were 79.9% vs 53.5%; 78.6% vs 85.7%; 80.6% vs 35.9% respectively. Diagnostic performance as assessed by area under the receiver operator curve (AUC) for CT FFR was superior to CTA (0.82 [95% CI 0.76-0.88] vs 0.61 [0.55-0.67]; P<0.001). Conclusion(s): On-site workstation CT-FFR demonstrated high per vessel diagnostic performance and was superior when compared with CTA in assessment of vessel specific ischaemia as assessed by invasive FFR in a multicentre setting.

Aim: To evaluate the trend in presentation and postoperative outcomes of infants with hypertrophic pyloric stenosis (HPS) over the last decade. Method(s): This was a multicentre retrospective study in two tertiary paediatric centres between 2005 and 2015 inclusive. Participants included 626 infants who underwent a pyloromyotomy for HPS. We collected data on presentation features (age, weight, clinical signs, blood gas results, ultrasound findings) and postoperative outcomes (length of stay (LOS), complications, time to first postoperative feed). Result(s): No trend was identified during the study period with regards to age, weight, biochemical findings (pH, chloride, base excess) or pre-operative ultrasound measurements. There was a downtrend in the number of palpated tumours over time, with a mean of 36% of tumours clinically palpated. Pyloric wall thickness had a moderate association with LOS in patients admitted for >8 days (correlation = 0.4752) but had a weak negative association with shorter lengths of stay (<=8 day, correlation = -0.094). Overall, median time to first feed was 7.80 h and improved yearly during the study period (hazard ratio = 1.07). Conclusion(s): Patients presenting with HPS are not being identified at an earlier age or with fewer biochemical derangements, in contrast to our initial perceptions. Subsequently, biochemical derangements can still play an important role in the diagnosis of HPS, and attention needs to be given to fluid management and electrolyte correction in all patients with HPS.Copyright © 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Objective: To evaluate the prevalence of unsuspected uterine sarcomas undergoing morcellation at the time of hysterectomy or myomectomy. Design(s): A retrospective cohort study. Setting(s): A teaching health service in Melbourne, Australia, consisting of four hospitals which provide gynecology and gynecology oncology services including one tertiary referral center. Population: All women undergoing any form of hysterectomy or myomectomy from 1998 to 2016. Method(s): Patient demographics and the presence of morcellation were collected. All cases of confirmed uterine sarcomas were further examined and their histological subtype, patient demographics, preoperative investigations, and surgical indication were also identified. Result(s): A total of 7584 cases were studied. Overall, 33 uterine sarcomas were identified. Of these, seven cases were unsuspected malignancies. All seven cases were leiomyosarcomas. None of the malignant specimens underwent morcellation. The overall prevalence of uterine sarcomas in the total study population was 0.44%. The rate of unsuspected uterine sarcomas in women undergoing hysterectomy or myomectomy for presumed benign indications was 0.13% or 1 in 769. The rate of unintended morcellation of a uterine sarcoma in our center was 0%. The diagnosis of endometrial sarcoma was prompted by endometrial sampling in 58% of the cases when performed. Conclusion(s): The risk of inadvertent morcellation of unsuspected uterine sarcomas is low. Patients should be appropriately selected with adequate investigations and a detailed history and examination prior to surgery. Further studies are needed to identify effective preoperative screening methods for uterine sarcomas.Copyright © The Author(s) 2018.

Background/Objectives: Adjuvant chemotherapy for Stage II colon cancer offers a small (2-3%) overall survival benefit and is not universally recommended. Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. The aim of this study was to investigate the use of dMMR immunohistochemistry in two major cancer treatment centres. Method(s): Prospective data were collected on all patients with resected Stage II colon cancer between 2010 and 2015 across two large Australian hospitals. Data collected included patient demographics, tumour histology, dMMR immunohistochemistry, chemotherapy use, and outcomes. Result(s): All 355 patients (56.1% female, median age 81) with resected Stage 2 Colon cancer entered on to the surgical database were included in this analysis. MMR testing was performed on 167 patient samples (47%), most occurred post-2013 (73.1% vs. 26.9% patients). dMMR rates were 34.1%. 25 (7.3%) received adjuvant chemotherapy, with no patient >80 years receiving treatment. Presence of >=2 high-risk feature increased the likelihood of adjuvant chemotherapy. Only 3.6% dMMR patients received chemotherapy; both were young with high-risk features. 27/288 (7.6%) patients (with follow up) relapsed, with 7 disease-free post-resection of metastatic disease, 9 are alive with metastatic disease, and 11 deceased. Conclusion(s): Unlike clinical trial populations, Stage 2 colon cancer patients are often elderly, have high rates of dMMR tumours, are rarely offered chemotherapy, yet still have excellent outcomes. dMMR immunohistochemistry is being increasingly used to identify Stage 2 patients who do not require chemotherapy.Copyright © 2018 IJS Publishing Group Ltd

Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. Method(s): This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. Result(s): Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naive patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. Conclusion(s): Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.Copyright © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Objective: To evaluate the prevalence of unsuspected uterine sarcomas undergoing morcellation at the time of hysterectomy or myomectomy. Design(s): A retrospective cohort study. Setting(s): A teaching health service in Melbourne, Australia, consisting of four hospitals which provide gynecology and gynecology oncology services including one tertiary referral center. Population: All women undergoing any form of hysterectomy or myomectomy from 1998 to 2016. Method(s): Patient demographics and the presence of morcellation were collected. All cases of confirmed uterine sarcomas were further examined and their histological subtype, patient demographics, preoperative investigations, and surgical indication were also identified. Result(s): A total of 7584 cases were studied. Overall, 33 uterine sarcomas were identified. Of these, seven cases were unsuspected malignancies. All seven cases were leiomyosarcomas. None of the malignant specimens underwent morcellation. The overall prevalence of uterine sarcomas in the total study population was 0.44%. The rate of unsuspected uterine sarcomas in women undergoing hysterectomy or myomectomy for presumed benign indications was 0.13% or 1 in 769. The rate of unintended morcellation of a uterine sarcoma in our center was 0%. The diagnosis of endometrial sarcoma was prompted by endometrial sampling in 58% of the cases when performed. Conclusion(s): The risk of inadvertent morcellation of unsuspected uterine sarcomas is low. Patients should be appropriately selected with adequate investigations and a detailed history and examination prior to surgery. Further studies are needed to identify effective preoperative screening methods for uterine sarcomas.Copyright © The Author(s) 2018.

Background/Objectives: Adjuvant chemotherapy for Stage II colon cancer offers a small (2-3%) overall survival benefit and is not universally recommended. Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. The aim of this study was to investigate the use of dMMR immunohistochemistry in two major cancer treatment centres. Method(s): Prospective data were collected on all patients with resected Stage II colon cancer between 2010 and 2015 across two large Australian hospitals. Data collected included patient demographics, tumour histology, dMMR immunohistochemistry, chemotherapy use, and outcomes. Result(s): All 355 patients (56.1% female, median age 81) with resected Stage 2 Colon cancer entered on to the surgical database were included in this analysis. MMR testing was performed on 167 patient samples (47%), most occurred post-2013 (73.1% vs. 26.9% patients). dMMR rates were 34.1%. 25 (7.3%) received adjuvant chemotherapy, with no patient >80 years receiving treatment. Presence of >=2 high-risk feature increased the likelihood of adjuvant chemotherapy. Only 3.6% dMMR patients received chemotherapy; both were young with high-risk features. 27/288 (7.6%) patients (with follow up) relapsed, with 7 disease-free post-resection of metastatic disease, 9 are alive with metastatic disease, and 11 deceased. Conclusion(s): Unlike clinical trial populations, Stage 2 colon cancer patients are often elderly, have high rates of dMMR tumours, are rarely offered chemotherapy, yet still have excellent outcomes. dMMR immunohistochemistry is being increasingly used to identify Stage 2 patients who do not require chemotherapy.Copyright © 2018 IJS Publishing Group Ltd

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. Method(s): This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. Result(s): Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naive patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. Conclusion(s): Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.Copyright © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

The Australian and New Zealand Intensive Care Society Clinical Trials Group and other investigator-led trials groups in critical care publish policies and guidelines outlining the rationale for considering co-enrolment in large, randomised controlled trials in intensive care medicine. However, none present a checklist of criteria by which a request for permission to co-enrol in an existing trial can be assessed. Consequently, such requests tend to be made and assessed on an ad hoc basis. Based on our experience in the SPICE III randomised controlled trial, we propose eight broadly applicable criteria (the SPICE-8 criteria) to be satisfied before co-enrolment should be approved. Reporting co-enrolment in trials, for regulatory purposes and in publications, is uncommon, partly because of the complexity involved in explaining a lack of a plausible coenrolment effect. We suggest that noting compliance with these criteria would simplify such reporting and enhance transparency.

IMPORTANCE Mechanical thrombectomy (MT) improves clinical outcomes in patients with acute ischemic stroke (AIS) caused by a large vessel occlusion. However, it is not known whether intravenous thrombolysis (IVT) is of added benefit in patients undergoingMT. OBJECTIVE To examine whether treatment with IVT before MT with a stent retriever is beneficial in patients undergoingMT. DESIGN, SETTING, AND PARTICIPANTS This post hoc analysis used data from 291 patients treated with MT included in 2 large, multicenter, prospective clinical trials that evaluated MT for AIS (Solitaire With the Intention for Thrombectomy performed from January 1, 2010, through December 31, 2011, and Solitaire Flow Restoration Thrombectomy for Acute Revascularization from January 1, 2010, through December 31, 2012). An independent core laboratory scored the radiologic outcomes in each trial. INTERVENTIONS Patients were treated with IVT with tissue plasminogen activator followed by MT (IVT and MT group) with the use of a stent retriever orMT with a stent retriever alone (MT group). MAIN OUTCOMES AND MEASURES Successful reperfusion, functional independence (modified Rankin Scale score of 0-2) and mortality at 90 days, symptomatic intracranial hemorrhage, emboli to new territory, and vasospasm were compared. RESULTS Of 291 patients included in the analysis, 160 (55.0%) underwent IVT and MT (mean [SD] age, 67 [13] years; 97 female [60.6%]), and 131 (45.0%) underwent MT alone (mean [SD] age, 69 [12] years; 71 [55.7%] female). Median Alberta Stroke Program Early CT Score at baseline was lower in the IVT and MT group (8 vs 9, P = .04). There was no statistically significant difference in the duration from symptom onset to groin puncture (254 minutes for the IVT and MT group vs 262 minutes for the MT group, P = .10). The number of passes, rate of successful reperfusion, functional independence at 90 days, mortality at 90 days, and emboli to new territory were also similar among groups. Symptomatic intracr

Background: Non-invasive ventilation (NIV) with bi-level positive airway pressure (BiPAP) is commonly used to treat patients admitted to hospital with acute hypercapnic respiratory failure (AHRF) secondary to an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Objective(s): To compare the efficacy of NIV applied in conjunction with usual care versus usual care involving no mechanical ventilation alone in adults with AHRF due to AECOPD. The aim of this review is to update the evidence base with the goals of supporting clinical practice and providing recommendations for future evaluation and research. Search Method(s): We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and PsycINFO, and through handsearching of respiratory journals and meeting abstracts. This update to the original review incorporates the results of database searches up to January 2017. Selection Criteria: All randomised controlled trials that compared usual care plus NIV (BiPAP) versus usual care alone in an acute hospital setting for patients with AECOPD due to AHRF were eligible for inclusion. AHRF was defined by a mean admission pH < 7.35 and mean partial pressure of carbon dioxide (PaCO2) > 45 mmHg (6 kPa). Primary review outcomes were mortality during hospital admission and need for endotracheal intubation. Secondary outcomes included hospital length of stay, treatment intolerance, complications, changes in symptoms, and changes in arterial blood gases. Data Collection and Analysis: Two review authors independently applied the selection criteria to determine study eligibility, performed data extraction, and determined risk of bias in accordance with Cochra

Background: Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. Objective(s): To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents. The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. Search Method(s): We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. Selection Criteria: We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and stand

This study investigated the validity and reliability of fixed strain gauge measurements of isometric quadriceps force in patients with chronic obstructive pulmonary disease (COPD). A total cohort of 138 patients with COPD were assessed. To determine validity, maximal volitional quadriceps force was evaluated during isometric maximal voluntary contraction (MVC) manoeuvre via a fixed strain gauge dynamometer and compared to (a) potentiated non-volitional quadriceps force obtained via magnetic stimulation of the femoral nerve (twitch (Tw); n = 92) and (b) volitional computerized dynamometry (Biodex; n = 46) and analysed via correlation coefficients. Test-retest and absolute reliability were determined via calculations of intra-class correlation coefficients (ICCs), smallest real differences (SRDs) and standard errors of measurement (SEMs). For this, MVC recordings in each device were performed across two test sessions separated by a period of 7 days (n = 46). Strain gauge measures of MVC demonstrated very large correlation with Tw and Biodex results (r = 0.86 and 0.88, respectively, both p < 0.0001). ICC, SEM and SRD were numerically comparable between strain gauge and Biodex devices (ICC = 0.96 vs. 0.93; SEM = 8.50 vs. 10.54 N.m and SRD = 23.59 vs. 29.22 N.m, respectively). The results support that strain gauge measures of quadriceps force are valid and reliable in patients with COPD.Copyright © SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses.