Effect of Playing Position on Heart Rate and Blood Pressure in Brass and Wind Musicians.

OBJECTIVE: The purpose of this study was to compare the impact of playing brass and wind instruments in seated versus standing positions on cardiovascular parameters in musicians. We hypothesized that heart rate (HR) and blood pressure (BP) would be higher while playing compared to resting, and would be higher in standing compared to seated positions. METHODS: Ten musicians completed two study visits. In both, resting, supine HR and BP were recorded, followed by 30 minutes of playing. In one visit, participants played seated, and in the other, played while standing. The order of these positions was randomized. BP and HR were recorded every 5 minutes during playing. RESULTS: Systolic BP was not affected by playing (p = 0.09, eta2 = 0.046) or position (p = 0.35, eta2 = 0.024). Diastolic BP increased while playing (p < 0.0001, eta2 = 0.32), but did not differ between positions (p = 0.21, eta2 = 0.03). Mean arterial pressure (MAP) increased while playing (p < 0.0001, eta2 = 0.25), but did not differ between positions (p = 0.68, eta2 = 0.03). There was a significant time X position interaction for HR (p = 0.0001, eta2 = 0.037). Simple main effects analysis revealed that HR was higher while playing in the standing compared to the seated position at all but one time point. CONCLUSION: Playing brass and wind instruments increases diastolic BP and MAP, regardless of playing position, while playing in the standing position induces a higher HR compared to the seated position.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). INTERPRETATION: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer is the sixth most common cancer worldwide: 295,414 new cases were diagnosed in 2018, with 184,799 deaths. The lack of an effective screening strategy has led to the majority of women being diagnosed at an advanced stage. For these women, intravenous carboplatin combined with paclitaxel for six cycles is widely accepted as the standard first-line treatment for epithelial ovarian cancer, in combination with debulking surgery. However, there is conflicting evidence regarding the optimal dosing schedule of paclitaxel when combined with carboplatin in this setting. OBJECTIVES: To compare the efficacy and tolerability of intravenous weekly paclitaxel with that of tri-weekly paclitaxel, in combination with intravenous carboplatin, as first-line treatment for epithelial ovarian cancer (defined as epithelial ovarian, primary peritoneal and fallopian tube cancer). SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase databases for relevant studies up to 15 November 2021, using keywords and MeSH terms. We additionally handsearched conference libraries, online clinical trial databases and screened through lists of retrieved references. SELECTION CRITERIA: We Included randomised controlled trials (RCTs) comparing weekly paclitaxel in combination with carboplatin versus tri-weekly paclitaxel in combination with carboplatin, for treatment of newly-diagnosed epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: We used the hazard ratio (HR) to estimate the primary efficacy outcomes progression-free (PFS) and overall survival (OS). We used the risk ratio (RR) to estimate the primary toxicity outcome of severe neutropenia and secondary outcomes of quality of life (QoL) and treatment-related adverse events. Two review authors independently selected studies, extracted data, and assessed risk of bias, using standard Cochrane methodological procedures. We included individual participant data (IPD) from one of the included studies, ICON-8, provided by the study team. We analysed data using a random-effects model in Review Manager 5.4 software. Additionally, we reconstructed IPD for PFS and OS data from published Kaplan-Meier curves from all studies and subsequently pooled these to analyse the two primary efficacy outcomes. MAIN RESULTS: From 2469 records, we identified four eligible RCTs with data for 3699 participants. All eligible studies were included in the main meta-analysis and reported on PFS and OS. There was likely a slight improvement in PFS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.89, 95% confidence interval (CI) 0.81 to 0.98; 4 studies, 3699 participants; moderate-certainty evidence). We found little to no improvement in OS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.92, 95% CI 0.79 to 1.06; 4 studies, 3699 participants; high-certainty evidence). There was likely little to no difference in high-grade (grade 3 or 4) neutropenia when paclitaxel was dosed weekly compared to tri-weekly (RR 1.11, 95% CI 0.86 to 1.43; 4 studies, 3639 participants; moderate-certainty evidence). However, weekly paclitaxel increased high-grade (grade 3 or 4) anaemia when compared to tri-weekly dosing (RR 1.57, 95% CI 1.12 to 2.20; 4 studies, 3639 participants; high-certainty evidence). There may be little to no difference in high-grade neuropathy when paclitaxel was dosed weekly compared to tri-weekly (RR 1.12, 95% CI 0.64 to 1.94; 4 studies, 3639 participants; low-certainty evidence). The overall risk of detection bias and performance bias was low for OS, but was unclear for other outcomes, as treatments were not blinded. The risk of bias in other domains was low or unclear. We note that OS data were immature for three of the included studies (GOG-0262, ICON-8 and MITO-7). AUTHORS' CONCLUSIONS: Weekly paclitaxel combined with carboplatin for first-line treatment of epithelial ovarian cancer likely improves PFS slightly (moderate-certainty evidence) but not OS (high-certainty evidence), compared to tri-weekly paclitaxel combined with carboplatin. However, this was associated with increased risk for high-grade anaemia, treatment discontinuation, dose delays and dose omissions (high- to low-certainty evidence). Our findings may not apply to women receiving bevacizumab in first-line therapy, those receiving treatment in the neo-adjuvant setting, or those with rare subtypes of clear cell or mucinous ovarian cancer.

Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.

BACKGROUND: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. METHODS: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. INTERPRETATION: The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. FUNDING: Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Testing approaches to sharing trial results with participants: The Show RESPECT cluster randomised, factorial, mixed methods trial.

BACKGROUND: Sharing trial results with participants is an ethical imperative but often does not happen. We tested an Enhanced Webpage versus a Basic Webpage, Mailed Printed Summary versus no Mailed Printed Summary, and Email List Invitation versus no Email List Invitation to see which approach resulted in the highest patient satisfaction with how the results were communicated. METHODS AND FINDINGS: We carried out a cluster randomised, 2 by 2 by 2 factorial, nonblinded study within a trial, with semistructured qualitative interviews with some patients (ISRCTN96189403). Each cluster was a UK hospital participating in the ICON8 ovarian cancer trial. Interventions were shared with 384 ICON8 participants who were alive and considered well enough to be contacted, at 43 hospitals. Hospitals were allocated to share results with participants through one of the 8 intervention combinations based on random permutation within blocks of 8, stratified by number of participants. All interventions contained a written plain English summary of the results. The Enhanced Webpage also contained a short video. Both the Enhanced Webpage and Email contained links to further information and support. The Mailed Printed Summary was opt-out. Follow-up questionnaires were sent 1 month after patients had been offered the interventions. Patients' reported satisfaction was measured using a 5-point scale, analysed by ordinal logistic regression estimating main effects for all 3 interventions, with random effects for site, restricted to those who reported receiving the results and assuming no interaction. Data collection took place in 2018 to 2019. Questionnaires were sent to 275/384 randomly selected participants and returned by 180: 90/142 allocated Basic Webpage, 90/133 Enhanced Webpage; 91/141 no Mailed Printed Summary, 89/134 Mailed Printed Summary; 82/129 no Email List Invitation, 98/146 Email List Invitation. Only 3 patients opted out of receiving the Mailed Printed Summary; no patients signed up to the email list. Patients' satisfaction was greater at sites allocated the Mailed Printed Summary, where 65/81 (80%) were quite or very satisfied compared to sites with no Mailed Printed Summary 39/64 (61%), ordinal odds ratio (OR) = 3.15 (1.66 to 5.98, p < 0.001). We found no effect on patient satisfaction from the Enhanced Webpage, OR = 1.47 (0.78 to 2.76, p = 0.235) or Email List Invitation, OR = 1.38 (0.72 to 2.63, p = 0.327). Interviewees described the results as interesting, important, and disappointing (the ICON8 trial found no benefit). Finding out the results made some feel their trial participation had been more worthwhile. Regardless of allocated group, patients who received results generally reported that the information was easy to understand and find, were glad and did not regret finding out the results. The main limitation of our study is the 65% response rate. CONCLUSIONS: Nearly all respondents wanted to know the results and were glad to receive them. Adding an opt-out Mailed Printed Summary alongside a webpage yielded the highest reported satisfaction. This study provides evidence on how to share results with other similar trial populations. Further research is needed to look at different results scenarios and patient populations. TRIAL REGISTRATION: ISRCTN: ISRCTN96189403.

Pollinator effectiveness is affected by intraindividual behavioral variation.

Variation in pollinator quality is fundamental to the evolution of plant-pollinator mutualisms and such variation frequently results from differences in foraging behavior. Surprisingly, despite substantial intraindividual variation in pollinator foraging behavior, the consequences for pollen removal and deposition on flowers are largely unknown. We asked how two pollen foraging behaviors of a generalist pollinator (Bombus impatiens) affect removal and deposition of heterospecific and conspecific pollen, key aspects of pollinator quality, for multiple plant species. In addition, we examined how bee body size and pollen placement among body parts shaped pollen movement. We manipulated foraging behavior types using artificial flowers, which donated pollen that captive bees then deposited on three recipient plant species. While body size primarily affected donor pollen removal, foraging behavior primarily affected donor pollen deposition. How behavior affected donor pollen deposition depended on the plant species and the quantity of donor pollen on the bee's abdomen. Plant species with smaller stigmas received significantly less pollen and fewer bees successfully transferred pollen to them. For a single plant species, heterospecific pollen interfered with conspecific pollen deposition, such that more heterospecific pollen on the bee's abdomen resulted in less conspecific pollen deposition on the flower. Thus, intraindividual variation in foraging behavior and its interaction with the amount and placement of acquired pollen and with floral morphology can affect pollinator quality and may shape plant fitness via both conspecific and heterospecific pollen transfer.

Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial.

BACKGROUND: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. METHODS: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018). INTERPRETATION: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial.

BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

Spatial, climate and ploidy factors drive genomic diversity and resilience in the widespread grass Themeda triandra.

Global climate change poses a significant threat to natural communities around the world, with many plant species showing signs of climate stress. Grassland ecosystems are not an exception, with climate change compounding contemporary pressures such as habitat loss and fragmentation. In this study, we assess the climate resilience of Themeda triandra, a foundational species and the most widespread plant in Australia, by assessing the relative contributions of spatial, environmental and ploidy factors to contemporary genomic variation. Reduced-representation genome sequencing on 472 samples from 52 locations was used to test how the distribution of genomic variation, including ploidy polymorphism, supports adaptation to hotter and drier climates. We explicitly quantified isolation by distance (IBD) and isolation by environment (IBE) and predicted genomic vulnerability of populations to future climates based on expected deviation from current genomic composition. We found that a majority (54%) of genomic variation could be attributed to IBD, while an additional 22% (27% when including ploidy information) could be explained by two temperature and two precipitation climate variables demonstrating IBE. Ploidy polymorphisms were common within populations (31/52 populations), indicating that ploidy mixing is characteristic of T. triandra populations. Genomic vulnerabilities were found to be heterogeneously distributed throughout the landscape, and our analysis suggested that ploidy polymorphism, along with other factors linked to polyploidy, reduced vulnerability to future climates by 60% (0.25-0.10). Our data suggests that polyploidy may facilitate adaptation to hotter climates and highlight the importance of incorporating ploidy in adaptive management strategies to promote the resilience of this and other foundation species.

Mediating engagement in a social network intervention for people living with a long-term condition: A qualitative study of the role of facilitation.

BACKGROUND: Successful facilitation of patient-centred interventions for self-management support has traditionally focussed on individual behaviour change. A social network approach to self-management support implicates the need for facilitation that includes an orientation to connecting to and mobilizing support and resources from other people and the local environment. OBJECTIVE: To identify the facilitation processes through which engagement with a social network approach to self-management is achieved. METHOD: Thematic analysis was used to analyse data from a longitudinal study design using quasi-ethnographic methods comprising non-participant observation, video and qualitative interviews involving 30 participants living with a long-term condition recruited from a marginalized community. RESULTS: Findings centred on three themes about the social network approach facilitation processes: reversing the focus on the self by bringing others into view; visualization and reflection as a mediator of positive disruption and linking to new connections; personalized matching of valued activities as a means of realizing preference elicitation. DISCUSSION AND CONCLUSIONS: Engagement processes with a social network approach illuminated the relevance of cognizance of an individual's immediate social context and forefronting social participation with others as the bases of self-management support of a long-term condition. This differs from traditional guided facilitation of health behaviour interventions that frame health as a matter of personal choice and individual responsibility.

Identifying the processes of change and engagement from using a social network intervention for people with long-term conditions. A qualitative study.

BACKGROUND: Personal and community networks are recognized as influencing and shaping self-management activities and practices. An acceptable intervention which facilitates self-management by mobilizing network support and improves network engagement has a positive impact on health and quality of life. This study aims to identify the processes through which such changes and engagement take place. METHODS: The study was conducted in the south of England in 2016-2017 and adopted a longitudinal case study of networks design. Purposive sample of respondents with long-term conditions (n = 15) was recruited from local groups. Barriers and facilitators to implementation were explored in interviews with key stakeholders (5). RESULTS: Intervention engagement leads to a deepening of relationships within networks, adding new links and achieving personal objectives relevant for improving the health and well-being of users and network members. Such changes are supported through two pathways: the mobilization of network capabilities and by acting as a nudge. The first is a gradual process where potentially relevant changes are further contemplated by forefronting immediate concerns and negotiating acceptable means for achieving change, prioritizing objective over subjective valuations of support provided by network members and rehearsing justifications for keeping the status quo or adopting change. The second pathway changes are enacted through the availability of a potential fit between individual, network and environmental conditions of readiness. CONCLUSIONS: The two pathways of network mobilization identified in this study illuminate the individual, network and environmental level processes involved in moving from cognitive engagement with the intervention to adopting changes in existing practice.

Genomic diversity guides conservation strategies among rare terrestrial orchid species when taxonomy remains uncertain.

Background and Aims: Species are often used as the unit for conservation, but may not be suitable for species complexes where taxa are difficult to distinguish. Under such circumstances, it may be more appropriate to consider species groups or populations as evolutionarily significant units (ESUs). A population genomic approach was employed to investigate the diversity within and among closely related species to create a more robust, lineage-specific conservation strategy for a nationally endangered terrestrial orchid and its relatives from south-eastern Australia. Methods: Four putative species were sampled from a total of 16 populations in the Victorian Volcanic Plain (VVP) bioregion and one population of a sub-alpine outgroup in south-eastern Australia. Morphological measurements were taken in situ along with leaf material for genotyping by sequencing (GBS) and microsatellite analyses. Key Results: Species could not be differentiated using morphological measurements. Microsatellite and GBS markers confirmed the outgroup as distinct, but only GBS markers provided resolution of population genetic structure. The nationally endangered Diuris basaltica was indistinguishable from two related species ( D. chryseopsis and D. behrii ), while the state-protected D. gregaria showed genomic differentiation. Conclusions: Genomic diversity identified among the four Diuris species suggests that conservation of this taxonomically complex group will be best served by considering them as one ESU rather than separately aligned with species as currently recognized. This approach will maximize evolutionary potential among all species during increased isolation and environmental change. The methods used here can be applied generally to conserve evolutionary processes for groups where taxonomic uncertainty hinders the use of species as conservation units.

Regional Genetic Structure and Environmental Variables Influence our Conservation Approach for Feather Heads (Ptilotus macrocephalus).

Continued alterations to the Australian environment compromise the long-term viability of many plant species. We investigate the population genetics of Ptilotus macrocephalus, a perennial herb that occurs in 2 nationally endangered communities on the Victorian Volcanic Plain Bioregion (VVP), Australia, to answer key questions regarding regional differentiation and to guide conservation strategies. We evaluate genetic structure and diversity within and among 17 P. macrocephalus populations from 3 regions of southeastern Australia using 17 microsatellite markers developed de novo. Genetic structure was present in P. macrocephalus between the 3 regions but not at the population level. Environmental factors, namely temperature and precipitation, significantly explained differentiation between the North region and the other 2 regions indicating isolation by environment. Within regions, genetic structure currently shows a high level of gene flow and genetic variation. Our results suggest that within-region gene flow does not reflect current habitat fragmentation in southeastern Australia whereas temperature and precipitation are likely to be responsible for the differentiation detected among regions. Climate change may severely impact P. macrocephalus on the VVP and test its evolutionary resilience. We suggest taking a proactive conservation approach to improve long-term viability by sourcing material for restoration to assist gene flow to the VVP region to promote an increased adaptive capacity.

Spatial genetic structure reflects extensive clonality, low genotypic diversity and habitat fragmentation in Grevillea renwickiana (Proteaceae), a rare, sterile shrub from south-eastern Australia.

BACKGROUND AND AIMS: The association of clonality, polyploidy and reduced fecundity has been identified as an extinction risk for clonal plants. Compromised sexual reproduction limits both their ability to adapt to new conditions and their capacity to disperse to more favourable environments. Grevillea renwickiana is a prostrate, putatively sterile shrub reliant on asexual reproduction. Dispersal is most likely limited by the rate of clonal expansion via rhizomes. The nine localized populations constituting this species provide an opportunity to examine the extent of clonality and spatial genotypic diversity to evaluate its evolutionary prospects. METHODS: Ten microsatellite loci were used to compare genetic and genotypic diversity across all sites with more intensive sampling at four locations (n = 185). The spatial distribution of genotypes and chloroplast DNA haplotypes based on the trnQ-rps16 intergenic spacer region were compared. Chromosome counts provided a basis for examining genetic profiles inconsistent with diploidy. KEY RESULTS: Microsatellite analysis identified 46 multilocus genotypes (MLGs) in eight multilocus clonal lineages (MLLs). MLLs are not shared among sites, with two exceptions. Spatial autocorrelation was significant to 1·6 km. Genotypic richness ranged from 0 to 0·33. Somatic mutation is likely to contribute to minor variation between MLGs within clonal lineages. The eight chloroplast haplotypes identified were correlated with eight MLLs defined by ordination and generally restricted to single populations. Triploidy is the most likely reason for tri-allelic patterns. CONCLUSIONS: Grevillea renwickiana comprises few genetic individuals. Sterility has most likely been induced by triploidy. Extensive lateral suckering in long-lived sterile clones facilitates the accumulation of somatic mutations, which contribute to the measured genetic diversity. Genetic conservation value may not be a function of population size. Despite facing evolutionary stagnation, sterile clonal species can play a vital role in mitigating ecological instability as floras respond to rapid environmental change.

Presence and Relevance of Myocardial Bridge in LAD-PCI of CTO and Non-CTO Lesions.

BACKGROUND: Intravascular ultrasound (IVUS) studies show that one-quarter of left anterior descending (LAD) arteries have a myocardial bridge. An MB may be associated with stent failure when the stent extends into the MB. OBJECTIVES: The aim of this study was to investigate: 1) the association between an MB and chronic total occlusion (CTO) in any LAD lesions; and 2) the association between an MB and subsequent clinical outcomes after percutaneous coronary intervention in LAD CTOs. METHODS: A total of 3,342 LAD lesions with IVUS-guided percutaneous coronary intervention (280 CTO and 3,062 non-CTO lesions) were included. The primary outcome was target lesion failure (cardiac death, target vessel myocardial infarction, definite stent thrombosis, and ischemic-driven target lesion revascularization). RESULTS: An MB by IVUS was significantly more prevalent in LAD CTOs than LAD non-CTOs (40.4% [113/280] vs 25.8% [789/3,062]; P < 0.0001). The discrepancy in CTO length between angiography and IVUS was greater in 113 LAD CTOs with an MB than 167 LAD CTOs without an MB (6.0 [Q1, Q3: 0.1, 12.2] mm vs 0.2 [Q1, Q3: -1.4, 8.4] mm; P < 0.0001). Overall, 48.7% (55/113) of LAD CTOs had a stent that extended into an MB after which target lesion failure was significantly higher compared to a stent that did not extend into an MB (26.3% vs 0%; P = 0.0004) or compared to an LAD CTO without an MB (26.3% vs 9.6%; P = 0.02). CONCLUSIONS: An MB was more common in LAD CTO than non-CTO LAD lesions. If present, approximately one-half of LAD CTOs had a stent extending into an MB that, in turn, was associated with worse outcomes.

Comparative evaluation of the effectiveness of intracanal and intraoral cryotherapy on postendodontic pain in patients with symptomatic apical periodontitis: A randomized clinical trial.

Introduction: There is a rising need for controlling postendodontic pain (PEP) without using analgesics and other conventional methods. Aims: The aim of the study is to compare the effectiveness of various cryotherapy applications on controlling PEP in patients with symptomatic apical periodontitis. Methods: One hundred and eight patients were selected and preoperative pain and pain on percussion scores were recorded using Numeric Rating Scale (NRS) and Visual Analog Scale (VAS), respectively. After obtaining consent, the access cavity was prepared under local anesthesia. After cleaning and shaping, the patients were randomized into the following groups: Group A: Canals were given final irrigation with 20 mL room temperature saline solution for 5 min, Group B: Canals were given final irrigation with 20 mL cold (2°C-4°C) saline solution for 5 min, and Group C: After obturation and restoration procedures, small ice packs of size 2 cm × 2 cm × 2.5 cm (wrapped in sterile gauze) were placed intraorally on the vestibular surface of the treated tooth. At 6 h, postoperative pain was measured using NRS and at 24 h, pain and pain on percussion were measured using NRS and VAS, respectively. Results: Data were analyzed using SPSS software. There was a significant reduction in postoperative pain in the intracanal and intraoral groups at 6 and 24 h when compared with the control group individually. There was no significant difference in postendodontic between intracanal and intraoral cryotherapy groups at 6 and 24 h. Conclusions: Both intracanal and intraoral cryotherapy applications are effective in reducing PEP in patients with symptomatic apical periodontitis.

Effect of Iontophoresis on the Effectiveness of Nano-Hydroxyapatite and Pro-argin in In-Office Treatment of Dentin Hypersensitivity: A Split-Mouth Randomized Clinical Trial.

Background and objectives Dentin hypersensitivity (DH) treatment is one of the main challenges dentists face in their daily clinical practice. Current therapies provide only temporary relief and require multiple applications to exhibit results, and there is a lack of evidence related to the long-term effects of these agents. Nano-hydroxyapatite (n-HA) and pro-argin (8.0% arginine-calcium carbonate) have recently been used for dentin desensitization with a one-time in-office application, but the effects are interim. However, a standard treatment protocol demands definitive or enduring results. Since iontophoresis amplifies the transport of neutral and ionized drugs across a membrane, the use of these desensitizing agents with iontophoresis may be beneficial to accomplish satisfactory results. This study was conducted to evaluate whether iontophoresis could enable better penetration of nano-hydroxyapatite and pro-argin into the dentin, enhancing and prolonging their therapeutic effect. Materials and methods Forty-five participants with dentin hypersensitivity in the age group of 20 to 60 years were included. In each individual, four teeth with cervical lesions (one from each quadrant) were selected and divided randomly into four groups: group I: desensitizing paste containing nano-hydroxyapatite, group II: desensitizing paste containing nano-hydroxyapatite with iontophoresis, group III: desensitizing paste containing pro-argin, and group IV: desensitizing paste containing pro-argin with iontophoresis; followed by one-time application of the agents. Sensitivity was assessed by tactile, air blast, and cold-graded thermal tests (CGTTs) before and immediately after application, after one week, and at the end of the first, third, and sixth months. Statistical analysis Statistical analysis was done by repeated measures ANOVA for within-group comparison. Intergroup comparison was done using one-way ANOVA and Tukey's post-hoc test. Results All the groups showed a statistically significant reduction in dentin hypersensitivity (p<0.001). The reduction in hypersensitivity in various groups can be graded as group II (3.578/1.800/1.556) > group IV (3.367/1.755/1.555) > group I (2.3781/1.022/0.822) > group III (2.222/0.911/0.778) as evaluated by tactile, air blast, and cold-graded thermal tests, respectively. Group II and group IV presented a significant reduction in sensitivity levels consistent for up to six months. Conclusion Nano-hydroxyapatite and pro-argin can be used effectively for reducing dentin hypersensitivity. Iontophoresis can be a valuable adjunct for their improved delivery, enhancing and prolonging their effectiveness.

Examining the optimal factors that promote implementation and sustainability of a network intervention to alleviate loneliness in community contexts.

Community environments have the potential to alleviate loneliness and social isolation as they offer opportunity for sociality and to expand personal social network connections. Implementing a social network intervention in community environments to connect people to who are at risk of loneliness or social isolation could help alleviate these concerns. However, implementing interventions in community environments is made difficult by the interplay between the community context and intervention. Thus, to support implementation a detailed understanding of the types of community contexts is required. To examine the optimal factors that promote the implementation of a social network designed to alleviate loneliness and social isolation intervention in the community observations, interviews and documentary analysis were conducted. The Consolidated Framework for Implementation Research and a typology of community contexts were used to inform the data analysis and interpret the findings. Key factors were found to affect the implementation of the intervention in the different community contexts. These inter-related factors operated across three domains. Service User Needs affected intervention take up as its suitability varied. The stability of the workforce and nature of everyday work also impacted on implementation. Finally, the fluctuating capacity of organisations and the organisational culture were also influential. No single community environment was found to have all of the optimal factors required for implementation and sustainably. The UK policy agenda of austerity had negatively affected community environments' capacity to deliver such intervention through increasing service user needs and reducing available resources. Trial registration: ISRCTN19193075.

Effect of low dose acetylsalicylic acid and anticoagulant on clinical outcomes in COVID-19, analytical cross-sectional study.

Background and aims: The therapeutic strategy for the treatment of known sequelae of COVID-19 has shifted from reactive to preventative. In this study, we aim to evaluate the effects of acetylsalicylic acid (ASA), and anticoagulants on COVID-19 related morbidity and mortality. Methods: This record-based analytical cross-sectional study targeted 539 COVID-19 patients in a single United States medical center between March and December 2020. Through a random stratified sample, we recruited outpatient (n = 206) and inpatient (n = 333) cases from three management protocols, including standard care (SC) (n = 399), low-dose ASA only (ASA) (n = 112), and anticoagulation only (AC) (n = 28). Collected data included demographics, comorbidities, and clinical outcomes. The primary outcome measure was inpatient admission. Exploratory secondary outcome measures included length of stay, 30-day readmission rates, medical intensive care unit (MICU) admission, need for mechanical ventilation, the occurrence of acute respiratory distress syndrome (ARDS), bleeding events, clotting events, and mortality. The collected data were coded and analyzed using standard tests. Results: Age, mean number of comorbidities, and all individual comorbidities except for asthma, and malignancy were significantly lower in the SC compared to ASA and AC. After adjusting for age and comorbidity via binary logistic regression models, no statistical differences were found between groups for the studied outcomes. When compared to the SC group, ASA had lower 30-day readmission rates (odds ration [OR] 0.81 95% confidence interval [CI] 0.35-1.88, p = 0.63), MICU admission (OR 0.63 95% CI 0.34-1.17, p = 0.32), ARDS (OR 0.71 95% CI 0.33-1.52, p = 0.38), and death (OR 0.85 95% CI 0.36-1.99, p = 0.71). Conclusion: Low-dose ASA has a nonsignificant but potentially protective role in reducing the risk of COVID-19 related morbidity and mortality. Our data suggests a trend toward reduced 30-day readmission rates, ARDS, MICU admissions, need for mechanical ventilation, and mortality compared to the standard management protocol. Further randomized control trials are needed to establish causal effects.