Continuous Arm Research Articles

Effects of continuous positive airway pressure on blood pressure in obstructive sleep apnea patients: The Apnea Positive Pressure Long‐term Efficacy Study (APPLES)

Obstructive sleep apnea is associated with hypertension, and short-term studies have demonstrated a modest reduction in blood pressure with continuous positive airway pressure therapy. We evaluated the effects of continuous positive airway pressure versus sham continuous positive airway pressure on blood pressure in 1,101 participants with obstructive sleep apnea from the Apnea Positive Pressure Long-term Efficacy Study, a randomized, sham-controlled double-blinded study designed to assess the impact of continuous positive airway pressure on neurocognition. Participants with apnea-hypopnea index ≥10 were randomly assigned to continuous positive airway pressure or sham continuous positive airway pressure. Blood pressures measured in the morning and evening at baseline, 2months and 6months were analysed post hoc using a mixed-model repeated-measures analysis of variance. The largest magnitude reduction was approximately 2.4mmHg in morning systolic pressure that occurred at 2months in the continuous positive airway pressure arm as compared with an approximate 0.5mmHg reduction in the sham group (continuous positive airway pressure effect -1.9mmHg, p=.008). At 6months, the difference between groups was diminished and no longer statistically significant (continuous positive airway pressure effect -0.9mmHg, p=.12). Sensitivity analysis with use of multiple imputation approaches to account for missing data did not change the results. Treatment with continuous positive airway pressure for obstructive sleep apnea reduces morning but not evening blood pressure in a population with well-controlled blood pressure. The effect was greater after 2 than after 6months of treatment.

Randomized, Open-Label, Multicenter, Phase 2 Study of Asciminib (ABL001) As an Add-on to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response with Frontline Imatinib

Background: In patients with chronic myeloid leukemia in chronic phase (CML-CP), the efficacy of ATP-competitive tyrosine kinase inhibitors (TKIs) has resulted in treatment-free remission (TFR) as a primary treatment goal for those with a sustained deep molecular response (DMR). However, most patients treated with imatinib fail to achieve a sustained DMR, meaning that they cannot benefit from TFR. Asciminib is a potent and specific inhibitor of BCR-ABL1. Unlike BCR-ABL1 TKIs that target the ATP binding site, asciminib binds to the myristate pocket of ABL1. Preclinical data showed that the combination of asciminib with ATP-competitive TKIs may provide more potent BCR-ABL1 inhibition and prevent emergence of resistance mutations (Wylie et al. Nature. 2017;543:733-737). In an ongoing phase 1 study (NCT02081378), asciminib demonstrated clinical activity and was well tolerated as a single agent (Hughes et al. Blood. 2016;128 [abstract 625]). In the same study, asciminib in combination with imatinib showed promising preliminary efficacy and a good safety profile in patients resistant/intolerant of ≥2 prior TKIs (Cortes et al. HemaSphere. 2019;3(S1) [abstract S388]). These findings informed the dose of asciminib to be further evaluated in combination with imatinib. An ongoing phase 3 study (NCT03106779) is evaluating asciminib vs bosutinib in patients previously treated with ≥2 ATP-binding site TKIs (Mauro et al. J Clin Oncol. 2019;37 [abstract TPS7070]). Here, we describe the ASCiminib add-on 4-arm study evaluating MOlecular REsponse (ASC4MORE) in patients. This is a phase 2 study evaluating the efficacy of adding asciminib to ongoing imatinib therapy in patients with CML-CP who have not achieved DMR with long-term frontline imatinib (CABL001E2201; NCT03578367). Methods: Study participants are aged ≥18 years, have CML-CP, and have been treated with frontline imatinib for ≥12 months. Study entry requires patients to be receiving imatinib 400 mg once daily (QD) at randomization, have BCR-ABL1 transcript levels in the range of ≤1% to >0.01% on the International Scale (IS), no prior achievement of MR4 (BCR-ABL1IS ≤0.01%) confirmed by two consecutive tests, and no prior treatment failure. Overall, ~80 patients will be randomized 1:1:1:1 to one of four arms (Figure): either asciminib 40 mg QD or 60 mg QD added to imatinib 400 mg QD; continued treatment with imatinib 400 mg QD; or switch to nilotinib 300 mg twice daily. Study treatment will continue until treatment resistance or intolerance, or up to 96 weeks after the last randomized patient has begun treatment. The primary objective of this study is to assess whether asciminib add-on to imatinib is more effective than imatinib continuation; the primary endpoint is the rate of MR4.5 (BCR-ABL1IS ≤0.0032%) at 48 weeks. Secondary objectives include: to estimate the efficacy of switch to nilotinib; to estimate the difference in efficacy between asciminib add-on to imatinib and switch to nilotinib; and to characterize the safety of asciminib add-on to imatinib. Exploratory objectives include TFR eligibility at the end of the study and patient-reported outcomes. Patients in the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross over to receive add-on asciminib. This study is ongoing, with 23 patients randomized as of 22 July 2019. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Geissler:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Amgen: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Biomarin: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; UCB: Consultancy, Speakers Bureau; Servier: Consultancy. Kapoor:Novartis: Employment. Longin:Novartis: Employment. Mukherjee:Novartis: Employment. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations.

In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population. To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime. Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207. Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission. These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

A Comparison of Two Methods of Catheter Management After Pelvic Reconstructive Surgery

To compare effects on activity between two catheter management systems after failed voiding trial after pelvic reconstructive surgery. Women with a failed postoperative voiding trial after reconstructive pelvic surgeries were randomized to plug-unplug or continuous drainage catheters. The primary outcome was a mean activity assessment scale score. Secondary outcomes included urinary tract infection (UTI), time to passing outpatient voiding trial, and patient satisfaction. Enrollees who passed the voiding trial were assigned to a "Reference" arm. Ninety participants (30 per arm) provided more than 80% power to detect an effect size of 0.33 in the primary outcome, using a two-sided alpha of 0.05. Sixty-three patients were randomized (32 plug-unplug, 31 continuous drainage). The first 30 participants discharged without a catheter comprised the reference arm. There was no difference in postoperative activity assessment scale scores (total: plug-unplug 70.3, continuous drainage 67.7, reference arm 79.4; P=.090) between arms. Women in the continuous drainage arm noted more difficulty compared with the plug-unplug arm when managing the catheter "during the day" (P=.043) and "all the time" (P=.049) and felt the catheter impeded activities (P=.012) and wearing clothes (P=.005). The catheter arms had significantly higher rates of culture-positive UTI compared with the reference arm (58.7% vs 6.7%, P<.001). However, rate of UTI did not differ between catheter arms (plug-unplug, 68.8% vs continuous drainage, 48.4%, P=.625). The majority of patients passed their outpatient voiding trials at the initial postoperative visit (plug-unplug 71.9%, continuous drainage 58.1%, P=.250). There was no difference in patient satisfaction, with the majority reporting they were "very satisfied" (plug-unplug 78.1%, continuous drainage 80.0%, reference 66.7%, P=.202). Postoperative activity does not differ in patients discharged with plug-unplug or continuous drainage catheters, but those with plug-unplug perceive easier management and ability to complete activities of daily living. The plug-unplug method is an acceptable alternative to traditional catheterization after pelvic reconstructive surgery. ClinicalTrials.gov, NCT03071211.

Genomics of Plant Disease Resistance in Legumes.

The constant interactions between plants and pathogens in the environment and the resulting outcomes are of significant importance for agriculture and agricultural scientists. Disease resistance genes in plant cultivars can break down in the field due to the evolution of pathogens under high selection pressure. Thus, the protection of crop plants against pathogens is a continuous arms race. Like any other type of crop plant, legumes are susceptible to many pathogens. The dawn of the genomic era, in which high-throughput and cost-effective genomic tools have become available, has revolutionized our understanding of the complex interactions between legumes and pathogens. Genomic tools have enabled a global view of transcriptome changes during these interactions, from which several key players in both the resistant and susceptible interactions have been identified. This review summarizes some of the large-scale genomic studies that have clarified the host transcriptional changes during interactions between legumes and their plant pathogens while highlighting some of the molecular breeding tools that are available to introgress the traits into breeding programs. These studies provide valuable insights into the molecular basis of different levels of host defenses in resistant and susceptible interactions.

LBA58 - BAROCCO: A randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)

BackgroundHypoxia induced by antiangiogenic agents could cause a functional impairment of homologous recombination, thus sensitizing wild-type (wt) BRCA tumor cells to PARP inhibition. In a phase II study the combination of cediranib-olaparib increased progression free survival (PFS) in women with recurrent platinum sensitive OC with respect to olaparib. Methods123 patients were allocated in a 1:1:1 ratio to receive: 80mg/m2 weekly paclitaxel up to 24 weeks (control), olaparib 600mg tablet (300mg twice daily) together with 20mg cediranib daily (continuous schedule) or 20mg cediranib given 5 days/week (intermittent schedule) until progression. PFS comparison between experimental schedules and the control arm (alpha one-sided 5%; power 80% to detect a HR of 0.5) was the primary objective. ResultsMedian platinum-free interval was 1.8 mos, 59% of patients were pretreated with >3 chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.7, and 3.8 mos. Estimated HR for PFS in continuous arm vs control was 0.76 (90% CI: 0.49-1.17), p=0.28 by log-rank test. HR for PFS in intermittent arm vs. control was 1.08 (90% CI: 0.71-1.64), p=0.76 by log-rank test. In the subgroup gBRCA wt (n=109) the median PFS for paclitaxel, the continuous, and the intermittent schedules were 2.1, 5.8 and 3.8 mos and HR for PFS in continuous arm vs control was 0.63 (95% CI: 0.36 to 1.10; p=0.10). The toxicity profile of the study arms was as expected and similar between experimental arms. 11%, 18%, and 7% in control, continuous and intermittent arm discontinued treatment for adverse events. Five serious adverse drug reactions occurred and two of these were fatal: one in the control and one in the continuous arm. ConclusionsThe combination of cediranib and olaparib is effective in heavily pretreated PROC patients with the advantage of an oral administration and good tolerability. The continuous schedule of cediranib-olaparib showed a promising trend towards improved PFS in comparison with weekly paclitaxel particularly in the BRCA wt population. Clinical trial identificationIRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740. Legal entity responsible for the studyIstituto di Ricerche Farmacologiche Mario Negri IRCCS. FundingAstraZeneca. DisclosureN. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: BioCad; Advisory / Consultancy: Takeda. G. Tognon: Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Tesaro. M. Ratti: Travel / Accommodation / Expenses: Tesaro Bio. All other authors have declared no conflicts of interest.

573P - Randomized phase II trial of CAPOX with planned oxaliplatin stop-and-go strategy as adjuvant chemotherapy after curative resection of colon cancer (CCOG-1302 study)

BackgroundThe aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. MethodsPatients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. ResultsA total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p=0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p<0.001). The frequencies ofPSF lasting for 1-year and 3-year were 61% and 30% vs. 21% and 6%, respectively. ConclusionsCAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification000012535 (09/December/2013). Legal entity responsible for the studyYasuhiro Kodera (Chubu Clinical Oncology Group, Japan). FundingChubu Clinical Oncology Group. DisclosureAll authors have declared no conflicts of interest.

Effect of Exercise Mode and Intensity on Subsequent Postprandial Carbohydrate and Fat Metabolism in Persons with Spinal Cord Injury

PURPOSE: To determine the effects of pre-meal exercise mode and/or intensity on postprandial energy expenditure, substrate partitioning, and blood substrate and hormone concentrations in persons with spinal cord injury (SCI). METHODS: Nine adult men with chronic (≥1 yr) thoracic SCI consented to participation. Following assessment of neuromuscular strength and cardiorespiratory fitness, participants completed four experimental trials. On the first trial before the meal, participants completed ~42.5 min of circuit resistance exercise (CRT). The CRT energy cost was measured and subsequent exercise trials were designed to be isocaloric. Participants then completed seated control (CON), high intensity interval arm cycling (HIIT), and moderate intensity continuous arm cycling (MICT) trials in randomized order. Immediately after exercise or sitting, trial participants consumed a liquid mixed meal. During exercise and for 150 min following the meal, expired gases were collected continuously and analyzed via indirect calorimetry and blood samples were taken every 30 min. RESULTS: Participants exercised at 52±6, 53±7, and 65±5 %VO2peak for a cost of 120±19, 120±22, and 122±33 kcal during MICT, CRT, and HIIT, respectively. Only CRT appeared to have an elevated EE at 150 min post-exercise (1.43±0.15 vs 1.34-1.32 kcal·min-1 in other conditions). The greatest increases in accumulated whole-body fat oxidation during recovery were seen in CRT and HIIT (15.1±3.2 and 13.3±4.8 g·150 min-1, respectively) compared to MICT and CON (11.9±4.7 and 10.6±4.1 g·150 min-1, respectively). As with energy expenditure, only CRT appeared to have elevated fat oxidation at 150 min post-exercise (83.1±19.1 vs 64.8-67.9 mg·min-1 in other conditions). In accordance, integrated area under the curve (iAUC) of blood triglyercides and glycerol was lowest and highest, respectively, in CRT. Blood glucose was similar in all conditions, but CRT showed the lowest iAUC for insulin. CONCLUSIONS: Pre-meal exercise changed postprandial energy metabolism in persons with SCI. Independent of exercise energy expenditure, intensity is an important determinant of post-exercise energy expenditure. Furthermore, exercise mode incorporating resistance and high intensity exercise appears to stimulate greater fat oxidation during recovery.

Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in patients with advanced triple-negative breast cancer.

1066 Background: PD-1/PD-L1 blockade monotherapy delivered positive outcomes in early-phase trials in advanced triple-negative breast cancer (TNBC). However, t he highest objective response rate (ORR) is 18.5%. IMPassion130 trial has demonstrated that only PD-L1+ TNBC had overall survival benefit from anti-PD-L1 antibody combined with chemotherapy. Preclinical studies found that antiangiogenic therapy could sensitize anti-PD-1 treatment via inducing PD-L1 expression and increasing CTLs infiltration in tumor microenvironment. Thus, we designed a phase II, open-label trial (NCT03394287) of SHR-1210 (anti-PD-1 antibody) in combination with apatinib (VEGFR2 inhibitor) in patients with advanced TNBC. Methods: 20-58 advanced TNBC patients whose systemic therapy lines in the metastatic setting was less than 3, will be randomly (1:1) enrolled from Sun Yat-sen Memorial Hospital to receive either SHR-1210 200mg Q2W plus apatinib 250mg, continuous dosing (d1-d14), or SHR-1210 200mg Q2W plus apatinib 250mg, intermittent dosing (d1-d7), until progression or unacceptable toxicities. Primary endpoint was ORR. Secondary end points included PFS, DCR, TTR, DoR, CBR, one year-OS and toxicity. Results: Until Jan 30, 2019, 34 patients were enrolled, 10 in the intermittent dosing arm, and 24 in the continuous dosing arm. 26 (76.5%) patients had prior systemic therapy in the metastatic setting. At the cutoff date (Jan 30, 2019), 28 patients were evaluable for ORR as per RECIST. The ORR was 47.4% (9 of 19) in the continuous dosing cohort, and no confirmed objective response was found in the intermittent dosing arm. The DCR was 68.4% in the continuous dosing arm, whereas it was 44.4% in the other arm. The median PFS was 2 months in the intermittent dosing cohort, while it was not reached in the continuous dosing cohort. The most common adverse events (AEs) was fatigue (65.0%), hand-foot syndrome (63.3%), and elevated aspartate aminotransferase and/or alanine aminotransferase (73.3%). There were no treatment-related deaths. Another 5 patients will be enrolled into the continuous dosing arm because of its favorable response. Conclusions: Anti-PD-1 antibody SHR-1210 combined with apatinib demonstrates favorable clinical activity and a manageable safety profile in patients with advanced TNBC. Clinical trial information: NCT03394287.

SAT-LB022 Effects of Intermittent Versus Continuous Phentermine Therapy on Weight Reduction and Inflammatory Markers in Obese Non-diabetic Patients

Introduction: Intermittent phentermine therapy has been proposed as an alternative to overcome tolerance associated with continuous daily use of phentermine to promote greater weight loss. Aim: To compare the effects of intermittent versus continuous phentermine therapy on weight reduction, cardiometabolic profile, inflammatory and anti-inflammatory markers in obese non-diabetic patients. Methods: Non-diabetic obese adults [body mass index (BMI) 27.5 to 35kg/m2] were recruited from obesity clinic. Eligible subjects were randomized to receive either continuous phentermine (30mg daily) or intermittent phentermine therapy (30mg daily for 4 weeks alternate with 2 weeks of treatment-free periods) for a total of 24 weeks, in addition to lifestyle modification (comprising of calorie restriction of 1200 kcal per day and at least 150 minutes per week of moderate intensity exercise). Primary endpoints were change in body weight from baseline as well as proportion of subjects losing at least 5% and 10% of baseline body weight at week 24 respectively. Results: Thirty-eight subjects [86.8% females, median age 36.5 years (interquartile range, IQR 32, 41.3), BMI 31.8kg/m2 (IQR 30.4, 33.4) and waist circumference 94.9cm (IQR 90.2, 99.1)] were randomised to either continuous (n=19) or intermittent phentermine arm (n=19). Fourteen subjects in the former and all in the latter completed the study. There were no significant differences in the degree of weight reduction [ - 7.3 kg (IQR - 10.1, - 3.4) vs - 9.7 kg (IQR -11.2, -7.2), p=0.10] as well as the proportion of subjects who achieved at least 5% and 10% of weight loss (78.9% vs 94.7%, p=0.34; 47.4% vs 73.7%, p=0.18 respectively) at week 24 in both arms. Nonetheless, intermittent phentermine therapy resulted in greater decrease in waist circumference while continuous phentermine therapy produced greater reduction in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP). Both regimes reduced the prevalence of insulin resistance and showed no difference in reduction of the proportion of subjects with high cardiovascular risk (as defined by hsCRP > 3mg/L). No significant between-group differences were seen in changes of blood pressure, pulse rate, glycaemic indices, lipids, adiponectin, binge eating scale scores and 36-item Short Form Survey version 2 (SF-36v2) scores. The most common side effects were dry mouth and insomnia. There was no difference in the occurrence of adverse events between the 2 treatment arms. Conclusion: Intermittent phentermine therapy is as effective as conventional daily phentermine treatment in promoting weight reduction while having similar side effect profile. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Efficacy of Rilpivirine-Based Regimens as Switch Therapy From Nevirapine-Based Regimens in Human Immunodeficiency Virus-Infected Patients With Virological Suppression: A Randomized Controlled Trial

BackgroundNevirapine (NVP)-based antiretroviral therapy continues to be used in some human immunodeficiency virus (HIV)-infected patients. Rilpivirine (RPV) could be used as an alternative to NVP. We studied the efficacy of RPV-based regimens as switch therapy.MethodsA randomized controlled noninferiority trial was conducted in HIV-infected patients who received NVP-based regimens and had undetectable plasma viral loads (VLs). Patients were randomized to a continuation arm (NVP was continued) or a switch arm (NVP was switched to RPV). Tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine were the backbone of the regimens. The primary endpoint was an HIV VL <40 copies/mL at week 48.ResultsA total of 106 patients were enrolled, 55 patients were in the continuation arm and 51 patients were in the switch arm. The mean (standard deviation) age was 49.1 (9.2) years and 51.9% were females. The median (interquartile range) baseline CD4 count was 561 (443–732) cells/mm3. At week 48, 52 patients (94.6%) in the continuation arm and 50 patients (98.0%) in the switch arm had an HIV VL <40 copies/mL, with an efficacy difference of 3.5% (95% confidence interval [CI], −13.0 to 5.6; P = .619). Decreases in total cholesterol and triglyceride were observed in the switch arm (−17.1 mg/dL, 95% CI = −29.7 to −4.4, P = .008 and −36.0 mg/dL, 95% CI = −71.0 to −1.1, P = .044, respectively).ConclusionsSwitching from NVP to RPV can maintain virological suppression and decrease total cholesterol and triglyceride at week 48. In patients virologically suppressed with NVP-based regimens, RPV-based regimens can be a switch option.

Interrupted Midline Fascial Closure to Prevent Burst Abdomen in Emergency Laparotomy: Comparison between Continuous and Interrupted closure

Burst abdomen represents one of the most frustrating and difficult postoperative complication that concerns every abdominal surgeon. It occurs because of various predisposing factors which can be prevented to some extend by having knowledge regarding them. Despite many years of experience, the optimal technique of laparotomy closure remains controversial. The varieties of surgical excess as well as the varieties of abdominal closure techniques are the main difficulties in the proper standardization of this procedure. In this paper a randomized prospective study was designed to compare with a interrupted and continuous technique for closing a midline abdominal fascia in emergency laparotomy. A total of 300 patients of acute abdominal condition who underwent laparotomy were randomized into two groups of 150 patients in each group. Total 22(7.33%) of 300 patients developed burst in the postoperative period. Fourteen (14) (9.33%) in continuous arms and eight (08) (5.33%) patients in interrupted arms developed burst. Burst abdomen occurring mostly 40-60 years age group with a male to female ratio of 1.68: 1. Cough, anemia, malnutrition, DM, intraperitoneal sepsis, wound infection, uremia and abdominal distension were the important predisposing factors for the incidence of burst abdomen. Interrupted suturing was associated with significantly reduced the burst abdomen when comparing with continuous closure.TAJ 2017; 30(2): 69-75

Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study

Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study

An efficient motion generation method for redundant humanoid robot arms based on motion continuity

ABSTRACTThis paper proposes a novel method of motion generation for redundant humanoid robot arms, which can efficiently generate continuous collision-free arm motion for the preplanned hand trajectory. The proposed method generates the whole arm motion first and then computes the actuators’ motion, which is different from IK (inverse kinematics)-based motion generation methods. Based on the geometric constraints of the preplanned trajectory and the geometric structure of humanoid robot arms, the wrist trajectory and elbow trajectory can be got first without solving inverse kinematics and forward kinematics. Meanwhile, the constraints restrict all feasible arm configurations to an elbow-circle and reduce the arm configuration space to a two-dimension space. By combining the configuration space and collision distribution of arm motion, collision-free arm configurations can be identified and be used to generate collision-free arm motion, which can avoid unnecessary forward and inverse kinematics. The experiments show that the proposed method can generate continuous and collision-free arm motion for preplanned hand trajectories.

Continuous Arm Gesture Recognition Based on Natural Features and Logistic Regression

In this paper, we propose a new gesture modeling method by combining natural features with logistic regression to recognize continuous natural gestures, which is considered as a challenge. Instead of manually modeling gestures with criteria, gesture models can be derived from a few gesture instances. Arm gestures are modeled with three types of intuitive features, and logistic regression is employed to obtain the optimal weights to linearly combine all the features, which can deal with the differences among instances with the same gesture automatically and facilitate distinguishing different gestures, and as a result, improve the recognition accuracy. With these features, numbers of natural arm gestures can be modeled with good comprehensibility. To evaluate our method, we defined twelve natural gestures, including three static gestures and nine dynamic gestures. A continuous gesture database which includes 154024 data frames (102 minutes) and 1628 gesture instances was collected from 10 subjects with a wearable multi-IMU sensing system. Both subject-dependent and subject-mixed recognition tests were conducted with the database. In the subject-dependent test, models were trained with about 30% data, and the average accuracy over all subjects was 91.54%. In the subject-mixed test, only about 10% data was used for training, and the accuracy is 88.75%. The recognition accuracy is highly competitive with previous gesture recognition approaches.

Intermittent versus continuous first-line treatment for HER2-negative metastatic breast cancer: the Stop & Go study of the Dutch Breast Cancer Research Group (BOOG).

We determined if intermittent first-line treatment with paclitaxel plus bevacizumab was not inferior to continuous treatment in patients with HER2-negative, advanced breast cancer. Patients were randomized to 2 × 4 cycles or continuous 8 cycles of paclitaxel plus bevacizumab, followed by bevacizumab maintenance treatment until disease progression or unacceptable toxicity. The primary endpoint was overall progression-free survival (PFS). A proportional-hazards regression model was used to estimate the HR. The upper limit of the two-sided 95% CI for the HR was compared with the non-inferiority margin of 1.34. A total of 420 patients were included with well-balanced characteristics. In the intention-to-treat analysis, median overall PFS was 7.4months (95% CI 6.4-10.0) for intermittent and 9.7 months (95% CI 8.9-10.3) for continuous treatment, with a stratified HR of 1.17 (95% CI 0.88-1.57). Median OS was 17.5 months (95% CI 15.4-21.7) versus 20.9 months (95% CI 17.8-24.0) for intermittent versus continuous treatment, with a HR of 1.38 (95% CI 1.00-1.91). Safety results and actually delivered treatments revealed longer durations of treatment in the continuous arm, without significant unexpected findings. Intermittent first-line treatment cannot be recommended in patients with HER2-negative advanced breast cancer. EudraCT 2010-021519-18; BOOG 2010-02.

Mass azithromycin distribution for hyperendemic trachoma following a cluster-randomized trial: A continuation study of randomly reassigned subclusters (TANA II).

BackgroundThe World Health Organization recommends annual mass azithromycin administration in communities with at least 10% prevalence of trachomatous inflammation–follicular (TF) in children, with further treatment depending on reassessment after 3–5 years. However, the effect of stopping mass azithromycin distribution after multiple rounds of treatment is not well understood. Here, we report the results of a cluster-randomized trial where communities that had received 4 years of treatments were then randomized to continuation or discontinuation of treatment.Methods and findingsIn all, 48 communities with 3,938 children aged 0–9 years at baseline in northern Ethiopia had received 4 years of annual or twice yearly mass azithromycin distribution as part of the TANA I trial. We randomized these communities to either continuation or discontinuation of treatment. Individuals in the communities in the continuation arm were offered either annual or twice yearly distribution of a single directly observed dose of oral azithromycin. The primary outcome was community prevalence of ocular chlamydial infection in a random sample of children aged 0–9 years, 36 months after baseline. We also assessed the change from baseline to 36 months in ocular chlamydia prevalence within each arm. We compared 36-month ocular chlamydia prevalence in communities randomized to continuation versus discontinuation in a model adjusting for baseline ocular chlamydia prevalence. A secondary prespecified analysis assessed the rate of change over time in ocular chlamydia prevalence between arms. In the continuation arm, mean antibiotic coverage was greater than 90% at all time points. In the discontinuation arm, the mean prevalence of infection in children aged 0–9 years increased from 8.3% (95% CI 4.2% to 12.4%) at 0 months to 14.7% (95% CI 8.7% to 20.8%, P = 0.04) at 36 months. Ocular chlamydia prevalence in communities where mass azithromycin distribution was continued was 7.2% (95% CI 3.3% to 11.0%) at baseline and 6.6% (95% CI 1.1% to 12.0%, P = 0.64) at 36 months. The 36-month prevalence of ocular chlamydia was significantly lower in communities continuing treatment compared with those discontinuing treatment (P = 0.03). Limitations of the study include uncertain generalizability outside of trachoma hyperendemic regions.ConclusionsIn this study, ocular chlamydia infection rebounded after 4 years of periodic mass azithromycin distribution. Continued distributions did not completely eliminate infection in all communities or meet WHO control goals, although they did prevent resurgence.Trial registrationThis study was prospectively registered at clinicaltrials.gov (clinicaltrials.gov NCT01202331).

Abstract A072: Serum sex steroids as prognostic biomarkers in patients receiving androgen-deprivation therapy for recurrent prostate cancer post-radiotherapy: A post hoc analysis of the PR.7 trial

Abstract Background and Objective: Nadir testosterone values following initiation of androgen deprivation therapy have been shown in several studies to be prognostic for outcome, including time to castration-resistant prostate cancer (TTCRPC) and cancer specific survival (CSS). The biologic reasons for this remain unclear. Using cryopreserved serum from the PR.7 trial of intermittent vs. continuous androgen deprivation therapy(ADT), we determined to assess the role of related sex steroids as prognostic biomarkers in men on androgen deprivation therapy for recurrent cancer post-radiotherapy. Patients and Methods: Canadian patients in the PR.7 trial randomized to the continuous arm were included. Patients were excluded who did not receive ADT(n=3), had &amp;lt;2 years of follow-up (n=2), received exogenous estrogens or glucocorticoids(n=5), or samples were unavailable(n=36). LC-MS/MS was performed using a validated method to simultaneously analyze ten steroids: dehydroepiandrosterone (DHEA), testosterone (T), dihydrotestosterone (DHT), androst-5-ene-β,17β-diol (5-diol), androstenedione (4-dione), androsterone (AD), estrone (E1), estradiol (E2), progesterone, and androstane-3β,17β-diol (3βdiol). Descriptive statistics and correlation analyses were performed, with longitudinal changes categorized as stable, increasing, decreasing, or mixed. The prognostic value of individual steroid tertiles as well as E1:E2, E2:T, and DHT:T ratios were assessed by Kaplan-Meier analysis and Cox proportional hazards adjusted for baseline clinical variables. Outcomes assessed were TTCRPC, CSS, and overall survival (OS). Results: A total of 219 patients were included in the analysis who had a cryopreserved serum available within 2 years of randomization, with 104 patients having 2 subsequent annual samples available for measurement. Values for DHT, T, 4-dione, AD, DHEA, and 5-diol tended to be correlated among samples. Lower DHEA and AD values were significant associated with older age as was lower DHEA and DHT values with poorer performance status. Higher tertiles of E1 and E2 were associated with sooner TTCRP (log-rank, p=0.03, p=0.02, respectively). Similar trends were seen for 4-dione in predicting TTCRPC (log-rank, p=0.07). Upon adjustment, the highest tertile of E2:T had increased hazard ratios (HR) for CSS (HR=2.36, 95% CI I: 0.90-6.21; p=0.08) and TTCRPC (HR=1.70, 95% CI: 0.90-3.23; p=0.10) relative to the lowest tertile. In an analysis of the subset of patients with longitudinal values, increasing levels of AD over time were associated with poorer CSS and OS (log-rank: p=0.04 and p &amp;lt;0.01, respectively). On adjusted analysis, increasing AD levels had a HR for CSS of 3.43 (95% CI: 0.63-18.67; p=0.15) and a HR for OS of 4.75 (95% CI: 1.49-15.17; p &amp;lt;0.01). Limitations include the number of events for some groups. Conclusions: Increased levels of E1, E2, and AD during ADT correlated with adverse TTCRPC and CSS. Serum sex steroids, including both androgens and estrogens, may act as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Further investigation is warranted to support clinical use. Citation Format: Paul Toren, Azik Hoffman, Keyue Ding, France-Hélène Joncas, Frédéric Pouliot, Yves Fradet, Éric Lévesque, Chantal Guillemette, Laurence Klotz. Serum sex steroids as prognostic biomarkers in patients receiving androgen-deprivation therapy for recurrent prostate cancer post-radiotherapy: A post hoc analysis of the PR.7 trial [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A072.

Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2).

Guidelines recommend warfarin continuation rather than heparin bridging for pacemaker and defibrillator surgery, after the BRUISE CONTROL trial demonstrated an 80% reduction in device pocket haematoma with this approach. However, direct oral anticoagulants (DOACs) are now used to treat the majority of patients with atrial fibrillation. We sought to understand the best strategy to manage the DOACs at the time of device surgery and specifically hypothesized that performing device surgery without DOAC interruption would result in a reduced haematoma rate. We randomly assigned patients with atrial fibrillation and CHA2DS2-VASc score ≥2, to continued vs. interrupted DOAC (dabigatran, rivaroxaban, or apixaban). The primary outcome was blindly evaluated, clinically significant device pocket haematoma: resulting in re-operation, interruption of anticoagulation, or prolonging hospital stay. In the continued arm, the median time between pre- and post-operative DOAC doses was 12 h; in the interrupted arm the median time was 72 h. Clinically significant haematoma occurred in of 7 of 328 (2.1%; 95% CI 0.9-4.3) patients in the continued DOAC arm and 7 of 334 (2.1%; 95% CI 0.9-4.3) patients in the interrupted DOAC arm (P = 0.97). Complications were uncommon, and included one stroke and one symptomatic pericardial effusion in each arm. These results suggest that, dependent on the clinical scenario, either management strategy (continued DOAC or interrupted DOAC) might be reasonable, at least for patients similar to those enrolled in our trial.

A randomized trial comparing the pharmacology of magnesium sulfate when used to treat severe preeclampsia with serial intravenous boluses versus a continuous intravenous infusion

BackgroundMagnesium sulfate is the preferred pharmacological intervention for the prevention and treatment of eclamptic seizures in pregnancy. Pain associated with intramuscular injections and the need for an electronic infusion pump for use intravenously represent significant barriers to broader utilization. We hypothesize that an alternative regimen based on serial intravenous (IV) boluses can produce serum concentrations comparable to those produced by a continuous infusion.MethodsAn open-label randomized trial was performed at two hospitals in Egypt. Women with severe preeclampsia were eligible and enrolled between January 2015 and February 2016. Two hundred subjects were randomized by random numbers generated centrally in distinct blocks and stratified by study site. They were assigned to a continuous infusion arm, (4 g loading dose with 1 g/hr. continuous infusion) or a serial IV bolus arm, (6 g loading dose with 2 g bolus every 2 h using a Springfusor® pump). Sparsely sampled magnesium serum concentrations were collected, nonlinear mixed effect modeling was conducted and Monte Carlo simulations were used to generate 200 simulated subjects in each treatment arm. The simulated populations were used to determine area under the concentration-time curve (AUC) as a measure of total drug exposure and compared.ResultsSimulated area under the magnesium serum concentration-time curve was significantly higher in the serial IV bolus arm than in the continuous infusion arm (1107 ± 461 mmol•min /L vs. 1010 ± 398 mmol•min /L, (P = 0.02)). Four percent of women in the serial bolus arm considered the treatment unacceptable or very unacceptable compared to 2% in the continuous infusion arm, (P = 0.68).ConclusionsSerial IV boluses achieve serum magnesium concentrations statistically significantly higher but clinically comparable to those achieved with a continuous infusion and offer a third option for the administration of MgSO4 to women with preeclampsia that may reduce barriers to utilization.Trial registrationTrial no. NCT02091401, March 17, 2014.