Research on scheduling problems is an evergreen challenge for industrial engineers. The growth of digital technologies opens the possibility to collect and analyze great amount of field data in ...real-time, representing a precious opportunity for an improved scheduling activity. Thus, scheduling under uncertain scenarios may benefit from the possibility to grasp the current operating conditions of the industrial equipment in real-time and take them into account when elaborating the best production schedules. To this end, the article proposes a proof-of-concept of a simheuristics framework for robust scheduling applied to a Flow Shop Scheduling Problem. The framework is composed of genetic algorithms for schedule optimization and discrete event simulation and is synchronized with the field through a Digital Twin (DT) that employs an Equipment Prognostics and Health Management (EPHM) module. The contribution of the EPHM module inside the DT-based framework is the real time computation of the failure probability of the equipment, with data-driven statistical models that take sensor data from the field as input. The viability of the framework is demonstrated in a flow shop application in a laboratory environment.
Bone screws are used in almost every orthopaedic surgery to treat and fix fractured parts of the bone. In this new era, the ongoing revolution on manufacturing of bone screw uses innovative ...techniques of new generation such as the adaptation of additive manufacturing technology, intelligent technology automation and Industry 4.0. Additive manufacturing (AM) technology has been gaining much attention in fabricating orthopaedic bone screws. Moreover, the recent advancement in the materials and technologies used to manufacture the bone screw utilizing AM technology may reduce bone-screw-related complications. This review article presents a comprehensive and up-to-date review of various AM techniques used to fabricate metallic orthopaedic bone screws. Additionally, this article summarizes the characteristics, merits and demerits of the prominent biomaterials explored to fabricate orthopaedic bone screws until the twenty-first century. This state-of-the-art review is helpful for medical surgeons, researchers and design engineers to understand the complicated relationship among various parameters. Finally, this holistic review paper identifies significant challenges that need to be overcome before realizing the real potential of AM technology for fabrication of orthopaedic bone screws.
About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with ...treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
Objectives: This literature review seeks to identify based on the current literature how the burden of disease for IBD patients manifests itself as this cohort transitions simultaneously from ...pediatric to adult care and from secondary to post-secondary education. Methods: This paper reviews the current literature regarding postsecondary students with IBD and provides a summary of research regarding key factors in their quality of experience. The research was conducted through databases including Taylor & Francis, PubMed, as well as searches via Google Scholar. Results: Over the course of this search, thirty-three relevant studies were identified. These studies addressed the themes outlined in this paper, including academic performance, social adaptation, transition of care, as well as overall transition to a postsecondary institution. Each of these is further broken down to identify specific determinants of IBD student experience. Conclusions: Although students with IBD can demonstrate resilience and adaptive behavior, the evidence suggests there are significant limitations impacting their perceived experience. The barriers IBD students face impact their ability to experience postsecondary education as they intend to, forcing them to adjust in adaptive or maladaptive manners. This review also attempts to generate possible solutions to specific barriers identified from current research, generating directions of action for students, physicians, and academic supports.
Abstract Background The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant ...depression (TRD). Methods This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery–Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. Results Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery–Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were −16.8 (3.00) and −16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (−3.8 2.97). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. Conclusions A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-min IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy.
Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.
To assess the efficacy, safety, and dose-response of intranasal esketamine ...hydrochloride in patients with treatment-resistant depression (TRD).
This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.
In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.
The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
Sixty-seven participants (38 women, mean SD age, 44.7 10.0 years) were included in the efficacy and safety analyses. Change (least squares mean SE difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 2.09, P = .02; 56 mg: -6.3 2.07, P = .001; 84 mg: -9.0 2.13, P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 1.84) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).
In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.
clinicaltrials.gov identifier: NCT01998958.
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.
To assess the efficacy of esketamine nasal ...spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.
Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.
Among the 297 adults (mean age SD, 46.3 11.13 years; 197 66.3% female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat NNT, 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio HR, 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.
For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.
ClinicalTrials.gov identifier: NCT02493868.
About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.
This Phase 3, ...double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine 56 or 84 mg or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.
Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares LS means difference 95% CI: -3.2 -6.88, 0.45; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 -7.67, -0.49 (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.
Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.
ClinicalTrials.gov identifier: NCT02417064.
Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the ...efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.
In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).
In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 SD=12.8 on day 4; thrice-weekly, -14.0 SD=12.5 on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.
Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.
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