Discontinuous Strategy Research Articles

Real-life, long-term data on efficacy, safety, response and discontinuation patterns of omalizumab in a Greek population with chronic spontaneous urticaria.

Omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) not responding to antihistamines. Data on omalizumab use in real-world settings and in different populations are lacking. To record our five-year experience of omalizumab use in patients with refractory CSU in a real-world setting. A retrospective analysis of medical records of 80 patients with refractory CSU was performed. Demographic, and clinical characteristics, patterns of response, discontinuation strategies and rate of recurrence were analysed. Eighty individuals were included. UAS7 and DLQI significantly decreased from baseline. Complete response was achieved in 86.3%. Late response was observed at 27.5% of the patients. After discontinuation, 21.7% of patients reinitiated omalizumab due to relapse. The mean number of omalizumab administrations up to first discontinuation was 6.8 (based on an approach to shorten the treatment interval). Only 15.0% of patients experienced adverse events during treatment. Omalizumab, with long-term management, was highly effective and safe in achieving control of refractory CSU, with more favourable responses compared to Phase III clinical trials.

Carrier-Based Generalized Discontinuous PWM Strategy for Single-Phase Three-Legs Active Power Decoupling Converters

Three-legs active power decoupling (APD) converters are widely studied in the single-phase grid-connected systems to enhance the circuit lifetime by creating an alternative path for the typical existing dc-side power pulsating ripple. Therefore, this reduces the requirement of smoothing dc capacitors allowing compact designs even with the implementation of long life metalized film technology. In this article, to allow enhancement of the system power density by improving power conversion efficiency and thus reducing the requirement of thermal management of the semiconductors, a carrier-based generalized discontinuous PWM strategy is proposed. This method detects the converter ac currents and ac reference voltages to determine the optimum clamped duration in each one of the three bridge-legs, which will minimize the converter overall switching losses. The proposed modulation method is analyzed and validated on a PLECS simulation and a 2 kVA single-phase three-legs APD converter.

Minimum Switching Losses Discontinuous PWM Strategy for Bidirectional Single-Phase AC–DC Converter With Active Power Decoupling Circuit

Active power decoupling circuits are used in bidirectional single-phase grid-connected systems to enhance the circuit lifetime by creating an alternative path for the typical dc-side power pulsating ripple. Therefore, this reduces the requirement of smoothing dc capacitors allowing compact designs even with the implementation of long life metalized film technology. However, with the necessary addition of auxiliary components, extra power losses in the added switching devices and passive components will be introduced, which will inevitably reduce the system power conversion efficiency. To relieve this issue, a new discontinuous pulsewidth modulation (PWM) strategy with minimum switching losses is proposed in this article. This method detects the converter current and reference voltages synchronously to determine the optimum clamped duration of each circuit phase-leg. With such a characteristic, the proposed strategy can realize the minimum switching losses at any instant, thus improving the power conversion efficiency and potentially the power density of the converter. The proposed modulation method is described, analyzed, validated, and compared with different PWM methods on a 2-kVA bidirectional single-phase ac–dc converter with active power decoupling circuit.

Are down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity possible? - A Cochrane Review summary with commentary.

Are down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity possible? - A Cochrane Review summary with commentary.

Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus in adult patients with aneurysmal subarachnoid haemorrhage: a systematic review

ObjectivesTo summarise the evidence on benefits and harms of prompt closure versus gradual weaning of external ventricular drainage (EVD) in patients with hydrocephalus following aneurysmal subarachnoid haemorrhage (aSAH) based on...

Simple discontinuous PWM strategies to reduce the switching losses of an indirect matrix converter

This work proposes the new discontinuous pulse width modulation (DPWM) schemes for an indirect matrix converter (IMC) to reduce the switching losses. The use of discontinuous modulation signals reduces the switching losses of the IMC by reducing the switching counts per cycle of the output converter. The key feature of the proposed schemes is the easy implementation as compared to existing DPWM schemes of the IMC. The major drawback of the existing DPWM schemes is the absence of zero current commutation (ZCC). In the absence of ZCC, the switchings of the input converter are accomplished through four-step commutation which adds the difficulties to the implementation. The proposed scheme overcomes above limitation by using the triangular carrier instead of the sawtooth carrier for the modulation of input converter. Consequently, the ZCC is enabled on the input converter which allows the use of two-step commutation. The two-step commutation simplifies the implementation to a great extent. The presented scheme provides the required input/output performance similar to continuous PWM (CPWM) schemes. The proposed work is verified by the simulation and experimental results. The reduction in the switching losses of the IMC by the new scheme is verified based on the comparison with the CPWM scheme.

New fixed‐time synchronization control of discontinuous inertial neural networks via indefinite Lyapunov‐Krasovskii functional method

SummaryThe purpose of this article is to investigate the existence of periodic solutions and fixed‐time synchronization (FTS) of a class of discontinuous inertial neural networks (DINNs) with time‐varying delays. Due to the existence of the discontinuities, first, by using a generalized variable transformation, the original DINNs are transformed into a first‐order differential system. By using the differential inclusions theory and the set‐valued version of the Mawhin coincidence theorem, a new delay‐dependent criterion is derived to ensure the existence of periodic solutions. Furthermore, by designing some effective discontinuous control strategies and by constructing indefinite Lyapunov‐Krasovskii functional (LKF), algebraic criteria are derived to guarantee the FTS for the drive‐response system. The settling time is explicitly estimated. In comparison with the related results on INNs, it is the first time to study the existence result of the DINNs and the Lyapunov approaches applied to investigate the FTS are entirely different. Finally, the correctness of the main results is verified via numerical examples.

Impact of discontinuous treatments on the generalized epidemic model

This paper presents a generalized epidemic model with discontinuous treatment strategies and time-varying delays. Under the concept of Filippov solution, by applying the differential inclusions and the topological degree theory in set-valued analysis, we employ a novel argument to establish new results on the existence of the periodic solutions for the considered epidemic model. After that, we derive some criteria on the uniqueness, global exponential stability of the considered epidemic model and convergence of the corresponding autonomous case of the considered epidemic model, in terms of nonsmooth analysis theory with the Lyapunov-like approach. Our results extend previous works on the epidemic model to the discontinuous cases, some corresponding results in the literature can be enriched and extended. Finally, typical examples and the corresponding numerical simulations have been carried out to support the analytic findings.

Prespecified-time synchronization of switched coupled neural networks via smooth controllers

This paper considers the prespecified-time synchronization issue of switched coupled neural networks (SCNNs) under some smooth controllers. Different from the traditional finite-time synchronization (FTS), the synchronization time obtained in this paper is independent of control gains, initial values or network topology, which can be pre-set as to the task requirements. Moreover, unlike the existing nonsmooth or even discontinuous FTS control strategies, the new proposed control protocols are fully smooth, which abandon the common fractional power feedbacks or signum functions. Finally, two illustrative examples are provided to illustrate the effectiveness of the theoretical results.

Energy efficient discontinuous reception strategy in LTE and beyond using an adaptive packet queuing technique

The next generation of mobile communication systems is being developed for high-bandwidth mobile networks to accommodate applications with high data rates and low delay requirements such as voice over internet protocol, video streaming, cyber-physical systems and gaming. These applications consume a considerable amount of energy and hence drain the user equipment (UE) battery quickly. Long-term evolution (LTE)/LTE-advanced has adopted a discontinuous reception (DRX) mechanism to improve the energy efficiency of the UE. DRX allows UEs to monitor the physical downlink control channel in a discontinuous manner when there is no downlink traffic to reduce energy consumption. However, DRX results in higher latency due to its sleep cycle. In this study, the authors present a new scheme that improves energy efficiency in UE while maintaining an average packet delay around a permissible delay threshold. Numerical analysis and system simulation show that this scheme can achieve a significant power saving.

A Fast Processing Discontinuous Control Strategy for Vienna Rectifier

In this paper, Vienna rectifier has been inspected as one of the prominent topologies among three-level switched-mode rectifiers. A fast processing discontinuous modulation strategy has been proposed with the aim of improving the rectifier’s performance. The proposed method not only takes advantage of special properties available in three-phase three-level rectifiers, but also reduces the control design complexity and the switching loss. Moreover, neutral point voltage balancing is inherently realized. To achieve these goals, the rectifier is decoupled into two 2-level boost converters in every defined region, leading to simple modulation algorithm and fast processing control strategy. The validity of the proposed technique has been verified via simulation and experimental results conducted on a laboratory prototype.

EFFECTS OF DISCONTINUING VS TAPERING VASOPRESSIN INFUSION ON HEMODYNAMIC RECOVERY IN VASODILATORY SHOCK

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Vasopressin (AVP) discontinuation strategies vary significantly despite its widespread use as an adjunctive agent in the treatment of vasodilatory shock. Several studies have looked at clinical outcomes associated with the discontinuation sequence of norepinephrine and AVP; however, these studies do not specify AVP de-escalation strategy. The purpose of our study is to compare the effect of gradual taper (GT) versus abrupt discontinuation (ADC) on the rates of clinically significant hypotension in patients recovering from vasodilatory shock. METHODS: This is a single-center, retrospective chart review of critically ill adult patients admitted to medical and surgical intensive care units from January 2016 to December 2019. The inclusion criterion was the confirmed administration of AVP infusion as an adjunct to catecholamine-based vasopressor therapy for at least one hour. Exclusion criteria included a primary diagnosis of cardiogenic shock, treatment with vasopressin as a sole vasopressor agent, vasopressin use for diabetes insipidus or organ donation, or transition to comfort care. The primary endpoint was the incidence of clinically significant hypotension after the initiation of vasopressin titration. Clinically significant hypotension was defined as hypotension requiring an increase or re-initiation of vasopressin, increase or re-initiation of catecholamine vasopressor, administration of fluid bolus, or a combination of these interventions. Secondary endpoints included duration of therapy and the number of vasopressors required. Additionally, ICU length of stay (LOS) and in-hospital mortality were evaluated. RESULTS: Of the 259 patients screened, a total of 46 patients were analyzed (15 in GT and 31 in ADC). Overall, the ADC group had a higher incidence of clinically significant hypotension, but this difference did not reach statistical significance (51.6% vs 26.7%, p = 0.11). While there were no differences in demographics or SOFA scores, the GT group tended to be on more vasopressors (3 vs 2, p = 0.05). In addition, of the 11 patients who received phenylephrine, the duration of therapy (59 hours vs 5 hours, p = 0.008) and the maximum dose (380 mcg/min vs 100 mcg/min, p = 0.0226) was higher in the GT group. There were no differences in ICU LOS or mortality between the two groups. CONCLUSIONS: Our study shows that, upon shock recovery, the abrupt discontinuation of vasopressin infusion was associated with numerically higher rates of clinically significant hypotension than gradual taper, although not statistically significant. There were no significant differences in LOS or in-hospital mortality. A larger study is needed to confirm these findings. CLINICAL IMPLICATIONS: The abrupt discontinuation of vasopressin may be relatively safe as it did not increase LOS or mortality. However, a gradual taper approach may be preferred in more profound shock, given the reduced rate of rebound hypotension. DISCLOSURES: No relevant relationships by Ola Elnadoury, source=Web Response No relevant relationships by Bhaskara Garimella, source=Web Response No relevant relationships by Andrew Lehr, source=Web Response No relevant relationships by Anthony Lubinsky, source=Web Response

Thermal optimized discontinuous modulation strategy for three phase impedance source inverter

A novel space vector modulation (SVM) strategy called maximum-boost discontinuous SVM (MBDSV) is proposed in this paper to reduce the thermal stress of three phase impedance source inverters (ISI). By exploiting the switch clamping mechanism and arranging the shoot-through (ST) states properly, the proposed strategy obtains the flowing merits: further optimize the thermal performance, improve the reliability, reduce the current stress and maximize the dc-link utilization of ISI. The proposed MBDSV was compared to the existing modulation strategies and the feasibility of the MBDSV had been benchmarked by simulation and experiments.

Treatment of neurogenic lower urinary tract symptoms: main contributions from 2018 and 2019.

This review aims to update the studies involving the treatment of lower urinary tract symptoms (LUTS) in neurogenic patients, published in the last two years. Treatment of neurogenic LUTS (NLUTS) patients with β3 adrenoreceptor agonists was investigated in real-life conditions. A randomized controlled trial compared the efficacy of antimuscarinics versus onabotulinum toxin A in neurogenic patients. The use of desmopressin to treat nocturia in multiple sclerosis patients is also reported. The long-term treatment with BontA efficacy, its discontinuation, and possible strategies to maintain patients on treatment were also evaluated. Sacral neuromodulation and tibial nerve stimulation are continuously being evaluated in neurogenic patients, especially in the last years. The management of urinary tract infections and vesical lithiasis, two common complications in NLUTS patients, and the management of both these patients was assessed in clinical trials.A trial evaluating the use of the anti-Nogo-A antibody after a spinal cord injury to facilitate neuronal rewiring and prevent or improve NLUTS was reported for the first time.

P-Multigrid matrix-free discontinuous Galerkin solution strategies for the under-resolved simulation of incompressible turbulent flows

In recent years several research efforts focused on the development of high-order discontinuous Galerkin (dG) methods for scale resolving simulations of turbulent flows. Nevertheless, in the context of incompressible flow computations, the computational expense of solving large scale equation systems characterized by indefinite Jacobian matrices has often prevented the simulation of industrially-relevant computations. In this work we seek to improve the efficiency of Rosenbrock-type linearly-implicit Runge-Kutta methods by devising robust, scalable and memory-lean solution strategies. In particular, we introduce memory saving p-multigrid preconditioners coupling matrix-free and matrix-based Krylov iterative smoothers. The p-multigrid preconditioner relies on cheap element-wise block-diagonal smoothers on the fine space to reduce assembly costs and memory allocation, and ensures an adequate resolution of the coarsest space of the multigrid iteration using Additive Schwarz smoothers to obtain satisfactory convergence rates and optimal parallel efficiency of the method. In addition, the use of specifically crafted rescaled-inherited coarse operators to overcome the excess of stabilization provided by the standard inheritance of the fine space operators is explored. Extensive numerical validation is performed. The Rosenbrock formulation is applied to test cases of growing complexity: the laminar unsteady flow around a two-dimensional cylinder at Re=200 and around a sphere at Re=300, the transitional flow problem of the ERCOFTAC T3L test case suite with different levels of free-stream turbulence. As proof of concept, the numerical solution of the Boeing rudimentary landing gear test case at Re=106 is reported. A good agreement of the solutions with experimental data is documented, whereas a reduction in memory footprint of about 92% and an execution time gain of up to 3.5 is reported with respect to state-of-the-art solution strategies.

A High Performance Interleaved Discontinuous PWM Strategy for Two Paralleled Three-Phase Inverter

This article aims to obtain the optimal combination of the switching loss, maximum zero-sequence circulating current (ZSCC), and line current ripple, which benefits most of the applications. The analysis shows that the interleaved discontinues pulsewidth modulation (IDPWM) maintains the minimum switching loss and line current ripples, but it introduces a larger ZSCC. Therefore, to obtain the optimal combination of the switching loss, maximum ZSCC peak, and line current ripple, it is essential to retain the minimum switching times and the optimal line current ripple of IDPWM but further reducing its overly large ZSCC. Further analysis reveals that IDPWM includes the vector combinations with medium ZSCC change rates, resulting in the larger ZSCC. Given the redundancies of the vector combinations, this article proposes a simple matrix to modify the original modulation signals of IDPWM, eliminating the medium ZSCC change rates. The proposed PWM scheme retains the minimum line current ripple and switching times as those of IDPWM while further reducing its overly large ZSCC, as validated by analytical results as well as experimental results. Since the proposed method obtains the optimal combination among switching loss, line current ripple, and maximum ZSCC peak, we name the proposed PWM scheme a high-performance DPWM.

Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax.

8006 Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS <2, ANC >1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all <0.02%); 3 pending. The most common tx emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (39%), and diarrhea (39%). Grade ≥3 AEs in ≥5% pts were neutropenia (13%), thrombocytopenia (5%), rash (5%), and pneumonia (5%). Of 17 pts at high risk for TLS on C1D1, 2 cycles of BO reduced TLS risk to low/medium at Ven initiation in 15 (88%). No pts had laboratory/clinical TLS (Howard). Conclusions: BOVen is well tolerated and achieves rapid uMRD: currently 68% PB uMRD and 51% BM uMRD with limited follow up (to be updated on presentation). Ten (27%) have discontinued treatment thus far. The value of MRD directed treatment duration will be evaluated with continued follow up. Clinical trial information: NCT03824483 .

Treatment-free remission in patients with chronic myeloid leukaemia.

In the past few years, international treatment guidelines for chronic myeloid leukaemia have incorporated recommendations for attempting discontinuation of treatment with tyrosine-kinase inhibitors (TKIs) outside of the setting of a clinical trial with the aim of a treatment-free remission (TFR). Physicians involved in the treatment of chronic myeloid leukaemia need to be sufficiently well informed to guide patients through decision-making about the discontinuation of treatment with TKIs targeting BCR-ABL1 by providing a balanced assessment of the potential risks and benefits of stopping or continuing therapy. These guidelines also seek to ensure that therisks associated with being off treatment are kept to a minimum. In this Review, we summarizethe clinical studies of TFR and how their results can guide routine clinical practice with a focus on specific aspects such as molecular monitoring and the pregnancy-specific risks associated with a TFR attempt in female patients. We also address the development of predictors of outcome after TKI discontinuation and present strategies that warrant further consideration to enable more patients to enter TFR.

Effect of Antibiotic Discontinuation Strategies on Mortality and Infectious Complications in Critically Ill Septic Patients: A Meta-Analysis and Trial Sequential Analysis.

To investigate methods of antibiotic duration minimization and their effect on mortality and infectious complications in critically ill patients. A systematic search of PubMed, Embase (via Ovid), clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials (via Wiley) (CENTRAL, Issue 2, 2015). Randomized clinical trials comparing strategies to minimize antibiotic duration (days) for patients with infections or sepsis in intensive care. A systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Dichotomous data are presented as relative risk (95% CIs) and p value, and continuous data are presented as mean difference (CI) and p value. We included 22 randomized clinical trials (6,046 patients). Strategies to minimize antibiotic use included procalcitonin (14 randomized clinical trials), clinical algorithms (two randomized clinical trials), and fixed-antibiotic duration (six randomized clinical trials). Procalcitonin (-1.23 [-1.61 to -0.85]; p < 0.001), but not clinical algorithm-guided antibiotic therapy (-7.41 [-18.18 to 3.37]; p = 0.18), was associated with shorter duration of antibiotic therapy. The intended reduction in antibiotic duration ranged from 3 to 7 days in fixed-duration antibiotic therapy randomized clinical trials. Neither procalcitonin-guided antibiotic treatment (0.91 [0.82-1.01]; p = 0.09), clinical algorithm-guided antibiotic treatment (0.67 [0.30-1.54]; p = 0.35), nor fixed-duration antibiotics (1.21 [0.90-1.63]; p = 0.20) were associated with reduction in mortality. Z-curve for trial sequential analyses of mortality associated with procalcitonin-guided therapy did not reach the trial sequential monitoring boundaries for benefit, harm, or futility (adjusted CI, 0.72-1.10). Trial sequential analyses for mortality associated with clinical algorithm and fixed-duration treatment accumulated less than 5% of the required information size. Despite shorter antibiotic duration, neither procalcitonin-guided therapy (0.93 [0.84-1.03]; p = 0.15) nor fixed-duration antibiotic therapy (1.06 [0.74-1.53]; p = 0.75) was associated with treatment failure. Although the duration of antibiotic therapy is reduced with procalcitonin-guided therapy or prespecified limited duration, meta-analysis and trial sequential analyses are inconclusive for mortality benefit. Data on clinical algorithms to guide antibiotic cessation are limited.

Discontinuation of External Ventricular Drainage in Patients with Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage - a Scandinavian Multi-institutional Survey.

Hydrocephalus requiring external ventricular drainage is common following aneurysmal subarachnoid hemorrhage (aSAH). Timing and strategy for the discontinuation of the external ventricular drain (EVD) are, however, controversial as guidelines are based on limited scientific evidence. A recent similar survey showed that guidelines and recommendations are not being followed. We conducted a questionnaire survey regarding the management of EVD treatment in patients with aSAH and investigated current treatment practice, consensus, and adherence to guidelines within the neurosurgical departments in Scandinavia. A questionnaire concerning the management of EVD discontinuation in patients with hydrocephalus following aSAH was distributed to all 14 neurosurgical departments in Scandinavia (Norway, Sweden, and Denmark). Neurosurgeons and neurosurgical trainees at all levels were asked to complete the questionnaire individually. A total of 175 completed questionnaires were received between May 2018 and April 2019, resulting in a response rate of 64 %. Eighty-five percent of respondents reported no knowledge of international guidelines regarding EVD discontinuation in patients with hydrocephalus following aSAH. Within every department, respondents disagreed on whether a common discontinuation strategy was followed or not. Seventy-four percent decided upon the EVD discontinuation strategy mainly determined by patients' clinical condition and drainage volume. Forty-five percent considered Glasgow Coma Score (GCS) the most important clinical variable when assessing the timing of EVD discontinuation. There was general agreement towards the initiation of EVD discontinuation 4-7days after ictus of aSAH in a stable patient with a drainage volume of < 150ml/day and intracranial pressure (ICP) < 15mmHg. Awareness of and adherence to international guidelines regarding EVD discontinuation in patients with hydrocephalus following aSAH were limited in Scandinavia. Internal consensus at department level was absent. Initiation of the discontinuation process appeared to be case dependent and mainly influenced by the patients' clinical condition and drainage volume. GCS was the clinical variable considered most important when deciding on the initiation of EVD discontinuation.