De-escalation Strategies Research Articles

Educators’ Sensemaking about Seclusion and Restraint in a Changing Regulatory Context

Policies governing the use of seclusion and restraint in schools may only have a modest effect on the use of these procedures, particularly the frequency these are used. This study explored educators’ sensemaking about seclusion and restraint after a statute and new policy were introduced. A case-study design was used to analyze the meanings educators created in the new regulatory environment. The new regulations had a significant guiding effect on educators as they adjusted their thinking and use of seclusion and restraint to align with the new law and policy. Educators reported becoming much more cautious and thoughtful in their use of these procedures. They viewed the new regulations as a strong protection for students against the misuse of seclusion and restraint. They reported becoming more proactive to prevent seclusion and restraint, and they put more effort into de-escalation strategies with students who were becoming aggressive and agitated. These new meanings caused their threshold for seclusion and restraint to change. This study illustrates the influence a legal mandate can have on the seriousness in which educators view specific policy positions.

Safety and Efficacy of Antibiotic De-escalation and Discontinuation in High-Risk Hematological Patients With Febrile Neutropenia: A Single-Center Experience.

BackgroundThere is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk hematological patients.MethodsWe studied 446 admissions after introduction of an ECIL-4–based protocol (hereafter “ECIL-4 group”) in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission, and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteremia, and antibiotic consumption.ResultsBacteremia occurred more frequently in the ECIL-4 group (46.9% [209/446] vs 30.5% [156/512]; P < .001), without an associated increase in septic shock (4.7% [21/446] vs 4.5% [23/512]; P = .878) or infection-related ICU admission (4.9% [22/446] vs 4.1% [21/512]; P = .424). Overall mortality was significantly lower in the ECIL-4 group (0.7% [3/446] vs 2.7% [14/512]; P = .016), resulting mainly from a decrease in infection-related mortality (0.4% [2/446] vs 1.8% [9/512]; P = .058). Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 vs 14; P = .001) and 7 daily antibiotic doses (17 vs 24; P < .001) per admission period.ConclusionsOur results support implementation of ECIL-4 recommendations to be both safe and effective based on real-world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced.

The TRAR gene classifier to predict response to neoadjuvant therapy in HER2-positive and ER-positive breast cancer patients: an explorative analysis from the NeoSphere trial.

As most erb‐b2 receptor tyrosine kinase 2 (HER2)‐positive breast cancer (BC) patients currently receive dual HER2‐targeting added to neoadjuvant chemotherapy, improved methods for identifying individual response, and assisting postsurgical salvage therapy, are needed. Herein, we evaluated the 41‐gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre‐ and 166 post‐treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico‐pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER‐positive specimens but not in ER‐negative counterparts. Among ER‐positive BC patients not achieving a pCR, those with TRAR‐low scores in surgical specimens showed a trend for lower distant event‐free survival. In conclusion, in HER2‐positive/ER‐positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti‐HER2‐based neoadjuvant therapy and to assist treatment escalation and de‐escalation strategies in this setting.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

BackgroundAlectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor.Patients and methodsPatients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy.ResultsEleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual.ConclusionsAlectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

Contemporary surgical management of inflammatory breast cancer: a narrative review.

The purpose of this review is to outline the surgical management of inflammatory breast cancer (IBC) including the clinical decision making, operative approach and current controversies. IBC is a rare and aggressive form of breast cancer. Trimodality therapy consisting of neoadjuvant therapy, modified radical mastectomy (MRM) and radiation therapy improves survival and is the recommended course of treatment. Advancements in systemic therapy and de-escalation strategies in non-IBC have accelerated discussions regarding several aspects of care in IBC including feasibility of de-escalation of surgical care, timing of reconstruction and the role of surgery in de novo stage IV disease. We discuss the evidence to support the surgical approach and decision-making in this rare disease. We reviewed existing literature using multiple electronic databases and clinical consensus guidelines to identify historical and current publications addressing current management recommendations and clinical controversies in IBC. Breast conserving surgery (BCS), skin- or nipple-sparing mastectomy should not be performed in IBC as surgical resection to negative margins results in improved locoregional recurrence rates. Level I and II axillary lymph node dissection should be performed regardless of response to therapy and initial nodal status. Reconstruction should be delayed and contralateral prophylactic mastectomy (CPM) is discouraged in IBC. Surgery may be considered for de novo stage IV IBC patients who demonstrate durable response to neoadjuvant therapy to improve local-regional control.

Trends in Diagnosis of Noninvasive Follicular Thyroid Neoplasm With Papillarylike Nuclear Features and Total Thyroidectomies for Patients With Papillary Thyroid Neoplasms

Increasing detection of early-stage papillary thyroid neoplasms without improvements in mortality has prompted development of strategies to prevent or mitigate overtreatment. To determine adoption rates of 2 recent strategies developed to limit overtreatment of low-risk thyroid cancers: (1) a new classification, noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP), and (2) hemithyroidectomy for selected papillary thyroid carcinomas (PTCs) up to 4 cm in size. This is a cross-sectional analysis of 3368 pathology records of 2 cohorts of patients from 18 hospitals in 6 countries during 2 time periods (2015 and 2019). Participating hospitals were included from the US (n = 12), Canada (n = 2), Denmark (n = 1), South Korea (n = 1), South Africa (n = 1), and India (n = 1). The records of the first 100 patients per institution for each year who underwent thyroid-directed surgery (hemithyroidectomy, total thyroidectomy, or completion thyroidectomy) were reviewed. Frequency of diagnosis of NIFTP, PTCs, and thyroidectomies during the study period. Of the 790 papillary thyroid neoplasms captured in the 2019 cohort, 38 (4.8%) were diagnosed as NIFTP. Diagnosis of NIFTP was observed in the US, South Africa, and India. There was minimal difference in the total proportion of PTCs in the 2015 cohort compared with the 2019 cohort (778 [47.1%] vs 752 [44.5%]; difference, 2.6% [95% CI, -16.9% to 22.1%]). The proportion of PTCs eligible for hemithyroidectomy but treated with total thyroidectomy in the 2 cohorts demonstrated a decreasing trend from 2015 to 2019 (341 of 453 [75.3%] vs 253 of 434 [58.3%]; difference, 17.0% [95% CI, -1.2% to 35.2%]). Results of this cohort study showed that the 2 mitigation strategies for preventing overtreatment of early-stage thyroid cancer have had mixed success. The diagnosis of NIFTP has only been applied to a small proportion of thyroid neoplasms compared with expected rates. However, more patients eligible for hemithyroidectomy received it in 2019 compared with 2015, showing some success with this deescalation strategy.

Acceptance and outcome of interventions in a meropenem de-escalation antimicrobial stewardship program in pediatrics.

Prospective audit and feedback is a method that allows the antimicrobial stewardship program (ASP) team to interact with attending physicians to tailor antibiotic therapy, including de-escalation, as appropriate. This study aimed to evaluate the acceptance and outcomes of ASP de-escalation recommendations in children who received meropenem. A prospective cohort study was conducted in children aged 1 month to 18 years who received meropenem in a tertiary-care teaching hospital. The ASP team gave recommendation between 72 and 120 h after initiating meropenem therapy. Acceptance of de-escalation recommendations among primary physicians was evaluated within 24 h of recommendation. Outcomes included clinical success rate on the 7th day and incidence rate of acquisition of carbapenem-resistant gram-negative bacteria (CR-GNB) within 30 days. From March to December 2019, 217 children with a median (interquartile range) age of 2.1 (0.6, 9.5) years received meropenem. The ASP team gave recommendations in 127 (58.5%) of cases for continuation of meropenem therapy and 90 (41.5%) of cases for de-escalation. The overall acceptance of ASP de-escalation recommendations was 57.8% (95%CI: 46.9-68.1%). Clinical success rates were 85.2% in the accepted group compared to 77.5% in the rejected group (P = 0.06). The incidence rate of acquisition of CR-GNB within 30 days after treatment was 5.8% in the accepted group and 15.8% in the rejected group (P = 0.03). About half of the recommendations to de-escalate meropenem prescriptions were accepted through the ASP intervention. Carbapenem-resistant gram-negative bacteria acquisitions was less likely in the de-escalation group. A robust de-escalation strategy 72 h following carbapenem initiation should be encouraged to combat multidrug-resistant organisms.

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Dose and Volume De-Escalation for Elective Nodal Regions in Patients With Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer (OPC) Undergoing Curative-Intent Concurrent Chemoradiation (CCRT)

Several de-escalation strategies for HPV-associated OPC have focused on treatment de-intensification to the gross disease. We propose that by systematically reducing the volume and dose to the elective regions, toxicity can be decreased without compromising tumor control. Here we report our long-term results.Since 2010, we started our systemic de-escalation approach by first reducing the treatment volumes for the node-negative neck. Retropharyngeal, level IB, high level II, and levels IV-V nodal basins were not included in the subclinical target volume. For the node-positive neck, levels IB and V were not covered unless involved. Using this approach, we have observed high control rates. Starting March 2017, we subsequently reduced the dose to all elective regions to 30 Gy in 15 fractions for all patients with HPV-positive OPC undergoing curative CCRT. This is followed by a cone-down to the gross disease with a 3-5 mm margin delivering 40 Gy in 20 fractions. Patients were required to receive concurrent cisplatin or other chemotherapy.From March 2017 to July 2019, 276 consecutive HPV-positive OPC patients underwent CCRT. Median age was 61 (range: 34-87), 90% were male, and 26% had ≥ 15 pack-year of smoking history. Overall, 35% had cT3-4 and 24% had cN2-3 per AJCC 8th Edition. The majority (77%) received high-dose cisplatin and 81% of them had a cumulative dose of 300mg/m2. With a median follow-up of 23 months (range: 1-42), 7 patients (2.5%) developed locoregional recurrence - 6 had disease recurrence in the primary site and/or gross nodes that received 70 Gy and 1 patient had a gross nodal recurrence in the 30 Gy region due to mistargeting. All patients with gross nodal recurrence in the neck were successfully salvaged with surgery. There was no disease recurrence in the subclinical fields receiving 30 Gy or in the omitted radiation fields. Seventeen (6.2%) patients developed distant metastasis. The 2-year locoregional recurrence-free survival was 92.5%, distant metastasis-free survival 90.0%, and overall survival 94.6%. Fifty-six of the 276 patients were also enrolled on an adaptive radiotherapy protocol (NCT03096808) to study modification of the radiation treatment plan during treatment course to account for temporal variations in anatomy, with toxicities and quality-of-life (QoL) metrics evaluated at baseline and follow-up visits. Of the 56 patients on adaptive protocol, 5.8% had feeding tube placement during treatment. No patient had feeding tube dependence at 6 months after radiotherapy. At 2-year follow-up, most of the QoL metrics (pain, social contact, social eating, speech, and swallow) were comparable or superior to baseline measures except for taste and xerostomia.The systematic de-escalation strategy of volume and dose resulted in favorable locoregional control and acute toxicities profile. This regimen can be adapted for treating a wide range of HPV-associated OPC patients undergoing primary CCRT.

Long-Term Locoregional Control With Unilateral Radiation for AJCC-7 T1-2N2b Tonsillar Cancer

Given the historical toxicity of radiotherapy for head & neck cancer, there has been an emphasis on de-escalation for patients with favorable disease features. The use of unilateral radiation to cervical nodes is a prominent de-escalation strategy in well-lateralized tonsil cancers. However, the safety of this approach for patients with AJCC-7 N2b disease was less well-established in the landmark studies guiding its use. The study hypothesis was that unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure.This study was a retrospective chart review of 66 patients treated from 2005 to 2016 at two academic institutions. Eligible patients had AJCC-7 T1-2N2b squamous cell carcinoma of the tonsil and were treated with unilateral radiation therapy. The primary endpoint was the rate of contralateral nodal failure at the time of last follow-up. Ipsilateral recurrence rates and overall survival were additional endpoints of interest. When available, data were collected regarding the presence of clinical extracapsular extension (ECE). Human papillomavirus/p16 status was also assessed.The median age at diagnosis was 55.5 years and 53 patients (80.3%) were male. 38 patients (57.6%) had T1 disease and 28 patients (42.4%) had T2 disease based upon AJCC-7 staging. Of the 52 patients who had information on tumor HPV status, all were positive. In regards to systemic therapy, 18 patients (27.3%) had induction therapy, 26 (39.4%) had concurrent therapy, and 4 (6.1%) had both. The median time to last post-radiation follow-up was 80.9 months; 87.9% of patients remained alive at last follow-up and median OS was not reached. Contralateral nodal failure occurred in 2/66 (3.0%) patients at 3.6 and 20.9 months, respectively. Both patients underwent salvage treatment. The first survived an additional 65 months and the second remains alive at last follow-up 37 months after recurrence. Sixteen patients (24.2%) were felt to have extracapsular extension by clinical exam, radiology, or pathology; one of the two contralateral recurrences occurred in this group. Two patients (3%) experienced recurrence at the treated primary site and/or neck. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached.The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral treatment in patients with a high ipsilateral nodal burden. Further assessments are needed to determine the impact of radiation volume reduction on patient quality of life.

THE TWOFOLD MEANING OF BRINKMANSHIP: EXPLAINING STRATEGIC AMBIGUITY IN RUSSIA’S NUCLEAR POLICY

Discussions and debates about whether or not the role of Russia’s Non-Strategic Nuclear Weapons underpins a so-called “Escalation to De-Escalation” strategy culminated in the 2018 Nuclear Posture Review, which declared the need for deploying a new low-yield nuclear warhead for submarine-launched ballistic missiles in order to prevent Russia from escalating to the limited nuclear level and successfully terminate the conflict. While unofficial evidence barely suggests that Russia may exhort to its NSNWs in order to stave off the adversary in crisis situations, common Western discussions on Escalation to De-Escalation revolve around the alleged existence of an “offensive” Escalation to De-Escalation strategy. Thereby, Moscow would pre-emptively escalate to the limited nuclear level over NATO's Eastern flank in order to take over it while leaving Western countries without no escalation options, given the doubts surrounding the ability of B61s’ delivery systems at going beyond Russian air-defence. However, while Western countries are often busy with self-deterrence, thus perceiving immediate threats at each deployment by the adversary, they tend to overlook strategic manipulation of deployed capabilities. That is why analysis of ambiguity surrounding Russian NSNWs have been less popular in Western contexts. Based upon critical analysis of Escalation to De-Escalation and classic deterrence and escalation studies, this paper argues that ambiguity surrounding Russia’s NSNWs is part of a brinkmanship strategy, which inadvertently triggered destabilizing dynamics in US-Russia relations. The article proceeds as follows. First, an introduction sets the scene and the aim of the article, as well as the methodology, including the scope and background of facts. Second, the Escalation to De-escalation debate is broken down in the attempt of shedding light on the ambiguity it builds on. Third, it is argued that ambiguity surrounding NSNWs is strategically exploited according to Schelling’s concept of brinkmanship, though exacerbating the risk of inadvertent escalation with Western countries. Finally, a conclusion wraps up the argument and indicates its implications.

Das pharmakologische Management kinder- und jugendpsychiatrischer Notfälle

The Pharmacological Management of Emergencies in Child and Adolescent Psychiatry Abstract. Emergencies in child and adolescent psychiatry are highly prevalent and often pose significant challenges to physicians, since substantial danger to the patient or others must be avoided through the application of largely moderate interventions. Besides using de-escalating strategies and exploiting psychotherapeutic options, the physician frequently employs psychopharmacological interventions. because of a lack of systematically assessed data, however, in emergencies in child and adolescent psychiatry most administrations of psychotropic drugs occur "off label." This review deduces practice-relevant recommendations for the pharmacological management of occurring child and adolescent emergencies such as acute suicidality, acute psychotic episodes, delirium, disorders of consciousness, acute intoxication, and alcohol withdrawal syndrome. We discuss the issue of quality and safety in pharmacological emergency strategies.

De-escalation from Prasugrel or Ticagrelor to Clopidogrel in Patients with Acute Coronary Syndrome Managed with Percutaneous Coronary Intervention: An Updated Meta-analysis of Randomized Clinical Trials.

We aimed to evaluate the clinical benefits of a de-escalation strategy from prasugrel or ticagrelor to clopidogrel versus continuation of prasugrel or ticagrelor along with aspirin in both strategies for patients presenting with acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI), and to analyze the effect of the recently published randomized clinical trial (RCT) by Park et al., which included the largest sample size ever and the largest switched number of patients, on current guidelines and practices. The PubMed, EMBASE, Scopus, Web of Science, Cochrane Central, and Google Scholar databases were searched systematically from inception to May 2021 by using the search terms ('de-escalation' OR 'switching') AND ('antiplatelet' OR 'clopidogrel' OR 'ticagrelor' OR 'prasugrel') AND ('percutaneous coronary intervention' OR 'PCI'' OR 'Acute coronary syndrome' OR 'ACS'). We included RCTs that reported the primary outcomes, i.e. net clinical benefits and Bleeding Academic Research Consortium (BARC) type 2 or higher bleeding. A combination of both ischemic and bleeding events was defined as a net clinical benefit. A total of four RCTs were included, with 5952 patients. A random-effects meta-analysis revealed that a de-escalation strategy was associated with lower ischemic and bleeding events (net clinical benefits; risk ratio [RR] 0.63, 95% confidence interval [CI] 0.47-0.85; p=0.003), and lower BARC type 2 or higher bleeding (RR 0.51, 95% CI 0.29-0.91; p=0.02) when compared with a continuation strategy. The current guidelines recommend potent P2Y12 prasugrel or ticagrelor for 12 months despite their association with a high risk of bleeding. Our meta-analysis updates cardiologists, providing them with the best available evidence in managing patients with ACS who underwent PCI. Among patients with ACS treated with PCI, a de-escalation strategy (prasugrel or ticagrelor to clopidogrel) is associated with lower ischemic and bleeding events (net clinical benefits) and lower BARC type 2 or higher bleeding; however, due to the limited number of included studies, further high-quality studies are needed to establish the clinical efficacy of the de-escalation strategy.

Guided and unguided de-escalation from potent P2Y12 inhibitors among patients with ACS: a meta-analysis

Abstract Background Dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor is recommended in patients with acute coronary syndrome (ACS) and should be tailored according to ischemic and bleeding risks, which are highest in the acute phase, and gradually attenuate overtime. De-escalation strategies of DAPT aim to optimize this balance of risks. Purpose We compared guided or unguided DAPT de-escalation strategies from potent P2Y12 inhibitors to either clopidogrel or lower doses of potent P2Y12 inhibitors versus standard DAPT with potent P2Y12 inhibitors among patients with ACS. Methods PubMed, Google Scholar and Cochrane Central Register of Controlled Trials were searched from inception till March 10th 2021. 1633 records were screened on DAPT de-escalation strategies after ACS for inclusion. Aspirin monotherapy and non-randomized trials were excluded. The primary endpoint was BARC ≥2 bleeding. Other endpoints included MACE (defined according to the definitions reported in the original study protocols), all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, and stroke. Hazard ratios (HRs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. Heterogeneity was assessed with the I2 index. We assessed the interaction between de-escalation strategy (guided vs. unguided) and treatment with a random-effects meta-regression analysis with the empirical Bayes method. This study has been submitted to PROSPERO for registration. Preliminary findings Four randomised trials and a total of 8,082 patients randomly allocated to a de-escalation strategy (genetic guided to clopidogrel, n=1,242; platelet function guided to clopidogrel, n=1,304; unguided to clopidogrel (n=323); unguided to lower dose, n=1,170) or standard DAPT (n=4,043) were included in our analysis. De-escalation strategy had a reduction in BARC ≥2 bleeding (HR 0.57, 95% CI 0.37–0.89; I2=81%). MACE (HR 0.79, 95% CI 0.62–1.02; I2=0%), all-cause death (HR 0.89, 95% CI 0.58–1.36), cardiovascular death (HR 0.63, 95% CI 0.36–1.10; I2=0%), myocardial infarction (HR 0.81, 95% CI 0.56–1.17; I2=0%), stent thrombosis (HR 0.57, 95% CI 0.19–1.74; I2=0%) and stroke (HR 0.73, 95% CI 0.39–1.35; I2=0%) did not differ between patients with a de-escalation strategy and those without. Meta-regression analysis did not show any significant interaction between de-escalation method (guided vs. unguided) and treatment effects, except for BARC ≥2 bleeding (P interaction = 0.070), suggesting a greater reduction with unguided de-escalation. Conclusion A de-escalation strategy of DAPT after ACS was associated with a lower number of clinically relevant bleeding events, mostly in patients who underwent unguided de-escalation, while no association with increased ischemic events was found. However, the observed broad confidence intervals limit the certainty of our findings. Funding Acknowledgement Type of funding sources: None. BARC ≥2 bleedingMACE

Reduction of Elective Radiotherapy Treatment Volume in Definitive Treatment of Locally Advanced Head and Neck Cancer-Comparison of a Prospective Trial with a Revised Simulated Contouring Approach.

Definitive radiochemotherapy of locally advanced head and neck squamous cell cancer (HNSCC) achieves high locoregional tumor control rates; but is frequently associated with long-term toxicity. A future direction could be a de-escalation strategy focusing on treated volume rather than radiotherapy dose. This analysis evaluates radiotherapy dose and volume parameters of patients treated with a standard contouring approach in a clinical trial context compared with a revised volume-reduced contouring approach. In this case, 30 consecutive patients from the CheckRad-CD8 trial treated at a single study center were included in this analysis. Treatment toxicity and quality of life were assessed at the end of radiotherapy. Standard treatment plans (ST) following state of the art contouring guidelines that were used for patient treatment and volume reduced treatment plans (VRT) according to a revised simulated approach were calculated for each patient. Planning target volumes (PTV) and mean doses to 38 organs-at-risk structures were compared. At the end of radiotherapy patients reported high rates of mucositis; dysphagia and xerostomia. In addition; patient reported quality of life as assessed by the EORTC QLQ-HN35 questionnaire deteriorated. Comparing the two contouring approaches; the elective PTV_56 Gy and the high risk PTV_63 Gy (shrinking field) were significantly smaller in the VRT group. Significant reduction of mean dose to structures of the oral cavity; the larynx as well as part of the swallowing muscles and the submandibular glands was achieved in the simulated VRT-plan. Treatment de-intensification by reduction of the irradiated volume could potentially reduce treatment volume and mean doses to organs at risk. The proposed contouring approach should be studied further in the context of a clinical trial.

Introduction. Youth violence: De-escalation strategies and socio-legal responses

Despite media suggestions that youth violence is the result of an epidemic of young thugs “out of control”, this paper argues that youth violence is emblematic of complex political, economic and socio-cultural conditions. This introductory paper discusses some of the key themes and articles from our special issue on Youth violence: De-escalation strategies and socio-legal responses, which is the result of a workshop held at the Oñati International Institute for the Sociology of Law in July 2019. It seeks to reflect the rich tapestry of factors, contexts and processes that can place young people at risk of offending, or, perhaps even more importantly, at risk of criminalisation, as presented in the special issue collection. We reflect on the range of perspectives presented across the special issue on youth violence and the de-escalation of such violence, which seek to advance knowledge, and identify strategies for regulating and preventing this behaviour.

4.1 STANDARDIZED ACUTE AGITATION MANAGEMENT ACROSS HOSPITAL SETTINGS

Increasingly more children are presenting with worsening acuity of emotional dysregulation, aggression, and agitation in the emergency department (ED) and across other hospital systems. Timely implementation of consistent behavioral health strategies and standardized pharmacological interventions are essential in successfully responding to acute and severe agitation across the continuum of care. We describe the development of an acute agitation algorithm to standardize management of agitation and aggression in the ED and the general pediatric floor. Multidisciplinary workgroups in 2 separate hospital settings at Lurie Children’s Hospital were created to develop an acute agitation algorithm with the aim of standardizing the early identification of signs and symptoms of agitation, implementing a consistent nonpharmacological and pharmacological treatment response, and utilizing consistent debriefing strategies. We developed resources to screen high-risk special populations, build electronic health record identifiers to recognize at-risk patients, create documentation that drives clinical intervention, and develop systemwide workflows and staff education to ensure consistency of implementation through the continuum of care. Stratification of the severity of agitation was used in the algorithm to match behavioral and pharmacological interventions. We will present outcome measures related to pre- and postimplementation of the ED and pediatric acute agitation algorithm, patient acuity, consistency and timeliness of protocol implementation, psychopharmacological interventions, and documentation. Aggression is a serious problem in child and adolescent psychiatry. Pandemic-related factors have contributed to a significant rise in acuity and severity of behavioral dysregulation across hospital settings. Uniform staff training around mental health, implementation of consistent behavioral health de-escalation strategies, and standardized pharmacological approaches to challenging behaviors improve patient care and staff satisfaction.

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial

In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction. In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055. From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 [95% CI 0·40-0·76], psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42-1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35-0·77, p=0·0012). In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events. ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

Therapeutic strategies for systemic therapies of human papillomavirus-related oropharyngeal cancer.

Our understanding of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and its molecular basis continues to evolve and produce important insights into customized therapeutic strategies. Novel therapeutics exploiting HPV-related targets are being evaluated in the incurable setting, while the favorable prognosis of locoregionally advanced disease has stimulated investigation into de-escalation strategies. There is much opportunity for better personalization of standard therapy according to HPV status. This review discusses both current and investigational therapeutic strategies for HPV-related OPC.