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Objectives: This study aims to understand the breadth of practice around end-of-life withdrawal of non-invasive advanced respiratory support (encompassing both continuous positive airway pressure and non-invasive ventilation) by analysing NHS-published guidelines and guidance for clinicians. This study seeks validity in the guidelines through a confluence of findings and reassurance of practice despite having little to no high-quality research to inform the content of the guidelines. Ultimately, where discordance is found between guidelines, there will be a strong mandate for future research., Methods: Guidelines were gathered through snowball sampling and analysed using document analysis techniques. Analysis was mixed in inductive and deductive and facilitated across several authors using framework analysis. 20 guidelines were analysed but saturation was found after 15. Further guidelines were analysed beyond saturation to provide reassurance of the endpoint of the study., Results: There were common components to the guidelines presented as themes: legal and ethical frameworks, decision-making around withdrawal, the process of withdrawal, post-withdrawal care and when to contact palliative care. There were significant areas of confluence, where multiple guidelines were in agreement on best practice. However, there was significant discordance in some key areas including the use of post-withdrawal oxygen therapy and pressure weaning practice., Conclusion: This study provides reassurance through a confluence of findings for the majority of withdrawal practices. However, key areas of discordance highlight an urgent need for further research to support clinicians, patients and their families during challenging clinical events., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Withholding or withdrawing life-sustaining treatment in end-of-life patients is a challenging ethical issue faced by physicians. Understanding physicians' experiences and factors influencing their decisions can lead to improvement in end-of-life care., Objectives: To investigate the experiences of Thai physicians when making decisions regarding the withholding or withdrawal of life-sustaining treatments in end-of-life situations. Additionally, the study aims to assess the consensus among physicians regarding the factors that influence these decisions and to explore the influence of families or surrogates on the decision-making process of physicians, utilizing case-based surveys., Methods: A web-based survey was conducted among physicians practicing in Chiang Mai University Hospital (June - October 2022)., Results: Among 251 physicians (response rate 38.3%), most of the respondents (60.6%) reported that they experienced withholding or withdrawal treatment in end-of-life patients. Factors that influence their decision-making include patient's preferences (100%), prognosis (93.4%), patients' quality of life (92.8%), treatment burden (89.5%), and families' request (87.5%). For a chronic disease with comatose condition, the majority of the physicians (47%) chose to continue treatments, including cardiopulmonary resuscitation (CPR). In contrast, only 2 physicians (0.8%) would do everything, in cases when families or surrogates insisted on stopping the treatment. This increased to 78.1% if the families insisted on continuing treatment., Conclusion: Withholding and withdrawal of life-sustaining treatments are common in Thailand. The key factors influencing their decision-making process included patient's preferences and medical conditions and families' requests. Effective communication and early engagement in advanced care planning between physicians, patients, and families empower them to align treatment choices with personal values., (© 2024. The Author(s).)

Background Premature discontinuation of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention is related to higher short-term risks of adverse outcomes. Whether these risks persist in the long-term is uncertain. Methods and Results We assessed all patients having percutaneous coronary intervention with coronary second- or first-generation drug-eluting stents in the Veterans Affairs healthcare system between 2006 and 2012 who were free of major ischemic or bleeding events in the first 12 months. The characteristics of patients who stopped DAPT prematurely (1-9 months duration), compared with >9 to 12 months, or extended duration (>12 months) were assessed by odds ratios (ORs) from multivariable logistic models. The risk of adverse clinical outcomes over a mean 5.1 years in patients who stopped DAPT prematurely was assessed by hazard ratios (HRs) and 95% CIs from Cox regression models. A total of 14 239 had second-generation drug-eluting stents, and 8583 had first-generation drug-eluting stents. Premature discontinuation of DAPT was more likely in Black patients (OR, 1.54; 95% CI, 1.40-1.68), patients with greater frailty (OR, 1.04; 95% CI, 1.03-1.05), and patients with higher low-density lipoprotein cholesterol, and less likely in patients on statins (OR, 0.87; 95% CI, 0.80-0.95). Patients who stopped DAPT prematurely had higher long-term risks of death (second-generation drug-eluting stents: HR, 1.35; 95% CI, 1.19-1.56), myocardial infarction (second-generation drug-eluting stents: HR, 1.46; 95% CI, 1.22-1.74), and repeated coronary revascularization (second-generation drug-eluting stents: HR, 1.24; 95% CI, 1.08-1.41). Conclusions Patients who stop DAPT prematurely have features that reflect greater frailty, poorer medication use, and other social factors. They continue to have higher risks of major adverse outcomes over the long-term and may require more intensive surveillance many years after percutaneous coronary intervention.

Background: COVID-19 is caused by the coronavirus SARS-CoV-2, which uses angiotensin-converting enzyme 2 (ACE-2) as a receptor for cellular entry. It is theorized that ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) may increase vulnerability to SARS-CoV-2 by upregulating ACE-2 expression, but ACE-I/ARB discontinuation is associated with clinical deterioration., Objective: To determine whether ACE-I and ARB use is associated with acute kidney injury (AKI), macrovascular thrombosis and in-hospital mortality., Methods: A retrospective, single-centre study of 558 hospital inpatients with confirmed COVID-19 admitted from 1 March to 30 April 2020, followed up until 24 May 2020. AKI and macrovascular thrombosis were primary end-points, and in-hospital mortality was a secondary end-point., Results: AKI occurred in 126 (23.1%) patients, 34 (6.1%) developed macrovascular thrombi, and 200 (35.9%) died. Overlap propensity score-weighted analysis showed no significant effect of ACE-I/ARB use on the risk of occurrence of the specified end-points. On exploratory analysis, severe chronic kidney disease (CKD) increases odds of macrovascular thrombi (OR: 8.237, 95% CI: 1.689-40.181, P = 0.009). The risk of AKI increased with advancing age (OR: 1.028, 95% CI: 1.011-1.044, P = 0.001) and diabetes (OR: 1.675, 95% CI: 1.065-2.633, P = 0.025). Immunosuppression was associated with lower risk of AKI (OR: 0.160, 95% CI: 0.029-0.886, P = 0.036). Advancing age, dependence on care, male gender and eGFR < 60 mL min -1 /1.73 m 2 increased odds of in-hospital mortality., Conclusion: We did not identify an association between ACE-I/ARB use and AKI, macrovascular thrombi or mortality. This supports the recommendations of the European and American Societies of Cardiology that ACE-Is and ARBs should not be discontinued during the COVID-19 pandemic., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Background: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response., Methods: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs., Discussion: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients., Trial Registration: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Purpose: Withdrawal of dopamine agonist (DA) therapy in patients with prolactinoma who are controlled by a small dose of medication is recommended by several guidelines. So far, the likelihood of reaching withdrawal conditions based on baseline characteristics remains uncertain., Methods: We retrospectively examined early clinical, radiological, or biochemical features that may predict the likelihood of reaching withdrawal conditions in prolactinoma patients. Data were obtained in a single academic medical center in the United States from patients seen between 2000 and 2018. Using multiple logistic regression, we compared patients who reached withdrawal conditions with those who did not., Results: Of 213 patients, 78 (36.6%) reached withdrawal conditions after at least 2 years of DA treatment. Initial maximal tumor diameter was significantly smaller in those who reached withdrawal conditions than in those who did not. Percent prolactin change at the first check from initiation of DA therapy and parasellar invasiveness were predictors of reaching withdrawal conditions. With constant independent variables, there was a 7% increase in odds for reaching withdrawal conditions for every 1% decrease in percent prolactin change at first check after DA therapy start (P = 0.0000). Parasellar invasion decreased the odds of reaching withdrawal conditions by 84% (P = 0.0000)., Conclusions: DA remains a potential life-long treatment modality for most prolactinoma patients. Patients with parasellar invasiveness and low prolactin percent change from baseline to first prolactin check are more likely to require long-term treatment., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

On April 12, 2020, a bioethics guide for allocating scarce hospital resources during the current Covid-19 pandemic was posted on the website of the Consejo de Salubridad General(CSG) of the Government of Mexico. The guide, entitled Guía bioética para asignación de recursos limitados de medicina crítica en situación de emergencia, was intended as a preliminary document, but the website posting did not describe it as a first step in the process. The publicity resulted in a wide array of comments and criticisms. That first version posted on the CSG website contained an age-based criterion for breaking a tie between two or more medically eligible patients who needed of a ventilator: younger patients would have prefer-ence over older ones. The final version of the guide eliminated that criterion and instead, relied on the leading public health principle, "save the most lives", without regard to personal characteristics other than the possibility of benefitting from the scarce medical resources., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

The bioethical inquiry about allocating fairly scarce health resources is not new, all countries around the world that were seriously afflicted by SARS-CoV-2 have issued triage guidelines in order to address the dilemmas raised by the pandemic. There is no question about the need to create bioethical guidelines, since its creation provides a degree of certainty that fair and ethical decisions are taken. This also prevents that decisions are made in solitary and maybe motivated by corrupted actions. In Mexico, the creation of this guideline was a proactive and preventive measure to what was unavoidable, the exponential contagion phase of the pandemical scenario caused by Covid-19. On April 30, 2020 the General Sanitary Council published the Bioethical Guide to Allocate Scarce Resources on Critical Care Medicine in Emergency Situation. This guide has at its core that principle of utmost importance in social justice which main thesis is: "All lives have the same value". The aim of this contribution is to provide the ethical and legal principles established in the aforementioned bioethi-cal guideline. In sum, a brief exploration of the ethical reasons that support a specific way to allocate scarce health resources is provided, as well as the foundations of the procedural part from a human rights-based approach., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Background: Elderly, patients with chronic kidney disease (CKD) and patients with heart failure who continue using renin-angiotensin-aldosterone-system (RAAS) inhibitors, diuretics, or non-steroidal-anti-inflammatory drugs (NSAIDs) during times of fluid loss have a high risk of developing complications like acute kidney injury (AKI). The aim of this study was to assess how often advice to discontinue high-risk medication was offered to high-risk patients consulting the general practitioner (GP) with increased fluid loss. Furthermore, we assessed the number and nature of the complications that occurred after GP consultation., Methods: We performed a cross-sectional study with patients from seven Dutch general practices participating in the Family Medicine Network between 1 and 6-2013 and 1-7-2018. We included patients who used RAAS-inhibitors, diuretics, or NSAIDs, and had at least one of the following risk factors: age ≥ 70 years, CKD, or heart failure. From this population, we selected patients with a 'dehydration-risk' episode (vomiting, diarrhoea, fever, chills, or gastrointestinal infection). We manually checked their electronic patient files and assessed the percentage of episodes in which advice to discontinue the high-risk medication was offered and whether a complication occurred in 3 months after the 'dehydration-risk' episode., Results: We included 3607 high-risk patients from a total of 44.675 patients (8.1%). We found that patients were advised to discontinue the high-risk medication in 38 (4.6%) of 816 'dehydration-risk' episodes. In 59 of 816 episodes (7.1%) complications (mainly AKI) occurred., Conclusions: Dutch GPs do not frequently advise high-risk patients to discontinue high-risk medication during 'dehydration-risk' episodes. Complications occur frequently. Timely discontinuation of high-risk medication needs attention.

Simply treating opioid addiction isn't enough. Instead, reposition your patient's singular circumstances and needs at the center of efforts to end use of these agents.

Background: Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients., Aim: To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients., Methods: A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy., Results: Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences., Conclusion: The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer., Competing Interests: Conflict-of-interest statement: The authors declare they have no conflicts of interest to disclose.

Introduction: Research supports the use of specific strategies to discontinue mechanical ventilation (MV) in critically ill patients. Little is known about how clinicians actually wean and discontinue MV in practice or the association between different discontinuation strategies and outcomes. The primary objective of this study is to describe international practices in the use of (1) daily screening for readiness to discontinue MV, (2) modes of MV used before initial discontinuation attempts, (3) weaning and spontaneous breathing trial (SBT) protocols, (4) SBT techniques and (5) sedation and mobilisation practices to facilitate weaning and discontinuation. The secondary objectives are to identify patient characteristics and time-dependent factors associated with use of selected strategies, investigate associations between SBT outcome (failure vs success) and outcomes, explore differences between patients who undergo an SBT early versus later in their intensive care unit (ICU) stay, and investigate the associations between different SBT techniques and humidification strategies on outcomes., Methods and Analysis: We will conduct an international, prospective, observational study of MV discontinuation practices among critically ill adults who receive invasive MV for at least 24 hours at approximately 150 ICUs in six geographic regions (Canada, USA, UK, Europe, India and Australia/New Zealand). Research personnel at participating ICUs will collect demographic data, data to characterise the initial strategy or event that facilitated discontinuation of MV (direct extubation, direct tracheostomy, initial successful SBT, initial failed SBT or death before any attempt could be made), clinical outcomes and site information. We aim to collect data on at least 10 non-death discontinuation events in each ICU (at least 1500 non-death discontinuation events)., Ethics and Dissemination: This study received Research Ethics Approval from St. Michael's Hospital (11-024) Research ethics approval will be sought from all participating sites. The results will be disseminated through publications in peer-reviewed journals., Trial Registration Number: NCT03955874., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Statins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients., Objective: To investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients., Design: We invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment., Main Measures: Cases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (OR adj ) were calculated for GPs' advice to stop., Key Results: Two thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (OR adj 13.8, 95%CI 12.6-15.1), with side effects compared to without OR adj 1.62 (95%CI 1.5-1.7) and with frailty (OR adj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (OR adj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99)., Conclusions: The absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.

Aims: Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups., Methods and Results: A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days., Conclusion: When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Very preterm birth (24 to < 32 week's gestation) is a major public health issue due to its prevalence, the clinical and ethical questions it raises and the associated costs. It raises two major clinical and ethical dilemma: (i) during the perinatal period, whether or not to actively manage a baby born very prematurely and (ii) during the postnatal period, whether or not to continue a curative treatment plan initiated at birth. The Wallonia-Brussels Federation in Belgium counts 11 neonatal intensive care units., Methods: An inventory of key practices was compiled on the basis of an online questionnaire that was sent to the 65 neonatologists working in these units. The questionnaire investigated care-related decisions and practices during the antenatal, perinatal and postnatal periods, as well as personal opinions on the possibility of standardising and/or legislating for end-of-life decisions and practices. The participation rate was 89% (n = 58)., Results: The results show a high level of homogeneity pointing to overall agreement on the main principles governing curative practice and the gestational age that can be actively managed given the current state of knowledge. There was, however, greater diversity regarding principles governing the transition to end-of-life care, as well as opinions about the need for a common protocol or law to govern such practices., Conclusion: Our results reflect the uncertainty inherent in the complex and diverse situations that are encountered in this extreme area of clinical practice, and call for qualitative research and expert debates to further document and make recommendations for best practices regarding several "gray zones" of end-of-life care in neonatology, so that high quality palliative care may be granted to all neonates concerned with end-of-life decisions.

Background: Appropriate cessation of chemotherapy and timely referral of patients to hospice services are crucial for the quality of care near death. We investigated the quality of care in our Cancer Institute in very advanced metastatic colorectal cancer patients treated in real life., Patients and Methods: We performed a retrospective analysis of electronic medical data of patients with metastatic colorectal cancer who were candidates for chemotherapy during the study period (1 January 2007-30 June 2014) and died before 31 December 2014. Quality-of-cancer-care indicators were calculated for the overuse of chemotherapy and referral to hospice. Predictive factors of chemotherapy discontinuation and hospice referral in end-of life care were investigated using parametric and nonparametric methods., Results: Of the 365 patients who died before 31 December 2014, 26 (7.1%) received chemotherapy in the last 14 days of life and 36 (9.8%) started a new chemotherapy regimen in the last 30 days of life. Factors associated with the overuse of chemotherapy were being < 70 years of age for both indicators and not having received advanced chemotherapy treatments for the former indicator. The majority of patients (74.7%) had access to hospice services, of whom only a small percentage (7.2%) accessed them very near to death., Conclusions: According to the criteria used, our Institute provides a good quality of cancer care for dying colorectal cancer patients, measured by the use of chemotherapy and referral to hospice in their last days of life.

Background: Neonatal deaths are often associated with the complex decision to limit or withdraw life-sustaining interventions (LSIs) rather than therapeutic impasses. Despite the existence of a law, significant disparities in clinical procedures remain. This study aimed to assess deaths occurring in a Neonatal Intensive Care Unit (NICU) and measure the impact of a traceable Limitation or Withdrawal of Active Treatment (LWAT) file on the treatment of these newborns., Methods: In this monocentric retrospective study, we reviewed all consecutive neonatal deaths occurring during two three-year periods among patients in the NICU at the North Hospital of Marseille: cohort 1 (from 2009 to 2011 without the LWAT file) and cohort 2 (from 2013 to 2015 after introduction of the LWAT file). Newborns included were: gestational age over 22 weeks, birth weight over 500 g, and admission and death in the same NICU. Deaths were categorized according to the classification described by Verhagen et al.: 1) children who died despite cardiopulmonary resuscitation (CPR) (no withholding nor withdrawing of LSIs), (2) children who died while the ventilator, without CPR (no withdrawing of LSIs, but CPR withheld), (3) children who died after LSIs were withdrawn, or (4) LSIs were withheld., Results: 193 deaths were analyzed: 77 in cohort 1 and 116 in cohort 2. 50% of deaths followed the decision to limit or stop life-sustaining interventions. The mean age at death did not differ between the two cohorts (p = 0.525). An increase in the mortality rate after life-sustaining interventions were withdrawn was observed. The number of multidisciplinary decision meetings was statistically higher in cohort 2 (32.5% versus 55.2% p = 0.002), which were most often prompted due to neurological pathologies, with an increase in parental advice concerning the management of their child (p = 0.026). Even if the introduction of this file did not have an effect on patient age at death, it was significantly associated with a better understanding of end-of-life conditions (p = 0.019), including medication used to sedate and comfort the patient., Conclusions: Introduction of the LWAT file seems imperative to develop a personalized healthcare strategy for each child and situation.

Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host's immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare.

History has shown that without explicit and enforced guidelines, even well-intentioned researchers can fail to adequately examine the ethical pros and cons of study design choices. One area in which consensus does not yet exist is the use of placebo groups in vitamin supplementation studies. As a prime example, we focus on vitamin D research. We aim to provide an overview of the ethical issues in placebo-controlled studies and guide future discussion about the ethical use of placebo groups. Research in the field of vitamin D shows variation in how placebo groups are used. We outline four types of control groups in use: active-control, placebo-control with restrictions on supplementation, placebo-control without supplementation restrictions, and placebo-control with rescue repletion therapy. The first two types highlight discrete ethical issues: active-control trials limit the ability to detect a difference; placebo-control trials that restrict supplementation potentially place subjects at risk of undue harm. The final two, placebo-control without supplementation restrictions or with rescue repletion therapy, offer potential solutions to these ethical challenges. Building on this, guidelines should be established and enforced on the use of placebo in supplementation studies. Furthermore, the field of vitamin D research has the potential to set an example worthy of emulation., Competing Interests: The authors declare no conflict of interest.

Background: Oral contraceptive pills (OCPs) are currently used by approximately 16% of all women aged 15 to 44 in the United States and have been used by 80% of all sexually active women at some point in their lives. However, no guidelines exist for discontinuation of OCP therapy before or after elective cosmetic surgery., Objectives: The aim of this study is to establish current practice trends regarding perioperative OCP management in aesthetic surgery., Methods: An eight-item online survey was distributed to members of the American Society of Plastic Surgeons (ASPS). Survey results were analyzed to determine if surgeons' practice setting, years of experience, annual cosmetic volume, or types of cosmetic procedures performed affected their perioperative management of OCPs., Results: A total of 220 questionnaires were collected (11.9% response rate). Only 31.8% of surgeons reported any discontinuation of OCPs pre- or postoperatively. Among physicians, 7.3% reported only preoperative discontinuation, 24.5% reported OCP discontinuation both pre- and postoperatively, and 0.0% of physicians reported discontinuation of OCPs only postoperatively. There was no statistically significant difference between the percentage of surgeons in academic practice who discontinue OCPs perioperatively (P = 0.335). There was no statistical significance towards overall years in practice (P = 0.152). There were no significant differences between the three groups in the number of cosmetic procedures performed annually or percentage breakdown of procedures performed., Conclusions: Despite OCP therapy being a known risk factor for venous thromboembolic events, a majority of surgeons performing cosmetic surgery do not routinely recommend perioperative cessation., (© 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com)

Objective: We reviewed our decisions about continuation/withdrawal of life-sustaining treatments in a group of critically ill newborns who were discussed in structured medical ethical decision-making meetings, and provide the surviving children's outcomes at 2-year follow-up., Study Design: In an explorative observational study, 61 cases were evaluated. The children involved had been discussed in such a structured way from 2009 to 2012 in a level III-D neonatal intensive care unit., Results: Decisions made were: full treatment (n=6), earlier restriction cancelled (n=3), treatment restriction (n=30) and palliative care (n=22). Parents of six children disagreed with the decision proposed. Thirteen (54%) of the 24 children who survived (39%) had moderate to severe neurological problems; 8 (33%) had additional sequelae; only one 2-year-old child was healthy., Conclusions: Decisions made varied to a large extent. The poor outcomes should be disseminated among decision makers. Future studies must explore new ways to improve outcome prediction, extend follow-up periods and consider what living with severe handicaps really means for both child and family.

The multiple drug resistant organism (MDRO) and Clostridium difficile infection (CDI) epidemics are progressing relentlessly. Antibiotic stewardship (ABS) has evolved to confront these scourges. The Joint Commission has formulated a standard for its implementation and this should promote its use where others have failed. However, precisely how to intervene needs definition. Healthcare workers need practicable guidelines. The article discusses clinical scenarios where antibiotics should be withheld (Table 1), how they should be modified (Table 2) and when they should be discontinued (Table 3), three focal points of ABS.

Rationale: Predictions about neurologic prognosis that are based on early clinical findings after out-of-hospital cardiac arrest (OHCA) are often inaccurate and may lead to premature decisions to withdraw life-sustaining treatments (LST) in patients who might otherwise survive with good neurologic outcomes., Objectives: To improve adherence to recommendations for appropriate neurologic prognostication after OHCA and reduce deaths from premature decisions to withdraw LST., Methods: This was a pragmatic stepped wedge cluster randomized controlled trial evaluating a multifaceted quality intervention (education, pathways, local champions, audit-feedback). The primary outcome was appropriate neurologic prognostication, defined as (1a) no early withdrawal of LST (WLST) (within 72 h) based on estimates of poor neurologic prognosis and (1b) no WLST between 72 hours and 7 days in absence of clinical predictors of poor neurologic prognosis or (2) surviving beyond 7 days. Secondary outcomes were deaths from early WLST and survival with good neurologic outcome., Measurements and Main Results: Between June 1, 2011, and June 30, 2014, a total of 905 patients with OHCA were enrolled from ICUs of 18 Ontario hospitals. Rates of appropriate neurologic prognostication increased after the intervention (68% vs. 74% patients; odds ratio [OR], 1.79; 95% confidence interval [CI], 1.01-3.19; P = 0.05). However, rates of survival to hospital discharge (46% vs. 50%; OR, 1.71; 95% CI, 0.97-3.01; P = 0.06) and survival with good neurologic outcome remained similar (38% vs. 43%; OR, 1.43; 95% CI, 0.84-2.86; P = 0.19)., Conclusions: A multicenter quality intervention improved rates of appropriate neurologic prognostication after OHCA but did not increase survival with good neurologic outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 01472458).

In deciding whether it is time to stop hormone therapy, in addition to the patient's age we need to consider her preferences, symptoms, quality of life, time since menopause, hysterectomy status, and personal risks of osteoporosis, breast cancer, heart disease, stroke, and venous thromboembolism. This article presents the evidence for and against extending hormone therapy and a guide for making this highly individualized and shared decision., (Copyright © 2016 Cleveland Clinic.)

Background: During out-of-hospital cardiac arrest, it is unclear how long prehospital resuscitation efforts should be continued to maximize lives saved., Methods and Results: Between 2005 and 2012, we enrolled 282 183 adult patients with bystander-witnessed out-of-hospital cardiac arrest from the All-Japan Utstein Registry. Prehospital resuscitation duration was calculated as the time interval from call receipt to return of spontaneous circulation in cases achieving prehospital return of spontaneous circulation or from call receipt to hospital arrival in cases not achieving prehospital return of spontaneous circulation. In each of 4 groups stratified by initial cardiac arrest rhythm (shockable versus nonshockable) and bystander resuscitation (presence versus absence), we calculated minimum prehospital resuscitation duration, defined as the length of resuscitation efforts in minutes required to achieve ≥99% sensitivity for the primary end point, favorable 30-day neurological outcome after out-of-hospital cardiac arrest. Prehospital resuscitation duration to achieve prehospital return of spontaneous circulation ranged from 1 to 60 minutes. Longer prehospital resuscitation duration reduced the likelihood of favorable neurological outcome (adjusted odds ratio, 0.84; 95% confidence interval, 0.838-0.844). Although the frequency of favorable neurological outcome was significantly different among the 4 groups, ranging from 20.0% (shockable/bystander resuscitation group) to 0.9% (nonshockable/bystander resuscitation group; P<0.001), minimum prehospital resuscitation duration did not differ widely among the 4 groups (40 minutes in the shockable/bystander resuscitation group and the shockable/no bystander resuscitation group, 44 minutes in the nonshockable/bystander resuscitation group, and 45 minutes in the nonshockable/no bystander resuscitation group)., Conclusions: On the basis of time intervals from the shockable arrest groups, prehospital resuscitation efforts should be continued for at least 40 minutes in all adults with bystander-witnessed out-of-hospital cardiac arrest., Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/. Unique identifier: 000009918., (© 2016 American Heart Association, Inc.)

Objective: To determine the half-life of serum caffeine concentrations and its relation to apnea of prematurity (AOP) after caffeine is discontinued in preparation for hospital discharge., Study Design: Prospective cohort study involving preterm infants with gestational ages ⩽33 weeks at birth. After caffeine was discontinued, serum caffeine concentrations and electronic detection of pathologic apnea, defined a priori, were obtained at 24 and 168 h, respectively., Result: Caffeine levels decreased from 13.3±3.8 to 4.3±2 mg l(-1) (n=50, mean±s.d.) at 24 and 168 h, respectively (P<0.01). The mean caffeine half-life was 87±25 h at 35±1 weeks postmenstrual age. Seven days after discontinuation of caffeine, 64% of the infants had pathologic apnea., Conclusion: Hospital discharge planning for preterm infants with a history of AOP should be carefully considered after discontinuing caffeine. This study showed that caffeine may not reach subtherapeutic levels until around 11-12 days.

Great differences in end-of-life practices in treating the critically ill around the world warrant agreement regarding the major ethical principles. This analysis determines the extent of worldwide consensus for end-of-life practices, delineates where there is and is not consensus, and analyzes reasons for lack of consensus. Critical care societies worldwide were invited to participate. Country coordinators were identified and draft statements were developed for major end-of-life issues and translated into six languages. Multidisciplinary responses using a web-based survey assessed agreement or disagreement with definitions and statements linked to anonymous demographic information. Consensus was prospectively defined as >80% agreement. Definitions and statements not obtaining consensus were revised based on comments of respondents, and then translated and redistributed. Of the initial 1,283 responses from 32 countries, consensus was found for 66 (81%) of the 81 definitions and statements; 26 (32%) had >90% agreement. With 83 additional responses to the original questionnaire (1,366 total) and 604 responses to the revised statements, consensus could be obtained for another 11 of the 15 statements. Consensus was obtained for informed consent, withholding and withdrawing life-sustaining treatment, legal requirements, intensive care unit therapies, cardiopulmonary resuscitation, shared decision making, medical and nursing consensus, brain death, and palliative care. Consensus was obtained for 77 of 81 (95%) statements. Worldwide consensus could be developed for the majority of definitions and statements about end-of-life practices. Statements achieving consensus provide standards of practice for end-of-life care; statements without consensus identify important areas for future research.

Each year, out-of-hospital cardiac arrests occur in approximately 300,000 Americans. Of these patients, less than 10% survive. Survivors often live with neurologic impairments that neurologists classify as anoxic-ischemic encephalopathy (AIE). Neurologic impairments under AIE can vary widely, each with unique outcomes. According to the American Academy of Neurology Practice Parameter paper, the definition of poor outcome in AIE includes death, persistent vegetative state (PVS), or severe disability requiring full nursing care 6 months after event. In a recent survey, participants deemed an outcome of PVS as "worse than dead." Lay persons' assessments of quality of life for those in a PVS provide assistance for surrogate decision-makers who are confronted with the clinical decision-making for a loved one in a PVS, whereas clinical practice guidelines help health care providers to make decisions with patients and/or families. In 2000, the Renal Physicians Association and the American Society of Nephrology published a clinical practice guideline, "Shared Decision-Making in the Appropriate Initiation of and Withdrawal from Dialysis." In 2010, after advances in research, a second edition of the guideline was published. The updated guideline confirmed the recommendation to withhold or withdraw ongoing dialysis in "patients with irreversible, profound neurological impairments such that they lack signs of thought, sensation, purposeful behavior and awareness of self and environment," such as found in patients with PVS. Here, the authors discuss the applicability of this guideline to patients in a PVS. In addition, they build on the guideline's conception of shared decision-making and discuss how continued dialysis violates ethical and legal principles of care in patients in a PVS.

The Italian League Against Epilepsy has issued evidence-based guidelines to help practicing physicians in their decision to stop or withhold antiepileptic drugs (AEDs) in patients achieving a prolonged period of seizure freedom. Six adult and two child neurologists, divided into four pairs, critically appraised 128 published reports and provided graded recommendations answering 15 key questions: length of the seizure-free period after treatment initiation, difference in seizure-free periods in children and adults, electroencephalography (EEG) pattern at the time of discontinuation, etiology of epilepsy, seizure type(s), patient's age and sex, family history of epilepsy, history of febrile seizures, epilepsy syndrome, seizure frequency before entering remission, duration of active epilepsy, tapering period, number and type of AEDs taken at time of discontinuation, combination of risk factors for recurrence, and length of patient monitoring after treatment discontinuation. Based on the available data, the following recommendations can be outlined: (1) antiepileptic treatment might be discontinued after a minimum period of 2 years of seizure freedom; shorter seizure-free periods are associated to a higher risk of relapse; (2) in children, AED discontinuation could be considered after less than two seizure-free years because of a marginally higher risk of relapse for early withdrawal; (3) factors, such as abnormal EEG (including epileptiform abnormalities) at the time of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatal insults, and abnormal neurologic examination), partial seizures, or an older age at disease onset, enhance the risk of relapse; however, patients should not be encouraged to withhold treatment unless a combination of two or more of these factors is present; (4) female sex, family history of epilepsy, history of febrile seizures, disease length/severity, and number and type of drugs taken should not influence the decision to stop treatment; (5) epilepsy syndrome should be always included in the decision process; (6) slow (at least 6 months) AED discontinuation should be encouraged; in any case the duration of the tapering period should be tailored to the patient's needs and preference; and (7) patient discontinuing treatment should be followed for no <2 years. As a general habit, the decision to stop treatment should be discussed and shared with each patient, taking into account social and personal complications of a seizure relapse and the medical complications of chronic AED treatment., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Overuse or misuse of tests and treatments exposes patients to potential harm. The American Board of Internal Medicine Foundation's Choosing Wisely® campaign is a multiyear effort to encourage physician leadership in reducing harmful or inappropriate resource utilization. Via the campaign, medical societies are asked to identify five tests or procedures commonly used in their field, the routine use of which in specific clinical scenarios should be questioned by both physicians and patients based on the evidence that the test or procedure is ineffective or even harmful. The American Academy of Hospice and Palliative Medicine (AAHPM) was invited, and it agreed to participate in the campaign. The AAHPM Choosing Wisely Task Force, with input from the AAHPM membership, developed the following five recommendations: 1) Don't recommend percutaneous feeding tubes in patients with advanced dementia; instead, offer oral-assisted feeding; 2) Don't delay palliative care for a patient with serious illness who has physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment; 3) Don't leave an implantable cardioverter-defibrillator activated when it is inconsistent with the patient/family goals of care; 4) Don't recommend more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis; and 5) Don't use topical lorazepam (Ativan®), diphenhydramine (Benadryl®), and haloperidol (Haldol®) (ABH) gel for nausea. These recommendations and their supporting rationale should be considered by physicians, patients, and their caregivers as they collaborate in choosing those treatments that do the most good and avoid the most harm for those living with serious illness., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to evaluate shorter duration (3 months) dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation., Background: There have been few published reports of prospective randomized clinical studies comparing the safety and efficacy of shorter duration DAPT after DES implantation., Methods: We randomly assigned 2,117 patients with coronary artery stenosis into 2 groups according to DAPT duration and stent type: 3-month DAPT following Endeavor zotarolimus-eluting stent (E-ZES) implantation (E-ZES+3-month DAPT, n=1,059) versus 12-month DAPT following the other DES implantation (standard therapy, n=1,058). We hypothesized that the E-ZES+3-month DAPT would be noninferior to the standard therapy for the primary composite endpoint (cardiovascular death, myocardial infarction, stent thrombosis, target\vessel revascularization, or bleeding) at 1 year., Results: The primary endpoint occurred in 40 (4.7%) patients assigned to E-ZES+3-month DAPT compared with 41 (4.7%) patients assigned to the standard therapy (difference: 0.0%; 95% confidence interval [CI]: -2.5 to 2.5; p=0.84; p<0.001 for noninferiority). The composite rates of any death, myocardial infarction, or stent thrombosis were 0.8% and 1.3%, respectively (difference: -0.5%; 95% CI: -1.5 to 0.5; p=0.48). The rates of stent thrombosis were 0.2% and 0.3%, respectively (difference: -0.1%; 95% CI: -0.5 to 0.3; p=0.65) without its further occurrence after cessation of clopidogrel in the E-ZES+3-month DAPT group. The rates of target vessel revascularization were 3.9% and 3.7%, respectively (difference: 0.2%; 95% CI: -2.3 to 2.6; p=0.70)., Conclusions: E-ZES+3-month DAPT was noninferior to the standard therapy with respect to the occurrence of the primary endpoint. (REal Safety and Efficacy of a 3-month dual antiplatelet Therapy following E-ZES implantation [RESET]; NCT01145079)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the decision-making process of withholding and/or withdrawal (WH/WD) of life-sustaining treatment in cardiac intensive care units (ICUs) in Germany., Methods: A questionnaire regarding 16 medical and 6 ethical questions of WH/WD of life-sustaining treatment was distributed to the clinical director, senior ICU physician and head nurses of all German heart surgery centres (n = 237 questionnaires). Furthermore, we present a literature survey using the key words 'End-of-life care AND withholding/withdrawal of life support therapy AND intensive care unit'., Results: We received replies from 86 of 237 (36.3%) contacted persons. Concerning medical reasons, cranial computed tomography (CCT) with poor prognosis (91.9%), multi-organ failure (70.9%) and failure of assist device therapy (69.8%) were the three most frequently cited medical reasons for WH/WD life-sustaining treatment. Overall, 32.6% of persons answered that ethical aspects influence their decision-making processes. Poor expected quality of life (48.8%), the patient's willingness to limit medical care (40.7%) and the families' choice (27.9%) were the top three reported ethical reasons. There was a significant difference regarding the perception of the three involved professional groups concerning the decision-making parameters: multi-organ failure (P = 0.018), failure of assist device therapy (P = 0.001), cardiac index (P = 0.009), poor expected quality of life (P = 0.009), the patient's willingness to limit medical care (P = 0.002), intraoperative course (P = 0.054), opinion of family members (P = 0.032) and whether decision-making process are done collaboratively (clinical director, 45.7%; ICU physician, 52%; and head of nursing staff, 26.9%). Palliation medication in patients after WH/WD of life-support consisted of morphine (92%) and benzodiazepines (88%)., Conclusions: This survey is a step towards creating standards of end-of-life care in cardiac ICUs, which may contribute to build consensus and avoid conflicts among caregivers, patients and families at each step of the decision-making process.

Chronic migraine (CM) represents migraine natural evolution from its episodic form. It is realized through a chronicization phase that may require months or years and varies from patient to patient. The transition to more frequent attacks pattern is influenced by lifestyle, life events, comorbid conditions and personal genetic terrain, and it often leads to acute drugs overuse. Medication overuse headache (MOH) may complicate every type of headache and all the drugs employed for headache treatment can cause MOH. The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. The goal is not only to detoxify the patient and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs. Different methods have been suggested: gradual or abrupt withdrawal; home treatment, hospitalization, or a day-hospital setting; re-prophylaxes performed immediately or at the end of the wash-out period. Up to now, only topiramate and local injection of onabotulinumtoxinA have shown efficacy as therapeutic agents for re-prophylaxis after detoxification in patients with CM with and without medication overuse. Although the two treatments showed similar efficacy, onabotulinumtoxinA is associated with a better adverse events profile. Recently, the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program proved that patients with CM, even those with MOH, are the ones most likely to benefit from onabotulinumtoxinA treatment. Furthermore, it provided an injection paradigm that can be used as a guide for a correct administration of onabotulinumtoxinA.