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The excessive and uncontrolled use of pyrethroids, such as cypermethrin (CP), for pest control in Nigeria could adversely affect humans. This study aimed to investigate the oxidative stress response to cypermethrin exposure, focusing on measuring the parameters (i.e., malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)) and the potential therapeutic effects of single and co-administration of ascorbate and alpha-tocopherol. The lungs and hearts of the animals were histologically examined for cypermethrin-induced cytopathic changes. Twenty-five adult male Wistar rats weighing 180–200 g were randomly assigned to five groups, each consisting of five animals. Group I was the control group that was not subjected to any treatment. Group II was orally exposed to cypermethrin at a dosage of 10 mg/kg bw without any additional treatment. Groups III, IV, and V received cypermethrin at standard doses of 10 mg/kg bw and were orally administered with ascorbate (5,000 mg/kg bw), alpha-tocopherol (3,000 mg/kg bw), and a coadministration of ascorbate (5,000 mg/kg bw) and alpha-tocopherol (3,000 mg/kg bw), respectively. The animals were euthanized after 28 days, and samples were processed for histological analysis using hematoxylin and eosin staining. Analysis of variance (ANOVA) and Duncan's multiple range test were used to compare categorical variables of the biochemical parameters and determine the levels of MDA, SOD, GPx, and CAT. The data analysis revealed that the cypermethrin-exposed, untreated rats had elevated MDA levels and a concurrently marked decrease in SOD, GPx, and CAT activities (p<0.05). Additionally, the histopathological examination of the organs indicated inflammation and congestion. The co-administration of ascorbate and alpha-tocopherol restored the biochemical parameters more effectively compared to when the substances were administered individually. In conclusion, co-administration of ascorbic acid and alphatocopherol ameliorates cypermethrin-induced oxidative damage more effectively than a single administration of either substance. This may be due to the synergistic antioxidant properties of the substances. [ABSTRACT FROM AUTHOR]

Aim. The aim of this review was to support nursing management in creating frameworks for the care of people requesting hastened death, based on the best available evidence on the experiences of nurses. Background. The legalisation of hastened death presents nurses with a complex set of ethical and moral risks. The largely unregulated role of nurses in the politics of hastened death can lead to moral distress and burnout. Evaluation. A systematic database search was conducted in CINAHL, LIVIVO, Medline, OVID, and Web of Science. The meta-aggregative approach was used to synthesise the findings. Quality appraisal was done using criteria of the Joanna Briggs Institute. Key Issues. Sixteen studies from four different countries were included. Interview data were from 200 nurses. Meta-aggregation resulted in ten synthesised findings including the need for guidelines; time resources; a supporting team; and professional, social, and personal skills. Conclusions. A working environment with clear guidelines, sufficient resources, structured professional adjustment programmes, and educational measures is supportive for nurses. Implications for Nursing Management. Nursing management should create a professional strategy, guidelines, promote good team culture, implement education, and training activities. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The objectives were to describe mortality and causes of death in children with intraventricular hemorrhage (IVH) and to study neurodevelopmental outcomes. METHODS: The study was a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. Children were recruited in 2011. A standardized assessment was conducted at age 5. Children born before 32 weeks' gestation and admitted to a NICU were eligible. Exposure was IVH defined by the Papile classification. Main outcomes were mortality, causes of death, and neurodevelopmental outcomes at age 5. RESULTS: Among the 3468 children included, 578 (16.7%) had grade 1 IVH, 424 (12.2%) grade 2 IVH, and 114 (3.3%) grade 3 IVH; 144 (4.1%) had intraparenchymal hemorrhage (IPH). Mortality was 29.7% (36 of 114) for children with grade 3 IVH and 74.4% (109 of 144) for those with IPH; 67.6% (21 of 31) and 88.7% (86 of 97) of deaths, respectively, were because of withholding and withdrawing of life-sustaining treatment. As compared with no IVH, low-grade IVH was not associated with measured neurodevelopmental disabilities at age 5. High-grade IVH was associated with moderate and severe neurodevelopmental disabilities, reduced full-scale IQ, and cerebral palsy. CONCLUSIONS: Rates of neurodevelopmental disabilities at age 5 did not differ between children without IVH and those with low-grade IVH. For high-grade IVH, mortality rate was high, mostly because of withholding and withdrawal of life-sustaining treatment, and we found a strong association with overall neurodevelopmental disabilities in survivors. [ABSTRACT FROM AUTHOR]

Context: The provision of potentially non-beneficial life-sustaining treatments (LSTs) remains a challenging problem. In 2005, legislation in France established an interprofessional process by which non-beneficial LSTs could be withheld or withdrawn, permitting exploration of the effects of such a legally-protected process and its implementation.Objectives: To characterize intensive care unit (ICU) interprofessional team decision-making and consensus-building practices regarding withholding and withdrawing of LSTs in two Parisian hospitals and to explore physician and nurse perceptions of and experiences with these practices.Methods: This was an exploratory qualitative study utilizing thematic analysis of semi-structured, in-depth interviews of physicians and nurses purposively sampled based on level of training and experience from two hospitals in Paris, France.Results: A total of 25 participants were interviewed. Participants reported that the two Parisian hospitals in this study have each created an interprofessional process for withholding or withdrawing non-beneficial LSTs, providing insight into how norms of decision-making respond to systems-level legal changes. Participants reported that these processes tended to be consistent across several domains: maintaining unified messaging with patients, empowering nurses to participate in end-of-life decision-making, reducing moral distress provoked by end-of-life decisions, and shaping the ethical milieu within which end-of-life decision-making takes place.Conclusions: The architecture of the interprofessional process created at two Parisian hospitals and its perceived benefits may be useful to clinicians and policy-makers attempting to establish processes, policies, or legislation directed at withholding or withdrawing potentially non-beneficial LSTs in the United States and elsewhere. [ABSTRACT FROM AUTHOR]

Aim: To elicit preferences for prognostic information, attitudes towards withdrawal of life-sustaining treatment (WLST) and perspectives on acceptable quality of life after post-anoxic coma within the adult general population of Germany, Italy, the Netherlands and the United States of America.Methods: A web-based survey, consisting of questions on respondent characteristics, perspectives on quality of life, communication of prognostic information, and withdrawal of life-sustaining treatment, was taken by adult respondents recruited from four countries. Statistical analysis included descriptive analysis and chi2-tests for differences between countries.Results: In total, 2012 respondents completed the survey. In each country, at least 84% indicated they would prefer to receive early prognostic information. If a poor outcome was predicted with some uncertainty, 37-54% of the respondents indicated that WLST was not to be allowed. A conscious state with severe physical and cognitive impairments was perceived as acceptable quality of life by 17-44% of the respondents. Clear differences between countries exist, including respondents from the U.S. being more likely to allow WLST than respondents from Germany (OR = 1.99, p < 0.001) or the Netherlands (OR = 1.74, p < 0.001) and preferring to stay alive in a conscious state with severe physical and cognitive impairments more than respondents from Italy (OR = 3.76, p < 0.001), Germany (OR = 2.21, p < 0.001), or the Netherlands (OR = 2.39, p < 0.001).Conclusions: Over one-third of the respondents considered WLST unacceptable when there is any remaining prognostic uncertainty. Respondents had a more positive perspective on acceptable quality of life after coma than what is currently considered acceptable in medical literature. This indicates a need for a closer look at the practice of WLST based on prognostic information, to ensure responsible use of novel prognostic tests. [ABSTRACT FROM AUTHOR]

Background: Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet β-blockers are commonly used in HFpEF despite the lack of robust evidence.Objectives: This study aimed to evaluate the effect of β-blocker withdrawal on peak oxygen consumption (peak Vo2) in patients with HFpEF and chronotropic incompetence.Methods: This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with β-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) β-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo2 and percentage of predicted peak Vo2 (peak Vo2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used.Results: The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo2 and peak Vo2% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo2 and peak Vo2% increased significantly after β-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively).Conclusions: β-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. β-blocker use in HFpEF deserves profound re-evaluation. (β-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39). [ABSTRACT FROM AUTHOR]

Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system.Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group.Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine.Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of withholding doxycycline on the success rate of natural cycle frozen embryo transfers (NC-FET).Design: Retrospective cohort study.Setting: Single academic institution.Patient(s): Women undergoing 250 NC-FET with euploid blastocysts performed by a single provider.Intervention(s): One hundred and twenty-five NC-FET cycles performed after January 2019 without antibiotic administration compared with 125 NC-FET cycles before January 2019 with doxycycline administration.Main Outcome Measure(s): Primary outcome: live birth (LB) or ongoing pregnancy rate (OPR, defined as pregnancies ≥13 weeks); secondary outcomes included positive β-human chorionic gonadotropin (β-hCG) level and clinical pregnancy rate (CPR, defined as the presence of fetal cardiac activity on ultrasound).Result(s): Each group of women comprised 125 NC-FET during the study period of March 2017 to March 2020. The women's mean age was 36.3 years and mean body mass index was 24 kg/m2. Between the two groups, the baseline characteristics were similar, including age, body mass index, race, smoking status, parity, endometrial thickness, Society of Assisted Reproductive Technology diagnosis, and number of prior failed transfers. Comparing NC-FET with doxycycline administration versus without, we found no statistically significant difference in LB-OPR (64% vs. 62.6%), positive β-hCG (72.8% vs. 74.0%), or CPR (68% vs. 65.9%). After controlling for all variables in a logistic regression, doxycycline still had no effect on LB-OPR.Conclusion(s): In this analysis of similar patients undergoing NC-FET by a single provider, withholding doxycycline does not reduce success rates. Given the risks of antibiotics, our findings support withholding their use in NC-FET. [ABSTRACT FROM AUTHOR]

Background: More effective recruitment strategies like alternative approaches to consent are needed to facilitate adequately powered trials. Witholding Enteral feeds Around Transfusion was a multicentre, randomised, pilot trial that compared withholding and continuing feeds around transfusion. The primary clinical outcome was necrotising enterocolitis. The trial used simplified opt-out consent with concise parent information and no consent form.Objective: To explore the views and experiences of parents and health professionals on the acceptability and feasibility of opt-out consent in randomised comparative effectiveness trials.Methods: A qualitative, descriptive interview-based study nested within a randomised trial. Semistructured interview transcripts were analysed using inductive thematic analysis.Setting: Eleven neonatal units in England.Participants: Eleven parents and ten health professionals with experience of simplified consent.Results: Five themes emerged: 'opt-out consent operationalised as verbal opt-in consent', 'opt-out consent normalises participation while preserving parental choice', 'opt-out consent as an ongoing process of informed choice', 'consent without a consent form' and 'choosing to opt out of a comparative effectiveness trial', with two subthemes: 'wanting "normal care"' and 'a belief that feeding is better'.Conclusion: Introducing a novel form of consent proved challenging in practice. The principle of a simplified, opt-out approach to consent was generally considered feasible and acceptable by health professionals for a neonatal comparative effectiveness trial. The priority for parents was having the right to decide about trial participation, and they did not see opt-out consent as undermining this. Describing a study as 'opt-out' can help to normalise participation and emphasise that parents can withdraw consent. [ABSTRACT FROM AUTHOR]

Aims: The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.Methods/results: We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.Conclusion: Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation. [ABSTRACT FROM AUTHOR]

Introduction: The basic human right is the right to life, along with the issue of the right to die. Euthanasia, as the right to die, is an urgent problem, the solution of which takes place on the border of medical science and jurisprudence. The Aim: Analyze the international experience of social and legal regulation of euthanasia. Materials and Method: To achieve the set goal, research method such as a comparative law method, theoretical analysis, system-analytical method and a method of conclusions systematization were applied is not prohibited, but it is not legalized in Germany, Spain, France, Albania, Israel. Conclusions: Analyzing the current international experience of euthanasia legal regulation, it stands to mention that even with the prohibition of euthanasia, there are some gaps in the legislation, which create the possibility of passive euthanasia legal use by means of terminating life sustaining measures. It is important to enshrine the rules clearly regulating euthanasia in international law, otherwise this issue will be latent, and in the countries where there are legal gaps, excessive use of euthanasia will take place. [ABSTRACT FROM AUTHOR]

Background: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.Objectives: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).Methods: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.Results: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.Conclusions: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977). [ABSTRACT FROM AUTHOR]

Objectives: The influence of different forms of treatment limitation on mortality rate in the ICU is not known despite the common use of the latter as a quality indicator. The aim of the present study was to assess the prevalence of treatment limitation and its influence on ICU mortality rate. Primary outcomes were prevalence of treatment limitation and its influence on severity-adjusted ICU mortality rate. Secondary outcomes included the association of limitation with age, sex, type of admission, diagnostic group, treatment intensity, and length of ICU stay.Design: Retrospective, observational study.Setting: All Swiss adult ICUs.Interventions: None.Patients: A total of 166,764 patients were admitted to an ICU in 2016 and 2017. Of these, 9139 were excluded because of readmission or invalid coding.Measurements and Main Results: Of 157,625 ICU patients, 20,916 (13.3%) had a fully defined treatment limitation. Among this group, treatment limitation was defined upon ICU admission in 12,854 (61%), the decision to limit treatment was based on the patient's advance directives in 9,951 (48%), and in 15,341 (73%), there was a decision to deliberately withhold certain treatment modalities. The mortality odds ratio for the group with a treatment limitation, considering relevant cofactors, was 18.1 (95% CI 16.8-19.4).Conclusions: Every seventh patient in a Swiss ICU has some kind of treatment limitation, and this most probably affects the severity-adjusted mortality rate. Thus, mortality data as a quality indicator or benchmark in intensive care can only meaningfully be interpreted if existence, grade, cause, and time of treatment limitation are taken into account. [ABSTRACT FROM AUTHOR]

Background: Adjuvant trastuzumab for early-stage (I-III) HER2-positive breast cancer (BC) has led to statistically significant improvement in cancer outcomes but carries a risk of cardiotoxicity. Trastuzumab is discontinued early in many patients for asymptomatic changes in left ventricular ejection fraction. We evaluated the impact of early discontinuation of trastuzumab on cancer outcomes.Methods: We conducted a retrospective population-based cohort study of early BC patients treated with adjuvant trastuzumab in Ontario, Canada, 2007-2016. Four groups were analyzed: group A was full treatment, 17-18 cycles trastuzumab; group B was cardiac event (CE) within treatment period; group C was ≤16 cycles, no CEs, stopped within 30 days from last cardiac imaging; and group D was ≤16 cycles, no CEs, stopped more than 30 days from cardiac imaging. Primary outcome was disease-free survival (DFS); secondary outcomes were: overall survival, cancer-specific mortality, and cardiovascular mortality. Sensitivity analyses were performed 14 months after cycle 1 trastuzumab to control for early relapse.Results: A total of 5547 patients met the inclusion criteria: group A = 3921, group B = 309, group C = 362, and group D = 955. The 5-year DFS was 94.1% in group A, 80.1% in group B, 81.4% in group C, and 82.4% in group D. Using a Cox model, the hazard ratio for 5-year DFS was 3.15 (95% confidence interval [CI] = 2.13 to 4.65) for group B, 1.94 (95% CI = 1.30 to 2.89) for group C, and 1.92 (95% CI = 1.46 to 2.53) for group D. Overall, 26 patients (0.5%) died of cardiac causes.Conclusions: BC patients in Ontario who did not complete adjuvant trastuzumab had a statistically significantly higher risk of BC relapse and death and low incidence of cardiac death. These findings support 1 year of adjuvant trastuzumab in early-stage BC. [ABSTRACT FROM AUTHOR]

Background: Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA.Methods: We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored.Results: Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs <2000 IU/mL) was associated with increased risks of clinical relapse (hazard ratio, 3.47; 95% confidence interval, 1.56-7.73) and hepatic decompensation (9.91; 2.14-45.92). Of 51 patients with pretreatment viral load <2000 IU/mL, clinical relapse occurred in 10 (19.6 %) and hepatic decompensation in 2 (3.9%).Conclusions: Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Data are scarce on the withdrawal of life-sustaining therapies and limitation of care orders (LCOs) during physician-staffed Helicopter Emergency Medical Service (HEMS) missions. We investigated LCOs and the quality of information available when physicians made treatment decisions in pre-hospital care.Methods: A prospective, nationwide, multicentre study including all Finnish physician-staffed HEMS bases during a 6-month study period. All HEMS missions where a patient had pre-existing LCOs and/or a new LCO were included.Results: There were 335 missions with LCOs, which represented 5.7% of all HEMS missions (n = 5895). There were 181 missions with pre-existing LCOs, and a total of 170 new LCOs were issued. Usually, the pre-existing LCO was a do not attempt cardiopulmonary resuscitation order only (n = 133, 74%). The most frequent new LCO was 'termination of cardiopulmonary resuscitation' only (n = 61, 36%), while 'no intensive care' combined with some other LCO was almost as common (n = 54, 32%). When issuing a new LCO for patients who did not have any preceding LCOs (n = 153), in every other (49%) case the physicians thought that the patient should have already had an LCO. When the physician made treatment decisions, patients' background information from on-scene paramedics was available in 260 (78%) of the LCO missions, while patients' medical records were available in 67 (20%) of the missions.Conclusion: Making LCOs or treating patients with pre-existing LCOs is an integral part of HEMS physicians' work, with every twentieth mission involving LCO patients. The new LCOs mostly concerned withholding or withdrawal of cardiopulmonary resuscitation and intensive care. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined survival in intensive care unit (ICU) patients after the restriction of life-sustaining treatment (LST). We aimed to analyse independent factors associated with hospital and 12-month survival rates in ICU patients after treatment restrictions.Methods: This retrospective observational study examined all patients treated in adult ICUs from 1 January 2016 until 31 December 2016 included in the Finnish ICU Registry. Multivariable logistic regression analysis was performed to explain the effect on survival.Results: Decisions to limit LST were made for 2444 patients (13.7%; 95% CI 13.2-14.2). ICU, hospital, and 12-month survival rates were 71% (95% CI 69-73), 49% (95% CI 47-51), and 24% (95% CI 22-26), respectively. In patients for whom life support was withheld, increased 12-month survival rates were associated with admission from the operating theatre (OR 1.9, 95% CI 1.1-3.4), good pre-hospital physical fitness (OR 4.7, 95% Cl 1.2-16.8) and being housed at home (OR 2.0, 95% Cl 1.4-2.8). Decreased survival rates were associated with admission from a hospital ward (OR 0.67, 95% Cl 0.5-0.9), higher comorbidity (OR 0.6, 95% Cl 0.4-0.9), cancer (OR 0.4, 95%CI 0.2-0.9), greater illness severity (SAPS II; OR 0.98, 95% Cl 0.98-0.99), and higher care intensity (TISS-76; OR 0.93, 95% Cl 0.92-0.95).Conclusion: Survival among ICU patients with limited treatment was higher than expected. Advanced age was not associated with higher mortality, potentially because treatment restrictions may be set more easily for older patients. [ABSTRACT FROM AUTHOR]

Introduction: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.Materials and Methods: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.Results: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months.Discussion: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the 2-year clinical effectiveness of two gradual tapering strategies. The first strategy consisted of tapering the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) first (i.e., methotrexate in ~90%), followed by the tumour necrosis factor inhibitor (TNF-inhibitor), the second strategy consisted of tapering the TNF-inhibitor first, followed by the csDMARD.Methods: This multicentre single-blinded randomised controlled trial included patients with rheumatoid arthritis (RA) with well-controlled disease for ≥3 consecutive months, defined as a Disease Activity Score (DAS) measured in 44 joints ≤2.4 and a swollen joint count ≤1, which was achieved with a csDMARD and a TNF-inhibitor. Eligible patients were randomised into gradual tapering the csDMARD followed by the TNF-inhibitor, or vice versa. The primary outcome was the number of disease flares. Secondary outcomes were DMARD-free remission (DFR), DAS, functional ability (Health Assessment Questionnaire Disability Index (HAQ-DI)) and radiographic progression.Results: 189 patients were randomly assigned to tapering their csDMARD (n=94) or TNF-inhibitor (n=95) first. The cumulative flare rate after 24 months was, respectively, 61% (95% CI 50% to 71%) and 62% (95% CI 52% to 72%). The patients who tapered their csDMARD first were more often able to go through the entire tapering protocol and reached DFR more often than the group that tapered the TNF-inhibitor first (32% vs 20% (p=0.12) and 21% vs 10% (p=0.07), respectively). Mean DAS and HAQ-DI over time, and radiographic progression did not differ between groups (p=0.45, p=0.17, p=0.8, respectively).Conclusion: The order of tapering did not affect flare rates, DAS or HAQ-DI. DFR was achievable in 15% of patients with established RA, slightly more frequent in patients that first tapered csDMARDs. Because of similar effects from a clinical viewpoint, financial arguments may influence the decision to taper TNF-inhibitors first. [ABSTRACT FROM AUTHOR]

Background: Safe nucleos(t)ide analogue discontinuation in chronic hepatitis B (CHB) is an unmet need. We aimed to investigate whether combining hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) could perform satisfactorily in predicting off-treatment outcomes.Methods: The evaluation cohort included 127 hepatitis B e antigen (HBeAg)-positive patients from a multicenter prospective trial who stopped telbivudine-based therapy after achieving HBeAg seroconversion and HBV DNA < 50 IU/mL for > 48 weeks. As validation, 59 patients treated with entecavir or tenofovir before discontinuation were analyzed.Results: At the end of treatment (EOT), HBV RNA and HBcrAg were significant independent predictors of the clinical relapse risk. In the evaluation cohort, no clinical relapse occurred among patients with negative HBV RNA and HBcrAg < 4 log10 U/mL at EOT (low-risk group), whereas 46.8% patients with positive HBV RNA and HBcrAg ≥ 4 log10 U/mL (high-risk group) experienced clinical relapse during 4-year posttreatment follow-up (P < .001); the corresponding incidences in the validation cohort were 0% and 69.4% (P < .001), respectively. More patients in the low-risk group achieved HBsAg loss than the other patients after treatment cessation (16.1% vs 1.3%, P = .002).Conclusions: Combining HBV RNA and HBcrAg performed satisfactorily in predicting clinical relapse and HBsAg loss after treatment cessation in HBeAg-positive patients with CHB.The combination of hepatitis B virus RNA and hepatitis B core-related antigen performed satisfactorily in predicting clinical relapse and hepatitis B surface antigen loss after stopping nucleos(t)ide analogue treatment among noncirrhotic hepatitis B e antigen-positive patients with chronic hepatitis B and could be used to guide safe discontinuation. [ABSTRACT FROM AUTHOR]

Background: Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor has been shown to reduce the risk of major adverse cardiovascular events (MACE) compared with aspirin alone after percutaneous coronary intervention (PCI) or acute coronary syndrome but with increased risk of bleeding. The safety of discontinuing aspirin in favor of P2Y12 inhibitor monotherapy remains disputed.Methods: A meta-analysis was conducted from randomized trials (2001-2020) that studied discontinuation of aspirin 1 to 3 months after PCI with continued P2Y12 inhibitor monotherapy compared with traditional dual antiplatelet therapy. Five trials were included; follow-up duration ranged from 12 to 15 months after PCI. Primary bleeding and MACE outcomes were the prespecified definitions in each trial.Results: The study population included 32 145 patients: 14 095 (43.8%) with stable coronary artery disease and 18 046 (56.1%) with acute coronary syndrome. In the experimental arm, background use of a P2Y12 inhibitor included clopidogrel in 2649 (16.5%) and prasugrel or ticagrelor in 13 408 (83.5%) patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. Discontinuation of aspirin therapy 1 to 3 months after PCI significantly reduced the risk of major bleeding by 40% compared with dual antiplatelet therapy (1.97% versus 3.13%; hazard ratio [HR], 0.60 [95% CI, 0.45-0.79]), with no increase observed in the risk of MACE (2.73% versus 3.11%; HR, 0.88 [95% CI, 0.77-1.02]), myocardial infarction (1.08% versus 1.27%; HR, 0.85 [95% CI, 0.69-1.06]), or death (1.25% versus 1.47%; HR, 0.85 [95% CI, 0.70-1.03]). Findings were consistent among patients who underwent PCI for an acute coronary syndrome, in whom discontinuation of aspirin after 1 to 3 months reduced bleeding by 50% (1.78% versus 3.58%; HR, 0.50 [95% CI, 0.41-0.61]) and did not appear to increase the risk of MACE (2.51% versus 2.98%; HR, 0.85 [95% CI, 0.70-1.03]).Conclusions: Discontinuation of aspirin with continued P2Y12 inhibitor monotherapy reduces risk of bleeding when stopped 1 to 3 months after PCI. An increased risk of MACE was not observed after discontinuation of aspirin, including in patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Background: Patients are often prescribed opioids at discharge from hospital following surgery. Several studies have shown that a large number of patients do not taper off but continue to use opioids after surgery. Tapering plans and follow-up after discharge may reduce opioid consumption.Methods: This is a single-centre, investigator-initiated, randomized, controlled trial. One hundred and ten preoperative opioid users, scheduled to undergo spine surgery at Aarhus University Hospital, Denmark, are randomized into two groups: 1) an intervention group receiving an individually customized tapering plan at discharge combined with telephone counselling one week after discharge; 2) a control group receiving no tapering plan or telephone counselling. The primary outcome is number of patients exceeding their preoperative intake one month after discharge. Secondary outcomes are withdrawal symptoms during the first month after discharge, number of patients tapering off to zero three months after discharge, patient satisfaction and contacts with the health care system within the first two weeks after discharge.Conclusion: Our study is expected to provide valuable information on opioid tapering after surgery in patients with preoperative opioid use. [ABSTRACT FROM AUTHOR]

Background: Cotrimoxazole preventive therapy (CPT) in human immunodeficiency virus (HIV) infection is a World Health Organization-recommended standard of care in resource-limited settings, but the mechanism of CPT's beneficial effects is unclear. The COSTOP trial (ISRCTN44723643) evaluated the noninferiority of discontinuing CPT in stabilized patients on antiretroviral therapy. The COSTOP immunology substudy was conducted on a subset of COSTOP participants randomized to continue CPT (n = 86) or discontinue CPT (placebo, n = 86) as daily treatment for 1 year.Methods: We evaluated whether CPT reduces microbial translocation, indicated by the presence of bacterial lipopolysaccharide (LPS) and LPS control factors such as soluble CD14 (sCD14) and endotoxin core antibody (EndoCAb immunoglobulin M [IgM]) in plasma. Intestinal barrier damage as indicated by plasma intestinal fatty acid binding protein (IFABP), T-cell activation, and the inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were also evaluated.Results: We found no significant change in markers of microbial translocation (LPS, IFABP, sCD14, and T-cell activation), with decreased EndoCAb IgM. There was significant increase in inflammation markers (CRP and IL-6) after stopping CPT compared to those who continued CPT.Conclusions: These results add to the evidence of immunological benefits of CPT among HIV-infected populations in resource-limited settings. However, no evidence of reducing microbial translocation was observed. [ABSTRACT FROM AUTHOR]

Background: The best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA.Methods: C-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 at Weeks 32/36 and 48) were randomised to double-blind CZP 200 mg Q2W (full maintenance dose), CZP 200 mg every 4 weeks (Q4W; reduced maintenance dose) or placebo (withdrawal) for a further 48 weeks. The primary endpoint was remaining flare-free (flare: ASDAS ≥2.1 at two consecutive visits or ASDAS >3.5 at any time point) during the double-blind period.Results: At Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (p<0.001 vs placebo in both CZP groups). Responses in radiographic and non-radiographic axSpA patients were comparable.Conclusions: Patients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal.Trial Registration Number: NCT02505542, ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Background/aims: TNF-α inhibitors represent the most advanced approved therapeutic option for moderate and severe forms of hidradenitis suppurativa (HS). However, in recent years, cases of paradoxical HS secondary to the use of these biological drugs have been described, with very few cases reported in the literature. The aims of this study are (1) to present 2 new cases of paradoxical HS and (2) to perform a systematic review of scientific evidence regarding paradoxical HS with TNF-α inhibitors.Material and Methods: This is a retrospective study in which we searched all the cases of paradoxical HS secondary to the use of TNF-α inhibitors published in the literature and included two additional cases observed in our clinical practice.Results: A total of 34 patients under TNF-α inhibitor treatment were included (adalimumab = 21; infliximab = 9; etanercept = 4). The median delay from exposure to TNF-α inhibitor and the development of paradoxical HS was 12 months (range 1-72). The majority of patients were Hurley stage II (58.8%). Clinical improvement and complete remission were more frequent when the TNF-α inhibitor was stopped or switched to another biological agent with a different therapeutic target rather than maintenance or change to another TNF-α inhibitor.Conclusions: Paradoxical HS is an unusual adverse effect of TNF-α inhibitors. When this adverse effect appears, interruption or substitution of treatment is associated with a better clinical outcome. [ABSTRACT FROM AUTHOR]

While treatment is often withdrawn from patients in intensive care units (ICUs), few people outside the healthcare profession have witnessed a death under such circumstances. Family members who have made the decision to withdraw treatment may have expectations about the dying process, what constitutes a good death and how they should behave in an ICU based on popular prime‐time television series. An inductive comparative thematic coding strategy is therefore used to examine how death following treatment withdrawal as depicted in a US medical drama (Grey's Anatomy) differs from realities observed for 6 months fieldwork at an ICU in Canada. Three common frames (privacy, emotional control and memorialising) help patients' intimates normalise the unfamiliar experience and guide their behaviour during the event. However, discrepancies between media representations and experiences in the ICU, especially around the frames of timing of death and the physicality of the unbounded body (incontinence and agonal breathing), can traumatise them. The bereaved may be left viewing ventilator withdrawal and dying as chaotic processes and believing their loved one suffered through a bad death. Understanding these normative and discrepant frames should help healthcare professionals better prepare the public to witness death. [ABSTRACT FROM AUTHOR]

Objectives: To develop a consensus framework that can guide the process of decision-making on continuing or limiting life-sustaining treatments in ICU patients, using evidence-based items, supported by caregivers, patients, and surrogate decision makers from multiple countries.Design: A three-round web-based international Delphi consensus study with a priori consensus definition was conducted with experts from 13 countries. Participants reviewed items of the decision-making process on a seven-point Likert scale or with open-ended questions. Questions concerned terminology, content, and timing of decision-making steps. The summarized results (including mean scores) and expert suggestions were presented in the subsequent round for review.Setting: Web-based surveys of international participants representing ICU physicians, nurses, former ICU patients, and surrogate decision makers.Patients: Not applicable.Interventions: Not applicable.Measurements and Main Results: In three rounds, respectively, 28, 28, and 27 (of 33 invited) physicians together with 12, 10, and seven (of 19 invited) nurses participated. Patients and surrogates were involved in round one and 12 of 27 responded. Caregivers were mostly working in university affiliated hospitals in Northern Europe. During the Delphi process, most items were modified in order to reach consensus. Seven items lacked consensus after three rounds. The final consensus framework comprises the content and timing of four elements; three elements focused on caregiver-surrogate communication (admission meeting, follow-up meeting, goals-of-care meeting); and one element (weekly time-out meeting) focused on assessing preferences, prognosis, and proportionality of ICU treatment among professionals.Conclusions: Physicians, nurses, patients, and surrogates generated a consensus-based framework to guide the process of decision-making on continuing or limiting life-sustaining treatments in the ICU. Early, frequent, and scheduled family meetings combined with a repeated multidisciplinary time-out meeting may support decisions in relation to patient preferences, prognosis, and proportionality. [ABSTRACT FROM AUTHOR]

Importance: Nearly 1 in 3 patients with major depressive disorder who respond to antidepressants relapse within 6 months of treatment discontinuation. No predictors of relapse exist to guide clinical decision-making in this scenario.Objectives: To establish whether the decision to invest effort for rewards represents a persistent depression process after remission, predicts relapse after remission, and is affected by antidepressant discontinuation.Design, Setting, and Participants: This longitudinal randomized observational prognostic study in a Swiss and German university setting collected data from July 1, 2015, to January 31, 2019, from 66 healthy controls and 123 patients in remission from major depressive disorder in response to antidepressants prior to and after discontinuation. Study recruitment took place until January 2018.Exposure: Discontinuation of antidepressants.Main Outcomes and Measures: Relapse during the 6 months after discontinuation. Choice and decision times on a task requiring participants to choose how much effort to exert for various amounts of reward and the mechanisms identified through parameters of a computational model.Results: A total of 123 patients (mean [SD] age, 34.5 [11.2] years; 94 women [76%]) and 66 healthy controls (mean [SD] age, 34.6 [11.0] years; 49 women [74%]) were recruited. In the main subsample, mean (SD) decision times were slower for patients (n = 74) compared with controls (n = 34) (1.77 [0.38] seconds vs 1.61 [0.37] seconds; Cohen d = 0.52; P = .02), particularly for those who later relapsed after discontinuation of antidepressants (n = 21) compared with those who did not relapse (n = 39) (1.95 [0.40] seconds vs 1.67 [0.34] seconds; Cohen d = 0.77; P < .001). This slower decision time predicted relapse (accuracy = 0.66; P = .007). Patients invested less effort than healthy controls for rewards (F1,98 = 33.970; P < .001). Computational modeling identified a mean (SD) deviation from standard drift-diffusion models that was more prominent for patients than controls (patients, 0.67 [1.56]; controls, -0.71 [1.93]; Cohen d = 0.82; P < .001). Patients also showed higher mean (SD) effort sensitivity than controls (patients, 0.31 [0.92]; controls, -0.08 [1.03]; Cohen d = 0.51; P = .05). Relapsers differed from nonrelapsers in terms of the evidence required to make a decision for the low-effort choice (mean [SD]: relapsers, 1.36 [0.35]; nonrelapsers, 1.17 [0.26]; Cohen d = 0.65; P = .02). Group differences generally did not reach significance in the smaller replication sample (27 patients and 21 controls), but decision time prediction models from the main sample generalized to the replication sample (validation accuracy = 0.71; P = .03).Conclusions and Relevance: This study found that the decision to invest effort was associated with prospective relapse risk after antidepressant discontinuation and may represent a persistent disease process in asymptomatic remitted major depressive disorder. Markers based on effort-related decision-making could potentially inform clinical decisions associated with antidepressant discontinuation. [ABSTRACT FROM AUTHOR]

Background: The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.Objectives: The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.Methods: In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.Results: Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.Conclusions: The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822). [ABSTRACT FROM AUTHOR]

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome.Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis.Results: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2-risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 ×109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome.Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies. [ABSTRACT FROM AUTHOR]

Background: Many patients use opioids chronically before surgery; it is unclear if surgery alters the likelihood of ongoing opioid consumption in these patients.Methods: We performed a population-based matched cohort study of adults in Ontario, Canada undergoing one of 16 non-orthopaedic surgical procedures and who were chronically using opioids, defined as (1) an opioid prescription that overlapped the index date and (2) either a total of 120 or more cumulative calendar days of filled opioid prescriptions, or 10 or more prescriptions filled in the prior year. Each surgical patient was matched based on age, sex, Charlson comorbidity index, and daily preoperative opioid dose to three non-surgical patients who were also chronic opioid users. The primary outcome was time to opioid discontinuation.Results: The cohort included 4755 surgical and 14 265 matched non-surgical patients. After adjustment for sociodemographic characteristics and comorbidities, surgery was associated with an increased likelihood of opioid discontinuation (adjusted hazard ratio: 1.34, 95% confidence interval [CI]: 1.27, 1.42). Among surgical patients, factors associated with a reduced odds of discontinuation included a mean preoperative opioid dose above 90 morphine milligram equivalents (adjusted odds ratio [aOR]: 0.39; 95% CI: 0.32, 0.49) or filling a prescription for oxycodone (aOR: 0.73; 95% CI: 0.56, 0.98). Receipt of an in-patient Acute Pain Service consultation (aOR: 1.34; 95% CI: 1.06, 1.69) or residing in the highest neighbourhood income quintile (aOR: 1.35; 95% CI: 1.04, 1.79) were associated with a greater odds of opioid discontinuation.Conclusions: For chronic opioid users, surgery was associated with an increased likelihood of discontinuation of opioids in the following year compared with non-surgical chronic opioid users. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.Methods: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.Results: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable.Conclusions: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.Trial Registration Number: NCT02665364. [ABSTRACT FROM AUTHOR]

Objectives: To compare the efficacy to prevent flares of maintenance versus withdrawal of 5 mg/day prednisone in systemic lupus erythematosus (SLE) patients with clinically quiescent disease.Methods: A monocentric, 12-month, superiority, open-label, randomised (1:1) controlled trial was conducted with 61 patients continuing 5 mg/day prednisone and 63 stopping it. Eligibility criteria were SLE patients who, during the year preceding the inclusion, had a clinically inactive disease and a stable SLE treatment including 5 mg/day prednisone. The primary endpoint was the proportion of patient experiencing a flare defined with the SELENA-SLEDAI flare index (SFI) at 52 weeks. Secondary endpoints included time to flare, flare severity according to SFI and British Isles Lupus Assessment Group (BILAG) index and increase in the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI).Results: Proportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs 17; RR 0.2 (95% CI 0.1 to 0.7), p=0.003). Maintenance of 5 mg prednisone was superior with respect to time to first flare (HR 0.2; 95% CI 0.1 to 0.6, p=0.002), occurrence of mild/moderate flares using the SFI (3 patients vs 12; RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and occurrence of moderate/severe flares using the BILAG index (1 patient vs 8; RR 0.1 (95% CI 0.1 to 0.9), p=0.013). SDI increase and adverse events were similar in the two treatment groups. Subgroup analyses of the primary endpoint by predefined baseline characteristics did not show evidence of a different clinical response.Conclusion: Maintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse.Trial Registration Number: NCT02558517; Results. [ABSTRACT FROM AUTHOR]

Background: Decisions of withholding or withdrawing life-sustaining treatment are frequent in emergency departments (ED) and patients are often unable to communicate their wishes concerning end of life desires.Objective: To evaluate the participation of general practitioners (GPs) during the decision-making process of withholding or withdrawing life-sustaining treatments in ED.Design: Prospective observational multicenter study.Patients: We included patients for whom a decision of withdrawing or withholding life-sustaining treatments was made in ED. For each patient, we enrolled one general practitioner.Main Measures: GPs were interviewed about their perception of end of life patient's management and the communication with ED and families.Key Results: There were 109 potential patient participants. We obtained answers from 54 (49.5%) of the patient's associated GPs. Only 4 (7.4%) GPs were involved during the decision-making process of withholding or withdrawing life-sustaining treatments. Among GPs, 29 (53.7%) were contacted by family after the decision, most often to talk about their difficult experience with the decision. A majority (94%) believed their involvements in these decisions were important and 68% wished to "always" participate in end of life decisions despite the fact that they usually don't participate in these decisions. Finally, 66% of GPs believed that management of end of life in the emergency department was a failure and should be anticipated.Conclusions: GPs would like to be more involved and barriers to GP involvement need to be overcome. We do not have any outcome data to suggest that routine involvement of GPs in all end of life patients improves their outcomes. Moreover, it requires major system and process-based changes to involve all primary care physicians in ED decision-making.Nih Trial Registry Number: NCT02844972. [ABSTRACT FROM AUTHOR]

Background: Studies on forgoing treatment often ignore treatments that are continued until death.Objective: To investigate how often specific treatments are withdrawn or withheld before death and to describe the associated patient, physician, and care characteristics.Design: National mortality follow-back study in Switzerland in 2013/2014 using a standardized survey to collect information on the patient's end of life and demographics on the physician.Participants: A random sample of adults who died non-suddenly without an external cause and who had met the physician completing the survey (N = 3051).Main Measures: Any of nine specific treatments was continued until death, withdrawn, or withheld.Key Results: In 2242 cases (84%), at least one treatment was either continued until death or withheld or withdrawn. The most common treatment was artificial hydration, which was continued in 23%, withdrawn in 4%, and withheld in 22% of all cases. The other eight treatments were withdrawn or withheld in 70-94% of applicable cases. The impact of physician characteristics was limited, but artificial hydration, antibiotics, artificial nutrition, and ventilator therapy were more likely to be withheld at home and in nursing homes than in the hospitals.Conclusions: Large differences exist between care settings in whether treatments are continued, withdrawn, or withheld, indicating the different availability of treatment options or different philosophies of care. While certain patient groups are more likely to have treatment withheld rather than attempted, neither patient nor physician characteristics impact the decision to continue or withdraw treatment. [ABSTRACT FROM AUTHOR]

Background: Despite known risks of using chronic opioid therapy (COT) for pain, the risks of discontinuation of COT are largely uncharacterized.Objective: To evaluate mortality, prescription opioid use, and primary care utilization of patients discontinued from COT, compared with patients maintained on opioids.Design: Retrospective cohort study of patients with chronic pain enrolled in an opioid registry as of May 2010.Participants: Patients with chronic pain enrolled in the opioid registry of a primary care clinic at an urban safety-net hospital in Seattle, WA.Main Outcomes and Measures: Discontinuation from the opioid registry was the exposure of interest. Pre-specified main outcomes included mortality, prescription and primary care utilization data, and reasons for discontinuation. Data was collected through March 2015.Key Results: The study cohort comprised 572 patients with a mean age of 54.9 ± 10.1 years. COT was discontinued in 344 patients (60.1%); 254 (73.8%) discontinued patients subsequently filled at least one opioid prescription in Washington State, and 187 (54.4%) continued to visit the clinic. During the study period, 119 (20.8%) registry patients died, and 21 (3.7%) died of definite or possible overdose: 17 (4.9%) discontinued patients died of overdose, whereas 4 (1.75%) retained patients died of overdose. Most patients had at least one provider-initiated reason for COT discontinuation. Discontinuation of COT was associated with a hazard ratio for death of 1.35 (95% CI, 0.92 to 1.98, p = 0.122) and for overdose death of 2.94 (1.01-8.61, p = 0.049), after adjusting for age and race.Conclusions: In this cohort of patients prescribed COT for chronic pain, mortality was high. Discontinuation of COT did not reduce risk of death and was associated with increased risk of overdose death. Improved clinical strategies, including multimodal pain management and treatment of opioid use disorder, may be needed for this high-risk group. [ABSTRACT FROM AUTHOR]

Objectives: Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.Methods: We interrogated the circulatory reservoir of CD4+ immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.Results: An inflammatory memory subset of CD3+CD4+CD45RA-TNFα+ T cells deficient in immune checkpoints (PD1-CD152-) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.Conclusions: A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs. [ABSTRACT FROM AUTHOR]

As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24 months after entering TFR phase was 55% [95% confidence interval (CI) 0.51-0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24 months after stopping TKI. [ABSTRACT FROM AUTHOR]

Rationale: National guidelines have laid out a process to conflict resolution in cases of potentially inappropriate medical interventions. Objectives: To determine the association between information about a process-based approach and lay public perceptions of the appropriateness of withholding medically inappropriate interventions. Methods: Respondents from a nationwide sample completed a survey with two adult intensive care unit-based vignettes: one about advanced cancer where doctors told the family that additional chemotherapy would not be offered, and a second case of multiorgan failure after brain hemorrhage where dialysis would not be offered. Participants were randomly assigned to see or not see information about a detailed process for the determination to withhold (second opinion, ethics consultation, exploring transfer to another institution). The primary outcome was the perceived appropriateness of not providing the treatment (four-point scale, dichotomized for analysis, modified Poisson regression), and the secondary outcome was the negative emotional reaction to the case (positive and negative affect schedule, range 1-5, higher is greater negative emotional response, linear regression). Results: A total of 1,191 respondents were included. Providing detailed process information increased the perceived appropriateness of withholding treatment by approximately 10 percentage points in each vignette: (chemotherapy, 75.7-85.4%; dialysis, 68.0-79.3%). Process information remained associated with perceived appropriateness of withholding treatment after adjustment for order effects and prespecified respondent characteristics (chemotherapy: prevalence ratio, 1.13; 95% confidence interval [CI], 1.07-1.19) (dialysis: prevalence ratio, 1.17; 95% CI, 1.10-1.25). Process information was not associated with emotional response to the cases (chemotherapy: β = -0.04; 95% CI, -0.16 to 0.09) (dialysis: β = -0.02; 95% CI, -0.14 to 0.10; both adjusted for order effects). Conclusions: Providing process-based conflict resolution information increased public acceptance of determinations of medical futility, supporting the practice outlined in national consensus statements. [ABSTRACT FROM AUTHOR]

Background: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown.Methods: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.Findings: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure.Interpretation: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely.Funding: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust. [ABSTRACT FROM AUTHOR]

Parenteral iron is used to restore the body's iron pool before and during erythropoiesis-stimulating agent (ESA) therapy; together these agents form the backbone of anemia management in end-stage renal disease (ESRD) patients undergoing hemodialysis. ESRD patients receiving chronic intravenous iron products, which exceed their blood loss are exposed to an increased risk of positive iron balance. Measurement of the liver iron concentration (LIC) reflects total body iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Recent studies of LIC in hemodialysis patients, measured by quantitative MRI and magnetic susceptometry, have demonstrated a high risk of iron overload in dialysis patients treated with IV iron products at doses advocated by current anemia management guidelines for dialysis patients. Liver iron overload causes increased production of hepcidin and elevated plasma levels, which can activate macrophages of atherosclerotic plaques. This mechanism may explain the results of 3 long-term epidemiological studies which showed the association of excessive IV iron doses with increased risk of cardiovascular morbidity and mortality among hemodialysis patients. A more physiological approach of iron therapy in ESRD is needed. Peritoneal dialysis patients, hemodialysis patients infected with hepatitis C virus, and hemodialysis patients with ferritin above 1000 μg/L without a concomitant inflammatory state, all require specific and cautious iron management. Two recent studies have shown that most hemodialysis patients will benefit from lower maintenance IV iron dosages; their results are applicable to American hemodialysis patients. Novel pharmacometric and economic approaches to iron therapy and anemia management are emerging which are designed to lessen the potential side effects of excessive IV iron while maintaining hemoglobin stability without an increase in ESA dosing. [ABSTRACT FROM AUTHOR]

Objectives: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome.Design: Preplanned analysis of a prospective cohort study.Setting: Six academic hospitals in the United States.Patients: Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation.Interventions: Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation.Measures and Main Results: We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70-90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76).Conclusions: Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest. [ABSTRACT FROM AUTHOR]

Purpose: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment.Design: Prospective nonrandomized multicenter cohort study as an adjunct to COMS randomized clinical trials.Methods: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis.Results: Of 77 patients eligible for COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study (NHS). In all, 42 patients (42 eyes) had medium melanoma, and the median follow-up was 5.3 years (range, 4-10.7 years). In all, 22 patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, Kaplan-Meier estimate of 5-year mortality was approximately 30% [95% confidence interval (CI), 18%-47%]. For COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16%-20%), not statistically significantly different from the NHS patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for NHS patients versus COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in 8 (42%) of 19 deaths.Conclusion: Greater mortality and higher risk of death for NHS patients are probative but not conclusive evidence of a beneficial, life-extending effect of medium melanoma treatment. [ABSTRACT FROM AUTHOR]

Background: It is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non‐frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH. Methods: Patients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups. Results: Sixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non‐pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high‐performance functioning (FRs believed they are "forced" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to "passively accept" problems and showed avoidance‐related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms. Conclusions: Our results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH. [ABSTRACT FROM AUTHOR]

Purpose: Since the change in the United Network for Organ Sharing (UNOS) policy excluding patients with very early stage hepatocellular carcinoma (veHCC, single tumor nodule <2 cm) from receiving Model for End-stage Liver Disease (MELD) exception points, patients eligible to receive liver transplantation (LT) who fall in this category are commonly treated with locoregional therapy (LRT) after progression to UNOS T2 stage (1 nodule of 2-5 cm or up to 3 nodules, none above 3 cm). The aim of the current study is to compare the outcomes of patients treated with bridging LRT and LT with wait-and-not-treat approach with patients treated with definitive LRT.Methods: A retrospective study has been performed on patients with veHCC evaluated in multidisciplinary liver tumor clinic of a large academic center between 2004-2011. Patients eligible for LT were assigned to the wait-and-not-treat group while patients who were not eligible were assigned to the definitive LRT group. Tumor size, time to treatment, severity of liver disease, recurrence and survival from time of detection were reviewed and recorded.Results: A total of 19 patients were identified and treated with definitive LRT while 57 patients were treated with bridging LRT prior to LT after disease progression to T2 stage. Patients in the definitive LRT group were older (70.4±10.2 years vs. 58.7±5.9 years, P < 0.001) and had more comorbid conditions compared with the wait-and-not-treat group. Mean survival for definitive LRT group at the end of 5 years was 34.3±6.0 months with a median of 30.3 months (95% CI, 5.7-55.0 months) compared with 48.7±2.6 months for the wait-and-not-treat group, respectively (median not reached). The 3- and 5-year survival rates were 53.3% and 33.3% for the definitive LRT group compared with 78.9% and 68.4% for the patients in the wait-and-not-treat group. Survival rate at the end of 5 years was significantly better for the wait-and-not-treat group (P = 0.013).Conclusion: Based on the findings of current retrospective study, treating veHCC (UNOS T1 stage) patients listed for LT with bridging LRT after disease progression to T2 stage appears to be safe and effective with high 5-year survival rates. [ABSTRACT FROM AUTHOR]

Background: Knowledge of the factors associated with the decision to withdraw or withhold life support (WWLS) in brain-injured patients is limited. However, most deaths in these patients may involve such a decision.Objectives: To identify factors associated with the decision to WWLS in brain-injured patients requiring mechanical ventilation who survive the first 24 h in the ICU, and to analyse the outcomes and time to death.Design: A retrospective observational multicentre study.Settings: Twenty French ICUs in 18 university hospitals.Patients: A total of 793 mechanically ventilated brain-injured adult patients.Interventions: None.Main Outcome Measures: Decision to WWLS within 3 months of ICU admission, and death or Glasgow Outcome Scale (GOS) score at day 90.Results: A decision to WWLS was made in 171 patients (22%), of whom 89% were dead at day 90. Out of the 247 deaths recorded at day 90, 153 (62%) were observed after a decision to WWLS. The median time between admission and death when a decision to WWLS was made was 10 (5 to 20) days vs. 10 (5 to 26) days when no end-of-life decision was made (P < 0.924). Among the 18 patients with a decision to WWLS who were still alive at day 90, three patients (2%) had a GOS score of 2, nine patients (5%) had a GOS score of 3 and five patients (3%) a GOS score of 4. Older age, presence of one nonreactive and dilated pupil, Glasgow Coma Scale less than 7, barbiturate use, acute respiratory distress syndrome and worsening lesions on computed tomography scans were each independently associated with decisions to WWLS.Conclusion: Using a nationwide cohort of brain-injured patients, we observed a high proportion of deaths associated with an end-of-life decision. Older age and several disease severity factors were associated with the decision to WWLS. [ABSTRACT FROM AUTHOR]

Objectives: To determine the reasons of methotrexate (MTX) discontinuation, frequency of adverse events (AE) and whether the time in inactive disease before MTX withdrawal disease is associated with the risk of disease flare.Methods: Patients with juvenile idiopathic arthritis (JIA) beginning treatment with MTX were prospectively observed in the national JIA biologic register Biologika in der Kinderrheumatologie/Biologics in Paediatric Rheumatology and its follow-up register Juvenile arthritis Methotrexate/Biologics long-term Observation. Inactive disease was defined by a clinical Juvenile Arthritis Disease Activity Score ≤1, flare after MTX discontinuation by reoccurrence of at least moderate disease activity or restart of treatment with a disease-modifying antirheumatic drug .Results: MTX treatment was initiated in 1514 patients after a mean disease duration of 2.1 years (SD=2.8). 40% of the patients experienced oligoarticular onset of JIA. MTX was discontinued in 982 (64.9%) patients. Ineffectiveness (36.9%) and achieving inactive disease (32.1%) were the most common reasons. Among the latter (n=316), 184 (58.2%) patients experienced a flare on follow-up. The likelihood of a flare was a function of time in inactive disease prior to MTX discontinuation (HR 0.95; 95% CI 0.92 to 0.97). Patients with inactive disease for longer than 12 months had a significantly lower flare rate (58 of 119, 48.7%; HR 0.48; 95% CI 0.34 to 0.69). The most frequently reported AE was MTX intolerance, including nausea, aversion and vomiting, accounting for 441 events (13.0 events/100 exposure years) in 307 (20.3%) patients.Conclusions: Patients who spent at least 12 months in inactive disease before MTX discontinuation had a significantly lower flare rate. [ABSTRACT FROM AUTHOR]

Background Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of pneumonia and clinicians must determine when empiric antimicrobial therapy directed toward MRSA is needed. Objective To evaluate the effect of a pharmacy-driven protocol utilizing the nasal swab MRSA polymerase chain reaction (PCR) test to discontinue vancomycin on duration of vancomycin therapy and clinical outcomes in patients with suspected community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP). Setting A teaching hospital in Huntington, WV, USA. Methods This retrospective study included adult patients who received at least one dose of vancomycin for suspected CAP or HCAP. The pre-intervention group consisted of patients prior to the addition of the nasal swab MRSA PCR test to the CAP/HCAP order set. The post-intervention group consisted of patients after the addition of the nasal swab MRSA PCR test to the CAP/HCAP order set. Main outcome measure The primary outcome was vancomycin hours of therapy. Results Of the 196 patients included in the study, 121 patients were in the pre-intervention group and 75 patients were in the post-intervention group. The median duration of vancomycin therapy was significantly shorter in the post-intervention group than the pre-intervention group (49 vs. 18 h, p < 0.001). There were no statistically significant differences in the secondary outcomes including hospital length of stay, 30-day readmission rate, and in-hospital all-cause mortality. Conclusion The addition of a pharmacy-driven protocol utilizing the nasal swab MRSA PCR test was associated with shorter duration of empiric vancomycin therapy by approximately 31 h per patient without increasing adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: Clozapine is uniquely effective for treatment-resistant schizophrenia, and so treatment continuation is essential. We aimed to identify factors associated with an increased likelihood of clozapine discontinuation in a cohort of patients in South East London.Methods: We gathered demographic and treatment information such as duration of illness and antipsychotic treatment history. t-tests, chi-square tests and binary logistic regression were used to compare patients who continued and discontinued clozapine during the study and to identify predictor variables for discontinuation.Results: Out of the study population of 133 patients, 48 discontinued clozapine at least once during the study period. The majority of these (75%) stopped treatment within the first 4 years of clozapine therapy. Age, ethnicity, diagnosis and antipsychotic treatment history were not predictive of the risk of clozapine discontinuation. However, male patients were more likely to stop taking clozapine (χ2 = 6.81, p = 0.009). The odds of discontinuing clozapine were 2.15 times higher for male patients. The most common reason for discontinuation was patient refusal of treatment.Conclusion: We found that patients who discontinue clozapine are more likely to be male, but no other demographic variable was found to predict treatment cessation. Discontinuation usually occurred due to patient refusal of treatment. [ABSTRACT FROM AUTHOR]

Background: We sought to examine the factors associated with discontinuation of MMT among persons on methadone who use alcohol.Methods: We evaluated the impact of drug-related and other factors on discontinuation of MMT among persons enrolled in MMT and who reported any use of alcohol versus those who were enrolled in two community-recruited prospective cohorts of people who use illicit drugs (PWUD). Extended Cox models with time-dependent variables identified factors independently associated with time to first MMT discontinuation.Results: Between December 2005 and 2015, 823 individuals on MMT who also reported using alcohol at least once were included in these analyses. During the study period, 391 (47.5%) discontinued methadone. Daily heroin injection (Adjusted Hazard Ratio [AHR] = 2.67, 95% Confidence Interval [CI]: 2.10-3.40) and homelessness (AHR = 1.42, 95% CI: 1.10-1.83) were positively associated with MMT discontinuation, whereas receiving other concurrent addiction treatment in addition to MMT (AHR = 0.07, 95% CI: 0.05-0.08), as well as >60 mg methadone dose (AHR = 0.48, 95% CI: 0.39-0.60), Hepatitis C virus seropositivity (AHR = 0.65, 95% CI: 0.47-0.90), and HIV seropositivity (AHR = 0.72, 95% CI: 0.57-0.91) were negatively associated with MMT discontinuation. Any/heavy alcohol use was not independently associated with MMT discontinuation.Conclusions: This study reinforces the known risks of continued heroin injection and homelessness for MMT discontinuation among individuals who also consume alcohol and highlights the protective effect of both MMT dose and receipt of concurrent addiction treatment. [ABSTRACT FROM AUTHOR]