Withdrawal Of Therapy Research Articles

The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer

Three-dimensional (3D) epigenome remodeling is an important mechanism of gene deregulation in cancer. However, its potential as a target to counteract therapy resistance remains largely unaddressed. Here, we show that epigenetic therapy with decitabine (5-Aza-mC) suppresses tumor growth in xenograft models of pre-clinical metastatic estrogen receptor positive (ER+) breast tumor. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher-order chromatin structure and loss of boundary insulation of topologically associated domains. Significant DNA hypomethylation associates with ectopic activation of ER-enhancers, gain in ER binding, creation of new 3D enhancer–promoter interactions and concordant up-regulation of ER-mediated transcription pathways. Importantly, long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in a loss of ectopic 3D enhancer–promoter interactions and associated gene repression. Our study illustrates the potential of epigenetic therapy to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions, which are associated with the suppression of tumor growth.

Treatment-limiting decisions in patients with severe traumatic brain injury in the Netherlands

IntroductionTreatment-limiting decisions (TLDs) can be inevitable severe traumatic brain injury (s-TBI) patients, but data on their use remain scarce. Research questionTo investigate the prevalence, timing and considerations of TLDs in s-TBI patients. Material and methodss-TBI patients between 2008 and 2017 were analysed retrospecively. Patient data, timing, location, involvement of proxies, and reasons for TLDs were collected. Baseline characteristics and in-hospital outcomes were compared between s-TBI patients with and without TLDs. ResultsTLDs were reported in 117 of 270 s-TBI patients (43.3%) and 95.9% of deaths after s-TBI were preceded by a TLD. The majority of TLDs (68.4%) were categorized as withdrawal of therapy, of which withdrawal of organ-support in 64.1%. Neurosurgical intervention was withheld in 29.9%. The median time from admission to TLD was 2 days [IQR, 0–8] and 50.4% of TLDs were made within 3 days of admission. The main reason for a TLD was that the patients were perceived as unsalvageable (66.7%). Nearly all decisions were made multidisciplinary (99.1%) with proxies involvement (75.2%). The predicted mortality (CRASH-score) between patients with and without TLDs were 72.6 vs. 70.6%. The percentage of TLDs in s-TBI patients increased from 20.0% in 2008 to 42.9% in 2012 and 64.3% in 2017. Discussion and conclusionTLDs occurred in almost half of s-TBI patients and were instituted more frequently over time. Half of TLDs were made within 3 days of admission in spite of baseline prognosis between groups being similar. Future research should address whether prognostic nihilism contributes to self-fulfilling prophecies.

The predictive value of highly malignant EEG patterns after cardiac arrest: evaluation of the ERC-ESICM recommendations

PurposeThe 2021 guidelines endorsed by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) recommend using highly malignant electroencephalogram (EEG) patterns (HMEP; suppression or burst-suppression) at > 24 h after cardiac arrest (CA) in combination with at least one other concordant predictor to prognosticate poor neurological outcome. We evaluated the prognostic accuracy of HMEP in a large multicentre cohort and investigated the added value of absent EEG reactivity.MethodsThis is a pre-planned prognostic substudy of the Targeted Temperature Management trial 2. The presence of HMEP and background reactivity to external stimuli on EEG recorded > 24 h after CA was prospectively reported. Poor outcome was measured at 6 months and defined as a modified Rankin Scale score of 4–6. Prognostication was multimodal, and withdrawal of life-sustaining therapy (WLST) was not allowed before 96 h after CA.Results845 patients at 59 sites were included. Of these, 579 (69%) had poor outcome, including 304 (36%) with WLST due to poor neurological prognosis. EEG was recorded at a median of 71 h (interquartile range [IQR] 52–93) after CA. HMEP at > 24 h from CA had 50% [95% confidence interval [CI] 46–54] sensitivity and 93% [90–96] specificity to predict poor outcome. Specificity was similar (93%) in 541 patients without WLST. When HMEP were unreactive, specificity improved to 97% [94–99] (p = 0.008).ConclusionThe specificity of the ERC-ESICM-recommended EEG patterns for predicting poor outcome after CA exceeds 90% but is lower than in previous studies, suggesting that large-scale implementation may reduce their accuracy. Combining HMEP with an unreactive EEG background significantly improved specificity. As in other prognostication studies, a self-fulfilling prophecy bias may have contributed to observed results.

Beta-Blocker Usage in Patients With Heart Failure With Reduced Ejection Fraction During Acute Decompensated Heart Failure Hospitalizations.

Background: Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States every year. Beta-blockers are a first-line agent for patients experiencing heart failure with reduced ejection fraction, but beta-blocker use in patients hospitalized for acute decompensated heart failure remains low. We conducted an analysis of the existing evidence and guidelines to determine the conditions for prescribing beta-blockers to patients with acute decompensated heart failure. Methods: We searched the PubMed database for studies from 2004 to 2024 that included the search terms "beta blockers" and "acute decompensated heart failure." We included studies in which beta-blockers were used in patients with heart failure with reduced ejection fraction and excluded studies that did not study beta-blockers directly. We compiled recommendations from professional societies regarding beta-blocker usage-both for outpatients with heart failure with reduced ejection fraction and for patients hospitalized with acute decompensated heart failure. Results: Studies consistently demonstrated lower rates of mortality and rehospitalization when beta-blocker therapy was maintained for patients with heart failure with reduced ejection fraction who were already on beta-blocker therapy. Conversely, withdrawal of beta-blocker therapy was associated with increased in-hospital and short-term mortality. We summarized our findings in a guideline-based flowchart to help physicians make informed decisions regarding beta-blocker therapy in patients with acute decompensated heart failure. Based on the evidence, beta-blockers should be initiated at a low dose in patients with heart failure with reduced ejection fraction who have never been on beta-blockers, provided the patient is hemodynamically stable. Conclusion: Our research and our guideline-based flowchart promote guideline-directed use of beta-blockers to improve the outcomes of patients with heart failure with reduced ejection fraction.

The need for smoking cessation counselling and nicotine withdrawal therapy for hospitalised patients: A smoking point prevalence study at Groote Schuur Hospital, Cape Town, South Africa.

South Africa has high tobacco-attributable mortality and a smoking prevalence of 32.5% in males and 25.6% in females. There are limited data on smoking prevalence and desire to quit in hospitalised patients, who have limited access to smoking cessation services. To determine smoking prevalence and the extent of nicotine withdrawal symptoms, using a hospital-wide inpatient survey. A 1-day point prevalence survey was conducted at Groote Schuur Hospital, Cape Town. All wards except the haematology isolation, active labour and psychiatry lock-up wards were evaluated. Smoking status, withdrawal symptoms and desire to quit were established. Smoking status was confirmed in 85.8% of inpatients (n=501/584), of whom 31.9% (n=160) were current smokers; 43.5% (n=101/232) of male and 21.9% (n=59/269) of female inpatients were smokers. Documentation and confirmation of smoking status was highest in the maternity wards (100%) and lowest in the surgical wards (79.6%) and intensive care units (70.0%). Smoking prevalence ranged from 47.6% in male surgical patients to 15.2% in maternity patients. Of the smokers, 54.5% reported being motivated to quit, with a median (interquartile range) Fagerström test for nicotine dependence score of 4 (2 - 6), and 31.4% reported moderate to severe cravings to smoke, highest in the surgical wards. Smoking prevalence was higher in hospitalised patients than in the local general population. Many inpatients were not interested in quitting; however, a third had significant nicotine withdrawal symptoms. All inpatients who are active smokers should be identified and given universal brief smoking cessation advice. Patients with severe withdrawal symptoms should be allowed to smoke outside, and nicotine withdrawal pharmacotherapy should be provided to those who are bedbound or express a desire to stop smoking during the current admission. What the study adds. A single data point prevalence study of active smokers at Groote Schuur Hospital, Cape Town, was conducted. The prevalence of smoking was higher in the hospitalised patients than in the general community, but not all smokers were identified by the clinicians. Although symptoms of nicotine withdrawal were severe in some patients, motivation to quit smoking was not related to the degree of withdrawal being experienced. Many patients were not motivated to quit smoking.Implications of the findings. Better identification of inpatient smokers is required, and all should be given smoking cessation advice. Withdrawal symptoms can be severe in some patients, and those who are not interested in stopping smoking should allowed to smoke outside or be provided with nicotine withdrawal pharmacotherapy while in hospital. Those who are willing to quit should be supported as well as possible, including provision of nicotine replacement therapy or varenicline, and followed up after discharge as best practice.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 μm), width (350 μm), and tip diameter (10 μm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

The use of quantitative pupillometry in brain death determination: preliminary findings

PurposeQuantitative pupillometry (QP) has been increasingly applied in neurocritical care as an easy-to-use and reliable technique for evaluating the pupillary light reflex (PLR). Here, we report our preliminary findings on using QP for clinical brain death (BD) determination.MaterialsThis retrospective study included 17 patients ≥ 18 years (mean age, 57.3 years; standard deviation, 15.8 years) with confirmed BD, as defined by German Guidelines for the determination of BD. The PLR was tested using the NPi®-200 Pupillometer (Neuroptics, Laguna Hill, USA), a handheld infrared device automatically tracking and analyzing pupil dynamics over 3 s. In addition, pupil diameter and neurological pupil index (NPi) were also evaluated.ResultsIntracerebral bleeding, subarachnoid hemorrhage, and hypoxic encephalopathy were the most prevalent causes of BD. In all patients, the NPi was 0 for both eyes, indicating the cessation of mid-brain function. The mean diameter was 4.9 mm (± 1.3) for the right pupil and 5.2 mm (±1.2) for the left pupil.ConclusionsQP is a valuable tool for the BD certification process to assess the loss of PLR due to the cessation of brain stem function. Furthermore, implementing QP before the withdrawal of life-sustaining therapy in brain-injured patients may reduce the rate of missed organ donation opportunities. Further studies are warranted to substantiate the feasibility and potential of this technique in treating patients and identify suitable candidates for this technique during the BD certification process.

2021 European Resuscitation Council/European Society of Intensive Care Medicine Algorithm for Prognostication of Poor Neurological Outcome After Cardiac Arrest-Can Entry Criteria Be Broadened?

To explore broadened entry criteria of the 2021 European Resuscitation Council/European Society of Intensive Care Medicine (ERC/ESICM) algorithm for neuroprognostication including patients with ongoing sedation and Glasgow Coma Scale-Motor score (GCS-M) scores 4-5. Retrospective multicenter observational study. Four ICUs, Skane, Sweden. Postcardiac arrest patients managed at targeted temperature 36°C, 2014-2018. Neurologic outcome was assessed after 2-6 months according to the Cerebral Performance Category scale. None. In 794 included patients, median age was 69.5 years (interquartile range, 60.6-77.0 yr), 241 (30.4%) were female, 550 (69.3%) had an out-of-hospital cardiac arrest, and 314 (41.3%) had a shockable rhythm. Four hundred ninety-five patients were dead at follow-up, 330 of 495 died after a decision on withdrawal of life-sustaining therapies. At 72 hours after cardiac arrest 218 patients remained unconscious. The entry criteria of the original algorithm (GCS-M 1-3) was fulfilled by 163 patients and 115 patients with poor outcome were identified, with false positive rate (FPR) of 0% (95% CI, 0-79.4%) and sensitivity of 71.0% (95% CI, 63.6-77.4%). Inclusion of patients with ongoing sedation identified another 13 patients with poor outcome, generating FPR of 0% (95% CI, 0-65.8%) and sensitivity of 69.6% (95% CI, 62.6-75.8%). Inclusion of all unconscious patients (GCS-M 1-5), regardless of sedation, identified one additional patient, generating FPR of 0% (95% CI, 0-22.8) and sensitivity of 62.9% (95% CI, 56.1-69.2). The few patients with true negative prediction (patients with good outcome not fulfilling guideline criteria of a poor outcome) generated wide 95% CI for FPR. The 2021 ERC/ESICM algorithm for neuroprognostication predicted poor neurologic outcome with a FPR of 0%. Broadening inclusion criteria to include all unconscious patients regardless of ongoing sedation identified an additional small number of patients with poor outcome but did not affect the FPR. Results are limited by high rate of withdrawal of life-sustaining therapies and few patients with true negative prediction.

Ex Vivo Enriched Tumor Antigen-Specific T Cells Are Optimal Effectors of T Cell Engagers and Tumor-Specific T Cell Receptor/T Cell Engager Combination Provides Synergistic Efficacy Against Hematologic Malignancies

Multiple myeloma (MM) and acute myeloid leukemia (AML) are blood cancers that remain difficult to treat because a large proportion of patients have disease that does not respond to currently available therapies. NexImmune's Artificial Immune Modulation (AIM) platform mimics natural dendritic cell function by using nanoparticles engineered with MHC molecules loaded with tumor specific peptides (signal 1) and anti-CD28 (signal 2) for activation and expansion of HLA A*02:01 restricted tumor associated antigen (TAA)-specific cytotoxic CD8 T lymphocytes (CTL). Additionally, T cell engager (TCE) therapy allows for TAA-specific, but T cell receptor (TCR) independent T cell cytotoxicity mediated by immunological synapse formation between targeted cancer cells and T cells. Given that T cell function in MM and AML patients is often perturbed and the response to TCE therapy is determined by pre-existing endogenous T cells of the patient, we hypothesized adoptively transferred multi-antigen specific T cells with a rejuvenated phenotype in combination with TCE therapy might produce optimal efficacy. We compared polyclonal CTL with AIM CTL (CTL that were AIM primed and expanded for optimal antigen experience and specificity). We evaluated the preclinical efficacy of B cell maturation antigen (BCMA)xCD3 TCE+MM-specific AIM CTL combination therapy and CD123xCD3 TCE+AML-specific AIM CTL combination therapy both in vitro and in vivo. In co-culture assays with polyclonal CTL and AIM CTL, we investigated the effect of prior antigen exposure on the efficacy of the TCE against tumor cell lines by measuring the responses to T cells alone and in the presence of TCE treatment. We quantified tumor cell survival and thus determined cytotoxicity of the various culture conditions by luciferase assay. Our analysis showed that, as expected, CD4 T cells had little potency. Non-HLA matched control CTL (bulk or enriched for naïve cells) without TCE showed higher cytotoxicity (data not shown), but these cells were much less potent than AIM CTL (data not shown and Fig. 1A). Combined TCR and TCE-mediated target cell killing was most efficient when using AIM CTL as effector cells (Fig. 1B). Correcting the data for TCR mediated killing revealed that antigen-experienced AIM CTL were indeed superior effectors of TCE potency than antigen inexperienced control CTL. This finding was reproducible regardless of the HLA type of the target cells, consistent with the TCR independent mechanism of action of TCE-mediated killing. Nuclear factor of activated T cells (NFAT) transcriptional reporter assays with Jurkat effector cells and AML target cells revealed that TCE treatment decreased NFAT transcriptional activity in TCE effector cells; moreover, TCE treatment in vivo (treating mice with AIM CTL +/- TCE) increased CD3 levels on AIM CTL. Both observations are consistent with reduced TCR mediated T cell activation in the context of TCE therapy. Furthermore, BCMAxCD3 TCE treatment of mice in a MM xenograft model resulted in decreased PD-1 expression on AIM CTL and enhanced the in vivo efficacy of AIM CTL. Our studies show that AIM CTL display strong anti-tumor activity, and even subtherapeutic AIM CTL cell doses can be highly efficacious when armed with a TCE. Importantly, our data indicate that AIM CTL cells are optimal TCE effectors, superior to less experienced, polyclonal CTL (such as the patient's endogenous T cells). Combining AIM CTL with TCE therapy has the additional benefits of complementary targets and mechanisms of action, reducing the risk of immune escape. Moreover, our preclinical studies suggest that TCE treatment reduces NFAT transcriptional activity and PD-1 induction associated with physiological TCR mediated T cell activation. This suggests that TCE mediated T cell activation can partially suppress TCR mediated T cell activation in AIM CTL, resulting in excellent tumor-specific cytolytic activity while inducing a transcriptional signature that preserves T cell fitness. Following withdrawal of TCE therapy, less exhausted AIM CTL will be present, facilitating the persistence of long-lasting anti-tumor activity and immunosurveillance. Combination of AIM CTL (autologous or HLA matched allogeneic) with TCE therapy is therefore a highly promising and innovative strategy for the induction of durable antitumor activity, and this approach has potential for clinical translation as a novel combinatorial immunotherapy.

Recurrent giant cell myocarditis following orthotopic heart transplant resulting in urgent redo orthotopic heart transplantation: a case report

Abstract Background Giant cell myocarditis (GCM) is a severe and rapidly progressing condition that can lead to end-stage heart failure. We present a case of a 51-year-old male with a history of orthotopic heart transplantation (OHTx) for GCM, who experienced recurrent GCM in the allograft, leading to progressive heart failure and the need for a second heart transplant. Case summary A 51-year-old male with a history of OHTx for GCM presented with rapidly worsening heart failure symptoms. Despite initial stability, he deteriorated to cardiogenic shock and required intensive support. His clinical course was complicated by recurrent COVID-19 infections, worsened left ventricular ejection fraction, and withdrawal of guideline-directed medical therapy. Imaging showed extensive scar burden, and subsequent investigations ruled out coronary artery disease. With declining functional status and worsening cardiogenic shock, he was re-listed for OHTx and successfully underwent a second heart transplant. Discussion Giant cell myocarditis poses challenges due to its aggressive nature. Early, aggressive immunosuppression and mechanical circulatory support are crucial. The recurrence rate of GCM post-OHTx is notable, often within the first year, and the optimal immunosuppressive regimen remains uncertain. In this case, GCM recurrence following OHTx led to continued deterioration despite treatment, necessitating a second heart transplant. This unique case emphasizes the complexity of managing recurrent GCM post-OHTx.

Mortality and Timing of Withdrawal of Life-Sustaining Therapies After Out-of-Hospital Cardiac Arrest: Two-Center Retrospective Pediatric Cohort Study.

Pediatric out-of-hospital cardiac arrest (OHCA) is associated with substantial morbidity and mortality. Limited data exist to guide timing and method of neurologic prognostication after pediatric OHCA, making counseling on withdrawal of life-sustaining therapies (WLSTs) challenging. This study investigates the timing and mode of death after pediatric OHCA and factors associated with mortality. Additionally, this study explores delayed recovery after comatose examination on day 3 postarrest. This is a retrospective, observational study based on data collected from hospital databases and chart reviews. Data collection occurred in two pediatric academic hospitals between January 1, 2016, and December 31, 2020. Patients were identified from available databases and electronic medical record queries for the International Classification of Diseases , 10th Edition (ICD-10) code I46.9 (Cardiac Arrest). Patient inclusion criteria included age range greater than or equal to 48 hours to less than 18 years, OHCA within 24 hours of admission, greater than or equal to 1 min of cardiopulmonary resuscitation, and return-of-spontaneous circulation for greater than or equal to 20 min. None. One hundred thirty-five children (65% male) with a median age of 3 years (interquartile range 0.6-11.8) met inclusion criteria. Overall, 63 of 135 patients (47%) died before hospital discharge, including 34 of 63 patients (54%) after WLST. Among these, 20 of 34 patients underwent WLST less than or equal to 3 days postarrest, including 10 of 34 patients who underwent WLST within 1 day. WLST occurred because of poor perceived neurologic prognosis in all cases, although 7 of 34 also had poor perceived systemic prognosis. Delayed neurologic recovery from coma on day 3 postarrest was observed in 7 of 72 children (10%) who ultimately survived to discharge. In our two centers between 2016 and 2020, more than half the deaths after pediatric OHCA occurred after WLST, and a majority of WLST occurred within 3 days postarrest. Additional research is warranted to determine optimal timing and predictors of neurologic prognosis after pediatric OHCA to better inform families during goals of care discussions.

Efficacy and safety of inclisiran in real world practice: insights from the Cholinet registry

Abstract Background Inclisiran has been recently introduced in clinical practice. Thus, efficacy and safety data from real world settings are scarce. In Italy, reimbursement of inclisiran has been recently introduced for very high cardiovascular (CV) risk patients with LDL cholesterol (LDL-C) >70 mg/dl on statin/ezetimibe background lipid lowering therapy (LLT). Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence of inclisiran, and clinician’s behavior on LLT in very high CV risk patients with atherosclerotic CV disease and/or familial hypercholesterolemia (FH). Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran in Italian centers as part of their optimal medical therapy. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and in subsequent follow-up. Background therapy was assessed to evaluate treatment withdrawal, reduction of doses or any change from baseline during follow up. Results We enrolled 105 patients (14% with FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. Data on follow-up at 3 months (i.e., time of first reinjection dose) were available for 37 of them. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% mean reduction, 47,8 mg/dl absolute median reduction). None of the 37 patients reaching 3 months follow up missed the reinjection dose administration. Of 105 patients enrolled, 92 patients (88%) were on LLT, of them 16 (17%) were on ezetimibe alone, 11 (12%) on statin alone and 65 (71%) on a statin and ezetimibe combination. Of the enrolled patients, 6 (6%) were previously treated with evolocumab and 4 (4%) with alirocumab. At the end of the observation period, of the 37 patients with a follow-up, 18 (49%) did not change background LLT. Of 19 patients changing background LLT, 3 withdrew therapy (16%) and 16 (84%) reduced dose or changed type of LLT. Among patients evaluated at 3 months follow up, 23 patients (62%) achieved their target LDL-C (Figure 1), of them 21 (91%) were on LLT (Figure 2). No adverse drug reactions were reported. Conclusion These preliminary findings from the Cholinet Italian registry show that inclisiran effectively reduces (49%) LDL-C in real world settings, with no patients missing the first reinjection dose. Yet, concomitant LLT was reduced or discontinued in 51% of patients. Target LDL-C was achieved in 23 out of 37 patients, 21 of them receiving LLT background therapy. Thus, combination of oral therapy and inclisiran is needed in the majority of very high CV risk patients to achieve LDL target, and use of inclisiran should not prompt discontinuation or reduction of concomitant LLT.LLT in patient achieving LDL-C targetLDL-C target % by LLT

Patients’ Perspective on Termination of Pacemaker Therapy—A Cross-Sectional Anonymous Survey among Patients Carrying a Pacemaker in Germany

Objective: To determine the opinions of patients regarding the withdrawal of pacemaker therapy. Participants and methods: A cross-sectional anonymous questionnaire was administered to patients visiting an outpatient cardiologic clinic for routine follow-up visits of pacemaker therapy or patients carrying a pacemaker admitted to a hospital between 2021 and 2022. Results: Three-hundred and forty patients answered the questionnaire. A total of 56% of the participants were male. The mean age was 81 years. The majority of respondents were very comfortable with their PM and felt well informed, with one exception: more than half of respondents were missing information on withdrawal of pacemaker therapy. Almost two-thirds wanted to decide for themselves if their pacemaker therapy was withdrawn regardless of whether they were ill or healthy. Almost 60% of patients would like the pacemaker to be turned off when dying. Women expressed this wish significantly more often than men. Conclusion: Our survey shows that patients prefer to be informed on issues regarding the withdrawal of pacemakers as early as preimplantation. Also, patients would like to be involved in decisions that have to be made at the end of life, including decisions on withdrawal. Offers of conversations about this important issue should include information on special features of the patient’s pacemaker, e.g., the absence or presence of pacemaker dependency. Knowledge about the pacemaker’s functionality may prevent distress among individuals nearing their end of life when, for example, under the false impression that timely deactivation may allow for a more peaceful death.

(209) Bipolar and Menopause: Case Reports of Late Onset Bipolar Disorder Following Acute Withdrawal of Hormone Replacement Therapy

(209) Bipolar and Menopause: Case Reports of Late Onset Bipolar Disorder Following Acute Withdrawal of Hormone Replacement Therapy

Cardiac power output is associated with cardiovascular related mortality in the ICU in post-cardiac arrest patients

AimAlthough brain injury is the main determinant of poor outcome following cardiac arrest (CA), cardiovascular failure is the leading cause of death within the first days after CA. However, it remains unclear which hemodynamic parameter is most suitable for its early recognition. We investigated the association of cardiac power output (CPO) with early mortality in intensive care unit (ICU) after CA and with mortality related to post-CA cardiovascular failure. MethodsRetrospective analysis of adult comatose survivors of CA admitted to the ICU of a University Hospital. Exclusion criteria were treatment with extracorporeal cardiopulmonary resuscitation, ECMO or intra-aortic balloon pump. We retrieved CA characteristics; we recorded mean arterial pressure, cardiac output, CPO (as derived parameter) and the vasoactive-inotropic score for the first 72 hours after ROSC, at intervals of 8 hours. ICU death was defined as related to post-CA cardiovascular failure when death occurred as a direct consequence of shock, secondary CA or fatal arrhythmia, or related to neurological injury if this led to withdrawal of life-sustaining therapy or brain death. ResultsAmong the 217 patients (median age 66 years, 65% male, 61.8% out-of-hospital CA), 142 (65.4%) died in ICU: 99 (69.7%) patients died from neurological injury and 43 (30.3%) from cardiovascular-related causes. Comparing the evolution over time of CPO between survivors and non-survivors, a statistically significant difference was found only at +8 hours after CA (p = 0.0042). In multivariable analysis, CPO at 8-hour was significantly associated with cardiovascular-related mortality (p = 0.007). ConclusionsIn post-CA patients, the 8-hour CPO is an independent factor associated with ICU cardiovascular-related mortality.

50 Transcriptomic analysis of plaque psoriasis during anti-IL-17A biologic therapy and drug withdrawal

50 Transcriptomic analysis of plaque psoriasis during anti-IL-17A biologic therapy and drug withdrawal

RAPID PENTOSAN POLYSULFATE SODIUM MACULOPATHY PROGRESSION.

The purpose of this study was to report a unique case of pentosan polysulfate sodium (PPS) maculopathy with remarkable rapid progression over 2 years. These findings show the importance of early detection of macular disease to limit toxic exposure and reduce the risk of progression. Multimodal retinal imaging including fundus autofluorescence, near-infrared reflectance with pseudocolor, and spectral domain optical coherence tomography was performed in an elderly patient with a history of PPS therapy (cumulative dose of 1,205 g) at baseline and 2 years later. Baseline multimodal retinal imaging failed to show significant macular findings of PPS toxicity in either eye, but on repeat evaluation 2 years later, advanced features of PPS maculopathy were detected in both eyes with fundus autofluorescence, near-infrared reflectance, pseudocolor, and spectral domain optical coherence tomography. This report describes a remarkable case of rapid progression of PPS maculopathy as documented with multimodal retinal imaging. The dramatic progression of macular findings over just 2 years underscores the importance of early detection and prompt withdrawal of therapy, if systemically feasible, to retard the development and rate of progression of PPS maculopathy.

Tension between continuous and deep sedation and assistance in dying: a national survey of intensive care professionals’ perceptions

IntroductionThe situation in France is unique, having a legal framework for continuous and deep sedation (CDS). However, its use in intensive care units (ICU), combined with the withdrawal of life-sustaining therapies, still raises ethical issues, particularly its potential to hasten death. The legalization of assistance in dying, i.e., assisted suicide or euthanasia at the patient’s request, is currently under discussion in France. The objectives of this national survey were first, to assess whether ICU professionals perceive CDS administered to ICU patients as a practice that hastens death, in addition to relieving unbearable suffering, and second, to assess ICU professionals’ perceptions of assistance in dying. MethodsA national survey with online questionnaires for ICU physicians and nursesaddressed through the French Society of Anesthesiology and Critical Care Medicine. ResultsA total of 956 ICU professionals responded to the survey (38% physicians and 62% nurses). Of these, 22% of physicians and 12% of nurses (p < 0.001) felt that the purpose of CDS was to hasten death. For 20% of physicians, CDS combined with terminal extubation was considered an assistance in dying. For 52% of ICU professionals, the current framework did not sufficiently cover the range of situations that occur in the ICU. A favorable opinion on the potential legalization of assistance in dying was observed in 83% of nurses and 71% of physicians (p < 0.001), with no preference between assisted suicide and euthanasia. ConclusionOur findings highlight the tension between CDS and assisted suicide/euthanasia in the specific context of intensive care and suggest that ICU professionals would be supportive of a legislative evolution.

Management of respiratory distress in moderate and late preterm infants: clinical trajectories in the Neobs study

Management of respiratory distress (RD) in the extremely preterm newborn meets recommendations. Few data are available concerning the management and the clinical course of moderate and late preterms with RD. Clinical course and management among moderate (30–33 weeks (wks) of gestation) and late preterms (34–36 wks) were assessed in the Neobs study, a French neonatal observational cohort study (2018) of preterms with RD in the first 24 h of life. Clinical course was defined as stable (use of non-invasive ventilation (NIV) only), initially severe (initial use of invasive ventilation (IV)), and worsening (switch off IV after NIV support). Surfactant therapy instillation and withdrawal of all ventilator support at 72 h were recorded. Among moderate (n = 279) and late (n = 281) preterms, the clinical course was similar (p < 0.27): stable (82.1 and 86.8%), worsening (11.8% and 9.3%), and initially severe RD (6.1% and 3.9%), respectively. Surfactant was administered more frequently in the moderate versus late preterm groups (28.3% vs 16.7%; p < 0.001). The recommended surfactant dose (200 mg/kg) was administered in 53.3–83.3% of moderate and 42.1–63.2% of late preterms according to the clinical course. Withdrawal of ventilatory support at 72 h was observed in 40.0% and 70.0% of moderate and late preterms, respectively (p < 0.05), and was significantly (p < 0.001) associated with clinical course (the minus proportion among the worsening group). Conclusion: While the proportion of clinical course pattern is similar in moderate and late preterm infants, the management of RD varies with gestational age, with late preterm infants being managed later in life and moderate premature infants weaned from ventilation at a later stage.What is Known:• There is a lack of clear guidance on the management of respiratory distress (RD) in moderate-to-late preterm infants.• Neobs was a multicentre, observational study designed to characterise the real-world management of moderate-to-late preterm infants with RD in France.What is New:• Secondary analyses of Neobs study data found that ventilatory support strategies were dependent on gestational age despite a similar clinical course.• At 30–33 weeks of gestation (wks), infants were more likely to receive non-invasive ventilation at delivery, while 34–36 wks infants were more likely to be managed using a wait-and-see approach.

Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+ T cells and CD16bright natural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+ DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+ (IFN-γ+) CD4+ and CD8+ T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+ T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+ T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.