Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients:the EuRIDICE randomized clinical trial

Background:The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae.Methods:This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization.Results:The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73–1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18–0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12–1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29–1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22–2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study.Conclusions:Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation.Trial registration: ClinicalTrials.gov (#NCT03628391), October 9, 2017

Entomological Surveillance of Behavioural Resilience and Resistance in Residual Malaria Vector Populations.

The most potent malaria vectors rely heavily upon human blood so they are vulnerable to attack with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) within houses. Mosquito taxa that can avoid feeding or resting indoors, or by obtaining blood from animals, mediate a growing proportion of the dwindling transmission that persists as ITNs and IRS are scaled up. Increasing frequency of behavioural evasion traits within persisting residual vector systems usually reflect the successful suppression of the most potent and vulnerable vector taxa by IRS or ITNs, rather than their failure. Many of the commonly observed changes in mosquito behavioural patterns following intervention scale-up may well be explained by modified taxonomic composition and expression of phenotypically plastic behavioural preferences, rather than altered innate preferences of individuals or populations. Detailed review of the contemporary evidence base does not yet provide any clear-cut example of true behavioural resistance and is, therefore, consistent with the hypothesis presented. Caution should be exercised before over-interpreting most existing reports of increased frequency of behavioural traits which enable mosquitoes to evade fatal contact with insecticides: this may simply be the result of suppressing the most behaviourally vulnerable of the vector taxa that constituted the original transmission system. Mosquito taxa which have always exhibited such evasive traits may be more accurately described as behaviourally resilient, rather than resistant. Ongoing national or regional entomological monitoring surveys of physiological susceptibility to insecticides should be supplemented with biologically and epidemiologically meaningfully estimates of malaria vector population dynamics and the behavioural phenotypes that determine intervention impact, in order to design, select, evaluate and optimize the implementation of vector control measures

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Optimum risk stratification in early-stage endometrial cancer (EC) combines clinicopathological factors and the molecular EC classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid ECs from the PORTEC-1&-2 trials. The relationship between immune cell density and clinicopathological/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular EC classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate and low densities, with highly significant variation in the proportion of molecular EC subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of EC recurrence; multivariable analysis confirmed this was independent of pathological factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular EC classification in early-stage EC

Instruments to measure patient experience of healthcare quality in hospitals: a systematic review

Improving and sustaining the quality of hospital care is an international challenge. Patient experience data can be used to target improvement and research. However, the use of patient experience data has been hindered by confusion over multiple instruments (questionnaires) with unknown psychometric testing and utility.MethodsWe conducted a systematic review and utility critique of questionnaires to measure patient experience of healthcare quality in hospitals. Databases (Medical Literature Analysis and Retrieval System (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psychological Information (PsychINFO) and Web of Knowledge until end of November 2013) and grey literature were scrutinised. Inclusion criteria were applied to all records with a 10 % sample independently checked. Critique included (1) application of COSMIN checklists to assess the quality of each psychometric study, (2) critique of psychometric results of each study using Terwee et al. criteria and (3) development and critique of additional aspects of utility for each instrument. Two independent reviewers completed each critique. Synthesis included combining findings in a utility matrix.We obtained 1157 records. Of these, 26 papers measuring patient experience of hospital quality of care were identified examining 11 international instruments. We found evidence of extensive theoretical/development work. The quality of methods and results was variable but mostly of a high standard. Additional aspects of utility found that (1) cost efficiency was mostly poor, due to the resource necessary to obtain reliable samples; (2) acceptability of most instruments was good and (3) educational impact was variable, with evidence on the ease of use, for approximately half of the questionnaires.ConclusionsSelecting the right patient experience instrument depends on a balanced consideration of aspects of utility, aided by the matrix. Data required for high stakes purposes requires a high degree of reliability and validity, while those used for quality improvement may tolerate lower levels of reliability in favour of other aspects of utility (educational impact, cost and acceptability)

Swim-Training Changes the Spatio-Temporal Dynamics of Skeletogenesis in Zebrafish Larvae (Danio rerio)

Fish larvae experience many environmental challenges during development such as variation in water velocity, food availability and predation. The rapid development of structures involved in feeding, respiration and swimming increases the chance of survival. It has been hypothesized that mechanical loading induced by muscle forces plays a role in prioritizing the development of these structures. Mechanical loading by muscle forces has been shown to affect larval and embryonic bone development in vertebrates, but these investigations were limited to the appendicular skeleton. To explore the role of mechanical load during chondrogenesis and osteogenesis of the cranial, axial and appendicular skeleton, we subjected zebrafish larvae to swim-training, which increases physical exercise levels and presumably also mechanical loads, from 5 until 14 days post fertilization. Here we show that an increased swimming activity accelerated growth, chondrogenesis and osteogenesis during larval development in zebrafish. Interestingly, swim-training accelerated both perichondral and intramembranous ossification. Furthermore, swim-training prioritized the formation of cartilage and bone structures in the head and tail region as well as the formation of elements in the anal and dorsal fins. This suggests that an increased swimming activity prioritized the development of structures which play an important role in swimming and thereby increasing the chance of survival in an environment where water velocity increases. Our study is the first to show that already during early zebrafish larval development, skeletal tissue in the cranial, axial and appendicular skeleton is competent to respond to swim-training due to increased water velocities. It demonstrates that changes in water flow conditions can result into significant spatio-temporal changes in skeletogenesis

Study protocol: optimization of complex palliative care at home via telemedicine. A cluster randomized controlled trial

Contains fulltext : 97378.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Due to the growing number of elderly with advanced chronic conditions, healthcare services will come under increasing pressure. Teleconsultation is an innovative approach to deliver quality of care for palliative patients at home. Quantitative studies assessing the effect of teleconsultation on clinical outcomes are scarce. The aim of this present study is to investigate the effectiveness of teleconsultation in complex palliative homecare. METHODS/DESIGN: During a 2-year recruitment period, GPs are invited to participate in this cluster randomized controlled trial. When a GP refers an eligible patient for the study, the GP is randomized to the intervention group or the control group. Patients in the intervention group have a weekly teleconsultation with a nurse practitioner and/or a physician of the palliative consultation team. The nurse practitioner, in cooperation with the palliative care specialist of the palliative consultation team, advises the GP on treatment policy of the patient. The primary outcome of patient symptom burden is assessed at baseline and weekly using the Edmonton Symptom Assessment Scale (ESAS) and at baseline and every four weeks using the Hospital Anxiety and Depression Scale (HADS). Secondary outcomes are self-perceived burden from informal care (EDIZ), patient experienced continuity of medical care (NCQ), patient and caregiver satisfaction with the teleconsultation (PSQ), the experienced problems and needs in palliative care (PNPC-sv) and the number of hospital admissions. DISCUSSION: This is one of the first randomized controlled trials in palliative telecare. Our data will verify whether telemedicine positively affects palliative homecare. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2817

DeltaScan for the Assessment of Acute Encephalopathy and Delirium in ICU and non-ICU Patients, a Prospective Cross-Sectional Multicenter Validation Study

Objectives: To measure the diagnostic accuracy of DeltaScan: a portable real-time brain state monitor for identifying delirium, a manifestation of acute encephalopathy (AE) detectable by polymorphic delta activity (PDA) in single-channel electroencephalograms (EEGs). Design: Prospective cross-sectional study. Setting: Six Intensive Care Units (ICU's) and 17 non-ICU departments, including a psychiatric department across 10 Dutch hospitals. Participants: 494 patients, median age 75 (IQR:64-87), 53% male, 46% in ICUs, 29% delirious. Measurements: DeltaScan recorded 4-minute EEGs, using an algorithm to select the first 96 seconds of artifact-free data for PDA detection. This algorithm was trained and calibrated on two independent datasets. Methods: Initial validation of the algorithm for AE involved comparing its output with an expert EEG panel's visual inspection. The primary objective was to assess DeltaScan's accuracy in identifying delirium against a delirium expert panel's consensus. Results: DeltaScan had a 99% success rate, rejecting 6 of the 494 EEG's due to artifacts. Performance showed and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.86 (95% CI: 0.83-0.90) for AE (sensitivity: 0.75, 95%CI=0.68-0.81, specificity: 0.87 95%CI=0.83-0.91. The AUC was 0.71 for delirium (95%CI=0.66-0.75, sensitivity: 0.61 95%CI=0.52-0.69, specificity: 72, 95%CI=0.67-0.77). Our validation aim was an NPV for delirium above 0.80 which proved to be 0.82 (95%CI: 0.77-0.86). Among 84 non-delirious psychiatric patients, DeltaScan differentiated delirium from other disorders with a 94% (95%CI: 87-98%) specificity. Conclusions: DeltaScan can diagnose AE at bedside and shows a clear relationship with clinical delirium. Further research is required to explore its role in predicting delirium-related outcomes.</p