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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.

The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy ((1)H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized β=-0.23; 95% CIs: -0.39 to -0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized β=-0.23; 95% CIs: -0.40 to -0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned (1)H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype-phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies.

van Rens et al examine the changes in patterns of age-related visual impairment in people aged 50 and older who visited an eye clinic, and people who accepted an offer of rehabilitation. Findings of the study show that there was a change in the etiology of visual impairment from the first period to the second period.

Despite the recent progress in the field of causal inference, to date there is no agreed upon methodology to glean treatment effect estimation from observational data. The consequence on clinical practice is that, when lacking results from a randomized trial, medical personnel is left without guidance on what seems to be effective in a real-world scenario. This article proposes a pragmatic methodology to obtain preliminary but robust estimation of treatment effect from observational studies, to provide front-line clinicians with a degree of confidence in their treatment strategy. Our study design is applied to an open problem, the estimation of treatment effect of the proning maneuver on COVID-19 Intensive Care patients.

About 45% of dementia cases are attributable to known modifiable risk factors, yet public awareness remains low. The public awareness campaign \"We are the medicine ourselves\" (2018-2023) aimed to increase public awareness of dementia risk reduction in nine regions. This mixed methods study evaluated the campaign's effectiveness in reaching individuals aged 40-75 years and explored facilitators and barriers to successful implementation. Cross-sectional online surveys were conducted in independent samples of community-dwelling individuals aged 40-75 years before (n = 4,981) and after (n = 3,379) the campaign to assess awareness of dementia risk reduction, knowledge of dementia risk and protective factors, and campaign exposure. Differences between pre- and post-campaign samples were assessed using χ -tests for categorical variables and independent t-tests for continuous variables. Adjusted effects were estimated using probit regression for binary outcomes and linear regression for continuous outcomes, controlling for region, age, gender, educational level, and self-reported knowledge of dementia. Semi-structured interviews with 21 campaign coordinators and stakeholders explored facilitators and barriers for implementation. No significant difference in awareness was found between the pre-campaign (54.6% aware) and post-campaign (55.7% aware) samples (adjusted probit regression: z = 0.97, p = 0.334). Knowledge of risk and protective factors modestly increased (from 5.3 to 5.5; B = 0.18, 95% confidence interval: 0.04 - 0.33, p = 0.013). Self-reported campaign exposure was associated with higher awareness, better knowledge of risk and protective factors, and greater motivation to adopt brain-healthy lifestyle changes. Implementation barriers included limited financial resources, difficulty reaching younger individuals (40-60 years), and limited engagement with regional stakeholders. Facilitators included the campaign framework and strong local networks. While the multi-regional campaign did not lead to a general increase in population-level awareness of dementia risk reduction, it modestly improved knowledge of specific dementia risk and protective factors.