Intracellular calcium release: A conductor of compartmentalized dendritic plasticity.

Dendrites endow neurons with multiple compartments within their elaborate morphologies. In a recent study published in the journal Science, O'Hare et al. (2022) used elegant techniques to show that augmenting the intracellular calcium released by the endoplasmic reticulum caused behaviorally relevant plasticity to occur in spatially distinct dendritic compartments.

Dendritic Mechanisms for In Vivo Neural Computations and Behavior.

Dendrites receive the vast majority of a single neuron's inputs, and coordinate the transformation of these signals into neuronal output. Ex vivo and theoretical evidence has shown that dendrites possess powerful processing capabilities, yet little is known about how these mechanisms are engaged in the intact brain or how they influence circuit dynamics. New experimental and computational technologies have led to a surge in interest to unravel and harness their computational potential. This review highlights recent and emerging work that combines established and cutting-edge technologies to identify the role of dendrites in brain function. We discuss active dendritic mediation of sensory perception and learning in neocortical and hippocampal pyramidal neurons. Complementing these physiological findings, we present theoretical work that provides new insights into the underlying computations of single neurons and networks by using biologically plausible implementations of dendritic processes. Finally, we present a novel brain-computer interface task, which assays somatodendritic coupling to study the mechanisms of biological credit assignment. Together, these findings present exciting progress in understanding how dendrites are critical for in vivo learning and behavior, and highlight how subcellular processes can contribute to our understanding of both biological and artificial neural computation.

Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials.

BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

Why have trials of inhaled antibiotics for ventilator-associated infections failed?

PURPOSE OF REVIEW: Two recent large randomized placebo-controlled clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show a mortality effect or more rapid resolution of pneumonia symptoms. Does the failure of these studies to reach their endpoints suggest the end of inhaled therapy? This review will explain why inhaled therapy may still have an important role in the treatment of ventilated patients. RECENT FINDINGS: The recent interest in inhaled antimicrobial therapy is driven by the global emergence of increasingly resistant bacteria to systemic therapy. As fast as the pharmaceutical pipeline delivers more powerful systemic antibiotics to the ICU, the bacteria evolve and develop resistance to them. The hypothesis of recent trials has been that adjunctive inhaled therapy will make systemic treatment more effective. This review summarizes the available data from the two recent multisite randomized Phase 2 and Phase 3 trials of inhaled antimicrobials as adjunctive therapy and suggests why they failed to achieve their endpoints. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. The results of these trials and the data from many other smaller trials are compelling us to re-examine the indications for inhaled therapy as well as what clinical outcomes are most important. SUMMARY: This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Future investigations need to reevaluate the design and the outcomes that are most important in this era of multidrug-resistant bacteria.

Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients. METHODS: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded. RESULTS: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens. CONCLUSIONS: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.

Exploring the role of knowledge of condition and psycho-social profiles of young people with epilepsy during transition.

Transitioning from paediatric to adult care can be a particularly challenging time for young people with epilepsy and research has shown that there are a range of factors which may influence a young person's ability to successfully cope with this difficult time. The following study aimed to explore the psychosocial characteristics of this transitioning population, as well as investigate how knowledgeable the young person and their parent/carer are of their own condition throughout transition. Young people with epilepsy were recruited from two specialist epilepsy clinics in the North West and allocated to one of three groups; Group 1 pre-transition, Group 2 transitioning, and Group 3 post-transition. Results found that the young person's knowledge increased significantly throughout transition, whilst parent/carer's knowledge decreased. In addition, anxiety was found to be significantly lower in Group 2 (transitioning group) compared to Group 1 (pre-transition) and Group 3 (post-transition) and a number of significant gender differences were also identified across the groups. The study highlights the importance of considering all relevant psychosocial factors, such as anxiety, gender and the degree of knowledge the individual holds of their own condition during the transition process in order to develop psycho-educational programmes and transition pathways.

Is There a Role for Inhaled Antibiotics in the Treatment of Ventilator-Associated Infections?

The increasing emergence of multidrug-resistant organisms creates a therapeutic challenge for physicians treating ventilator-associated respiratory infections. As the production of new systemic antibiotics lags far behind the emergence of worsening antibiotic resistance, intensivists are turning to inhaled antibiotics to use as adjunctive therapy. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Inhaled adjunctive therapy has been described in numerous small nonrandomized studies and in six recent randomized placebo-controlled trials. Inhaled therapy has also been used to treat ventilator-associated tracheobronchitis. These preliminary data suggest aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations when used in time-limited protocols and delivered with devices known to deposit antibiotics in the area of infection. Large, multisite, clinical, randomized placebo-controlled studies are needed to confirm these data.

Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Patient experience of negative effects of psychological treatment: results of a national survey†.

BACKGROUND: To make informed choices, patients need information about negative as well as positive effects of treatments. There is little information about negative effects of psychological interventions. AIMS: To determine the prevalence of and risk factors for perceived negative effects of psychological treatment for common mental disorders. METHOD: Cross-sectional survey of people receiving psychological treatment from 184 services in England and Wales. Respondents were asked whether they had experienced lasting bad effects from the treatment they received. RESULTS: Of 14 587 respondents, 763 (5.2%) reported experiencing lasting bad effects. People aged over 65 were less likely to report such effects and sexual and ethnic minorities were more likely to report them. People who were unsure what type of therapy they received were more likely to report negative effects (odds ratio (OR) = 1.51, 95% CI 1.22-1.87), and those that stated that they were given enough information about therapy before it started were less likely to report them (OR = 0.65, 95% CI 0.54-0.79). CONCLUSIONS: One in 20 people responding to this survey reported lasting bad effects from psychological treatment. Clinicians should discuss the potential for both the positive and negative effects of therapy before it starts.

Patient preference in psychological treatment and associations with self-reported outcome: national cross-sectional survey in England and Wales.

BACKGROUND: Providers of psychological therapies are encouraged to offer patients choice about their treatment, but there is very little information about what preferences people have or the impact that meeting these has on treatment outcomes. METHOD: Cross-sectional survey of people receiving psychological treatment from 184 NHS services in England and Wales. 14,587 respondents were asked about treatment preferences and the extent to which these were met by their service. They were also asked to rate the extent to which therapy helped them cope with their difficulties. RESULTS: Most patients (12,549-86.0 %, 95 % CI: 85.5-86.6) expressed a preference for at least one aspect of their treatment. Of these, 4,600 (36.7 %, 95 % CI: 35.8-37.5) had at least one preference that was not met. While most patients reported that their preference for appointment times, venue and type of treatment were met, only 1,769 (40.5 %) of the 4,253 that had a preference for gender had it met. People who expressed a preference that was not met reported poorer outcomes than those with a preference that was met (Odds Ratios: appointment times = 0.29, venue = 0.32, treatment type = 0.16, therapist gender = 0.32, language in which treatment was delivered = 0.40). CONCLUSIONS: Most patients who took part in this survey had preferences about their treatment. People who reported preferences that were not met were less likely to state that treatment had helped them with their problems. Routinely assessing and meeting patient preferences may improve the outcomes of psychological treatment.

Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes.

Wingless acts as a morphogen in Drosophila wing discs, where it specifies cell fates and controls growth several cell diameters away from its site of expression. Thus, despite being acylated and membrane associated, Wingless spreads in the extracellular space. Recent studies have focussed on identifying the route that Wingless follows in the secretory pathway and determining how it is packaged for release. We have found that, in medium conditioned by Wingless-expressing Drosophila S2 cells, Wingless is present on exosome-like vesicles and that this fraction activates signal transduction. Proteomic analysis shows that Wingless-containing exosome-like structures contain many Drosophila proteins that are homologous to mammalian exosome proteins. In addition, Evi, a multipass transmembrane protein, is also present on exosome-like vesicles. Using these exosome markers and a cell-based RNAi assay, we found that the small GTPase Rab11 contributes significantly to exosome production. This finding allows us to conclude from in vivo Rab11 knockdown experiments, that exosomes are unlikely to contribute to Wingless secretion and gradient formation in wing discs. Consistent with this conclusion, extracellularly tagged Evi expressed from a Bacterial Artificial Chromosome is not released from imaginal disc Wingless-expressing cells.

Ventilator-associated infection: the role for inhaled antibiotics.

PURPOSE OF REVIEW: Despite multiple protocols for the prevention of ventilator-associated pneumonia (VAP), respiratory infections have not been eliminated in the ICU. The profound disruption in both airway integrity and mucociliary clearance caused by the endotracheal tube makes it unlikely there will ever be a zero rate of respiratory infection in critically ill ventilated patients or a 100% cure rate when infection is present. In fact, options for treatment are diminishing as bacteria resistant to most, or in some hospitals all, systemic antibiotics increase in prevalence from our liberal use of systemic antibiotics. Inhaled therapy with proper delivery will result in the high concentrations of antibiotics needed in the treatment of increasingly resistant organisms. RECENT FINDINGS: Data from many recent investigations have focused on inhaled antibiotics as: adjunctive therapy to systemic antibiotic for VAP, monotherapy for VAP, and as monotherapy for ventilator-associated tracheobronchitis. The clinical outcomes of these studies will be reviewed as well as their effect on multidrug-resistant organisms. SUMMARY: The present review will focus on the rationale for inhaled therapy, the current studies examining the delivery and clinical efficacy of inhaled antibiotics, and the potential role for this mode of delivery actually decreasing antibiotic resistance in the respiratory tract.

Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit.

RATIONALE: Multidrug-resistant organisms (MDRO) are the dominant airway pathogens in the intensive care unit (ICU) and present a major treatment challenge to intensivists. Aerosolized antibiotics (AA) result in airway concentrations of drug 100-fold greater than the minimal inhibitory concentration of most bacteria including MDRO. These levels, without systemic toxicity, may eradicate MDRO and reduce the pressure for selection of new resistant organisms. OBJECTIVES: To determine if AA effectively eradicate MDRO in the intubated patient without promoting new resistance. METHODS: In a double-blind placebo-controlled study, critically ill intubated patients were randomized if they exhibited signs of respiratory infection (purulent secretions and Clinical Pulmonary Infection Score ≥6). Using a well-characterized aerosol delivery system, AA or saline placebo was given for 14 days or until extubation. The responsible clinician determined administration of systemic antibiotics for ventilator-associated pneumonia and any other infection. MEASUREMENTS AND MAIN RESULTS: AA eradicated 26 of 27 organisms present at randomization compared with 2 of 23 organisms with placebo (P < 0.0001). AA eradicated the original resistant organism on culture and Gram stain at end of treatment in 14 out of 16 patients compared with 1 of 11 for placebo (P < 0.001). New drug resistance to AA was not seen. Compared with AA, resistance to systemic antibiotics significantly increased in placebo patients (P = 0.03). Compared with placebo, AA significantly reduced Clinical Pulmonary Infection Score (mean ± SEM, 9.3 ± 2.7 to 5.3 ± 2.6 vs. 8.0 ± 23 to 8.6 ± 2.10; P = 0.0008). CONCLUSIONS: In chronically intubated critically ill patients, AA successfully eradicated existing MDRO organisms and reduced the pressure from systemic agents for new respiratory resistance. Clinical trial registered with www.clinicaltrials.gov (NCT 01878643).

The plasticity of pyramidal neurons in the behaving brain.

Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the in vitro brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the in vivo intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons, with a specific focus on the latest developments from in vivo studies. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

LINE-1 retrotransposons contribute to mouse PV interneuron development.

Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis-regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 sequences are mobile in only some neuronal lineages or therein promote neurodevelopmental gene expression. Here we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters and express full-length L1 mRNAs and proteins. Using nanopore long-read sequencing, we identify unmethylated L1s proximal to PV interneuron genes, including a novel L1 promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV interneuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

Early exposure to alcohol leads to permanent impairment of dendritic excitability in neocortical pyramidal neurons.

Exposure to alcohol in utero is a well known cause of mental retardation in humans. Using experimental models of fetal alcohol spectrum disorder, it has been demonstrated that cortical pyramidal neurons and their projections are profoundly and permanently impaired. Yet, how the functional features of these cells are modified and how such modifications impact cognitive processes is still unknown. To address this, we studied the intrinsic electrophysiological properties of pyramidal neurons in young adult rats (P30-P60) exposed to ethanol inhalation during the first week of postnatal life (P2-P6). Dual whole-cell recordings from the soma and distal apical dendrites were performed and, following the injection of depolarizing current into the dendrites, layer 5 neurons from ethanol-treated (Et) animals displayed a lower number and a shorter duration of dendritic spikes, attributable to a downregulation of calcium electrogenesis. As a consequence, the mean number of action potentials recorded at the soma after dendritic current injection was also lower in Et animals. No significant differences between Et and controls were observed in the firing pattern elicited in layer 5 neurons by steps of depolarizing somatic current, even though the firing rate was significantly lower in Et animals. The firing pattern and the firing rate of layer 2/3 neurons were not affected by alcohol exposure.

A thalamocortical pathway controlling impulsive behavior.

Planning and anticipating motor actions enables movements to be quickly and accurately executed. However, if anticipation is not properly controlled, it can lead to premature impulsive actions. Impulsive behavior is defined as actions that are poorly conceived and are often risky and inappropriate. Historically, impulsive behavior was thought to be primarily controlled by the frontal cortex and basal ganglia. More recently, two additional brain regions, the ventromedial (VM) thalamus and the anterior lateral motor cortex (ALM), have been shown to have an important role in mice. Here, we explore this newly discovered role of the thalamocortical pathway and suggest cellular mechanisms that may be involved in driving the cortical activity that contributes to impulsive behavior.

Cocaine regulates sensory filtering in cortical pyramidal neurons.

Exposure to cocaine leads to robust changes in the structure and function of neurons within the mesocorticolimbic pathway. However, little is known about how cocaine influences the processing of information within the sensory cortex. We address this by using patch-clamp and juxtacellular voltage recordings and two-photon Ca2+ imaging in vivo to investigate the influence of acute cocaine exposure on layer 2/3 (L2/3) pyramidal neurons within the primary somatosensory cortex (S1). Here, cocaine dampens membrane potential state transitions and decreases spontaneous somatic action potentials and Ca2+ transients. In contrast to the uniform decrease in background spontaneous activity, cocaine has a heterogeneous influence on sensory encoding, increasing tactile-evoked responses in dendrites that do not typically encode sensory information and decreasing responses in those dendrites that are more reliable sensory encoders. Combined, these findings suggest that cocaine acts as a filter that suppresses background noise to selectively modulate incoming sensory information.