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Gangliosides, a diverse class of glycosphingolipids, are highly abundant in neural tissue and have been implicated in numerous aging-related diseases. Their characterization with methods such as liquid chromatography-tandem mass spectrometry is often precluded by their structural complexity, isomeric heterogeneity, and lack of commercially available authentic standards. In this work, we coupled high-resolution cyclic ion mobility spectrometry with multiple collision-induced dissociation-based tandem mass spectrometry strategies to sequence the sialic acid positions in various ganglioside isomers. Initially, as a proof-of-concept demonstration, we were able to characterize the sialic acid positions in several GD1 and GT1 species. From there, we extended our approach to identify the location of N-glycolylneuraminic acid (NeuGc) residues in previously uncharacterized GD1 and GQ1 isomers. Our results highlight the potential of this presented methodology for the de novo characterization of gangliosides within complex biological matrices without the need for authentic standards.
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Ion mobility spectrometry (IMS) coupled to mass spectrometry (MS) has become a versatile tool to fractionate complex mixtures, distinguish structural isomers, and elucidate molecular geometries. Along with the whole MS field, IMS/MS advances to ever larger species. A topical proteomic problem is the discovery and characterization of d-amino acid-containing peptides (DAACPs) that are critical to neurotransmission and toxicology. Both linear IMS and FAIMS previously disentangled d/l epimers with up to â¼30 residues. In the first study using all three most powerful IMS methodologiesâtrapped IMS, cyclic IMS, and FAIMSâwe demonstrate baseline resolution of the largest known d/l peptides (CHH from Homarus americanus with 72 residues) with a dynamic range up to 100. This expands FAIMS analyses of isomeric modified peptides, especially using hydrogen-rich buffers, to the â¼50-100 residue range of small proteins. The spectra for d and l are unprecedentedly strikingly similar except for a uniform shift of the separation parameter, indicating the conserved epimer-specific structural elements across multiple charge states and conformers. As the interepimer resolution tracks the average for smaller DAACPs, the IMS approaches could help search for yet larger DAACPs. The a priori method to calibrate cyclic (including multipass) IMS developed here may be broadly useful.
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Péptidos , Proteómica , Péptidos/química , Espectrometría de Masas/métodos , Proteínas , Espectrometría de Movilidad Iónica , Aminoácidos/químicaRESUMEN
BACKGROUND: Unused opioid prescriptions can be a driver of opioid misuse. Our objective was to determine the optimal quantity of opioids to prescribe to patients with acute pain at emergency department discharge, in order to meet their analgesic needs while limiting the amount of unused opioids. METHODS: In a prospective, multicentre cohort study, we included consecutive patients aged 18 years and older with an acute pain condition present for less than 2 weeks who were discharged from emergency department with an opioid prescription. Participants completed a pain medication diary for real-time recording of quantity, doses, and names of all analgesics consumed during a 14-day follow-up period. RESULTS: We included 2240 participants, who had a mean age of 51 years; 48% were female. Over 14 days, participants consumed a median of 5 (quartiles, 1-14) morphine 5 mg tablet equivalents, with significant variation across pain conditions (p < 0.001). Most opioid tablets prescribed (63%) were unused. To meet the opioid need of 80% of patients for 2 weeks, we found that those experiencing renal colic or abdominal pain required fewer opioid tablets (8 morphine 5 mg tablet equivalents) than patients who had fractures (24 tablets), back pain (21 tablets), neck pain (17 tablets), or other musculoskeletal pain (16 tablets). INTERPRETATION: Two-thirds of opioid tablets prescribed at emergency department discharge for acute pain were unused, whereas opioid requirements varied significantly based on the cause of acute pain. Smaller, cause-specific opioid prescriptions could provide adequate pain management while reducing the risk of opioid misuse. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT03953534.
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Dolor Agudo , Analgésicos Opioides , Servicio de Urgencia en Hospital , Humanos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Dolor Agudo/tratamiento farmacológico , Estudios Prospectivos , Adulto , Anciano , Prescripciones de Medicamentos/estadística & datos numéricos , Dolor Abdominal/tratamiento farmacológico , Cólico Renal/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Fracturas Óseas , Dolor de Espalda/tratamiento farmacológico , Visitas a la Sala de EmergenciasRESUMEN
PURPOSE: The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients. METHODS: We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-CÅur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L-1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa. RESULTS: Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0-152.3], 59.3 [21.1-74.4], and 25.3 [6.8-44.6] mg·L-1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L-1. The majority of patients who were underexposed were patients with normal to augmented renal clearance. CONCLUSION: In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.
RéSUMé: OBJECTIF: L'objectif de cette étude était d'évaluer l'exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs. MéTHODES: Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-CÅur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d'échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa. RéSULTATS: Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l'intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée. CONCLUSION: Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l'atteinte des cibles d'efficacité.
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Antibacterianos , Piperacilina , Adulto , Humanos , Combinación Piperacilina y Tazobactam/uso terapéutico , Piperacilina/farmacología , Unidades de Cuidados Intensivos , Estudios Prospectivos , Enfermedad Crítica/terapiaRESUMEN
PURPOSE: Agitation is a common behavioural problem following traumatic brain injury (TBI). Intensive care unit (ICU) physicians' perspectives regarding TBI-associated agitation are unknown. Our objective was to describe physicians' beliefs and perceived importance of TBI-associated agitation in critically ill patients. METHODS: Following current standard guidance, we built an electronic, self-administrated, 42-item survey, pretested it for reliability and validity, and distributed it to 219 physicians working in 18 ICU level-1 trauma centres in Canada. We report the results using descriptive statistics. RESULTS: The overall response rate was 93/219 (42%), and 76/93 (82%) respondents completed the full survey. Most respondents were men with ten or more years of experience. Respondents believed that pre-existing dementia (90%) and regular recreational drug use (86%) are risk factors for agitation. Concerning management, 91% believed that the use of physical restraints could worsen agitation, 90% believed that having family at the bedside reduces agitation, and 72% believed that alpha-2 adrenergic agonists are efficacious for managing TBI agitation. Variability was observed in beliefs on epidemiology, sex, gender, age, socioeconomic status, and other pharmacologic options. Respondents considered TBI agitation frequent enough to justify the implementation of management protocols (87%), perceived the current level of clinical evidence on TBI agitation management to be insufficient (84%), and expressed concerns about acute and long-term detrimental outcomes and burden to patients, health care professionals, and relatives (85%). CONCLUSION: Traumatic brain injury-associated agitation in critically ill patients was perceived as an important issue for most ICU physicians. Physicians agreed on multiple approaches to manage TBI-associated agitation although agreement on epidemiology and risk factors was variable.
RéSUMé: OBJECTIF: L'agitation est un problème de comportement courant à la suite d'un traumatisme crânien (TC). Le point de vue des médecins des unités de soins intensifs (USI) sur l'agitation associée aux traumatismes crâniens est inconnu. Notre objectif était de décrire les croyances et l'importance perçue par les médecins de l'agitation associée aux traumatismes crâniens chez les patient·es gravement malades. MéTHODE: Conformément aux lignes directrices standard actuelles, nous avons élaboré un sondage électronique auto-administré de 42 questions, l'avons testé au préalable pour en vérifier la fiabilité et la validité, et l'avons distribué à 219 médecins travaillant dans les USI de 18 centres de traumatologie de niveau 1 au Canada. Les résultats sont présentés à l'aide de statistiques descriptives. RéSULTATS: Le taux de réponse global a été de 93 sur 219 (42 %) et 76 sur 93 (82 %) personnes interrogées ont répondu à l'ensemble du sondage. La plupart des répondant·es étaient des hommes comptant dix ans ou plus d'expérience. Les répondant·es sont d'avis que la démence préexistante (90 %) et la consommation régulière de drogues à des fins récréatives (86 %) sont des facteurs de risque d'agitation. En ce qui concerne la prise en charge, 91 % des répondant·es estiment que l'utilisation de contentions physiques peut aggraver l'agitation, 90 % croient que le fait d'avoir de la famille au chevet du patient ou de la patiente réduit l'agitation et 72 % pensent que les agonistes alpha-2 adrénergiques sont efficaces pour gérer l'agitation causée par les traumatismes crâniens. Une variabilité a été observée dans les croyances concernant l'épidémiologie, le sexe, le genre, l'âge, le statut socio-économique et d'autres options pharmacologiques. Les répondant·es considéraient que l'agitation liée aux traumatismes crâniens était suffisamment fréquente pour justifier la mise en Åuvre de protocoles de prise en charge (87 %), estimaient que le niveau actuel de données probantes cliniques sur la prise en charge de l'agitation causée par un traumatisme crânien était insuffisant (84 %), et se sont dit·es préoccupé·es par les conséquences préjudiciables aiguës et à long terme et par le fardeau pour les patient·es, les professionnel·les de la santé et les proches (85 %). CONCLUSION: L'agitation associée à un traumatisme crânien chez les patient·es gravement malades était perçue comme un problème important pour la plupart des médecins des soins intensifs. Les médecins s'entendaient sur plusieurs approches pour gérer l'agitation associée aux traumatismes crâniens, bien que l'accord sur l'épidémiologie et les facteurs de risque était variable.
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Lesiones Traumáticas del Encéfalo , Médicos , Masculino , Humanos , Femenino , Enfermedad Crítica , Reproducibilidad de los Resultados , Canadá/epidemiología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/epidemiología , Encuestas y CuestionariosRESUMEN
BACKGROUND: In traumatic brain injury patients (TBI) admitted to the intensive care unit (ICU), agitation can lead to accidental removal of catheters, devices as well as self-extubation and falls. Actigraphy could be a potential tool to continuously monitor agitation. The objectives of this study were to assess the feasibility of monitoring agitation with actigraphs and to compare activity levels in agitated and non-agitated critically ill TBI patients. METHODS: Actigraphs were placed on patients' wrists; 24-hour monitoring was continued until ICU discharge or limitation of therapeutic efforts. Feasibility was assessed by actigraphy recording duration and missing activity count per day. RESULTS: Data from 25 patients were analyzed. The mean number of completed day of actigraphy per patient was 6.5 ± 5.1. The mean missing activity count was 20.3 minutes (±81.7) per day. The mean level of activity measured by raw actigraphy counts per minute over 24 hours was higher in participants with agitation than without agitation. CONCLUSIONS: This study supports the feasibility of actigraphy use in TBI patients in the ICU. In the acute phase of TBI, agitated patients have higher levels of activity, confirming the potential of actigraphy to monitor agitation.
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Actigrafía , Lesiones Traumáticas del Encéfalo , Unidades de Cuidados Intensivos , Agitación Psicomotora , Humanos , Actigrafía/métodos , Masculino , Femenino , Lesiones Traumáticas del Encéfalo/complicaciones , Adulto , Agitación Psicomotora/etiología , Agitación Psicomotora/diagnóstico , Persona de Mediana Edad , Estudios de Factibilidad , Monitoreo Fisiológico/métodos , Anciano , Descanso/fisiología , Adulto JovenRESUMEN
Toxicology studies in early fish life stages serve an important function in measuring the impact of potentially harmful substances, such as crude oil, on marine life. Morphometric analysis of larvae can reveal the effects of such substances in retarding growth and development. These studies are labor intensive and time consuming, typically resulting in only a small number of samples being considered. An automated system for imaging and measurement of experimental animals, using flow-through imaging and an artificial neural network to allow faster sampling of more individuals, has been described previously and used in toxicity experiments. This study compares the performance of the automated imaging and analysis system with traditional microscopy techniques in measuring biologically relevant endpoints using two oil treatments as positive controls. We demonstrate that while the automated system typically underestimates morphometric measurements relative to analysis of manual microscopy images, it shows similar statistical results to the manual method when comparing treatments across most endpoints. It allows for many more individual specimens to be sampled in a shorter time period, reducing labor requirements and improving statistical power in such studies, and is noninvasive allowing for repeated sampling of the same population.
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Gadus morhua , Larva , Petróleo , Contaminantes Químicos del Agua , Animales , Petróleo/toxicidad , Contaminantes Químicos del Agua/toxicidad , Redes Neurales de la Computación , Procesamiento de Imagen Asistido por Computador/métodos , Microscopía/métodosRESUMEN
OBJECTIVE: Dissociative symptoms are both a pathological consequence of exposure to psychological trauma as well as a side effect of N-methyl-d-aspartate (NMDA) receptor antagonist medications; therefore, accurate and valid assessment of these symptoms is important. The psychometric properties of the 23-item Clinician Administered Dissociative States Scale (CADSS) have been characterized in the ketamine and esketamine literatures. Here, we examine its performance in a sample with and without posttraumatic stress disorder (PTSD) and a history of exposure to psychological trauma. METHODS: Participants with a history of psychological trauma with (N = 148) and without (N = 100) the diagnosis of PTSD and healthy participants without a psychiatric disorder or history of trauma (N = 28) were assessed with the 23-item CADSS and other psychometric and neuropsychological assessments. Analyses were performed to examine internal consistency, convergent and discriminant validity, factor structure, differential performance in populations reported to be more or less likely to report dissociative symptoms (e.g., patients with and without PTSD), and sensitivity to change resulting from exposure to trauma-related sights and sounds. RESULTS: The 23-item CADSS was found to have high internal consistency (Cronbach's alpha 0.91) and a single-factor structure. CADSS total scores in trauma-exposed participants with PTSD were higher than those in trauma-exposed participants without PTSD and non-traumatized non-PTSD participants. Finally, veterans with Iraq combat-related PTSD showed a significant increase in CADSS total score after exposure to combat-related slides and sounds. CONCLUSION: The 23-item CADSS, already validated as a tool to measure dissociation related to administration of NMDA receptor antagonist medication, performs in a reliable and valid manner in the assessment of dissociation in psychologically traumatized participants.
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The unexpected finding that isotopomers (i.e., isotopic isomers) can be separated with high-resolution ion mobility spectrometry-mass spectrometry (IMS-MS) has raised new structural considerations affecting an ion's mobility, namely its center of mass (CoM) and moments of inertia (MoI). Unfortunately, thus far, no studies have attempted to experimentally isolate either CoM or MoI, as they are intrinsically linked by their definitions, where MoI is calculated in relation to CoM. In this study, we designed and synthesized four isotopically labeled tetrapropylammonium (TAA3) ions, each with a unique mass distribution. Three of the synthesized TAA3 ions were labeled symmetrically, thus having identical CoM but differing MoI, which we verified using density functional theory (DFT) calculations. Consequently, we were able to isolate the effect of MoI changes in high-resolution IMS-MS separations. Cyclic ion mobility spectrometry-mass spectrometry (cIMS-MS) separations of the isotopically labeled TAA3 variants revealed isotopic mobility shifts attributable solely to changes in MoI. A 60-m cIMS-MS separation demonstrated that two nominally isobaric TAA3 pseudoisotopomers could be partially resolved, showcasing potential feasibility for isotopomer separations on commercially available IMS-MS platforms. With our previously established collision cross section (CCS) calibration protocol, we also quantified the relationship between MoI and CCS. Our results represent the first demonstration of IMS-MS separations based solely on MoI differences. We believe these findings will contribute important evidence to the growing body of literature on the physical nature of isotopic shifts in IMS-MS separations and work toward more accurate CCS predictions.
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ABSTRACT: BACKGROUND: Delirium is a common neurological complication in patients admitted to the intensive care unit (ICU) after moderate to severe traumatic brain injury (TBI). Although current clinical guidelines prioritize delirium prevention, no specific tool is tailored to detect early signs of delirium in TBI patients. This preliminary 2-phase observational study investigated the correlation between the pupillary light reflex (PLR), measured with a pupillometer during mechanical ventilation, and the development of postextubation delirium in TBI patients. METHODS: A convenience sample of 26 adults with moderate to severe TBI under mechanical ventilation was recruited during their ICU stay. In phase I, PLR measurements were performed in the first 3 days of ICU admission using automated infrared pupillometry. In phase II, 2 raters independently extracted delirium data in the 72 hours post extubation period from medical records. Delirium was confirmed with a documented medical diagnosis. Point-biserial correlations ( rpb ) were used to examine the association between PLR scores and the presence of postextubation delirium. Student t tests were also performed to compare mean PLR scores between patients with and without delirium. RESULTS: Ten TBI patients (38%) were diagnosed with postextubation delirium, whereas 16 (62%) were not. Significant correlations between delirium and 2 PLR variables were found: pupil constriction percentage ( rpb (24) = -0.526, P = .006) and constriction velocity ( rpb (24) = -0.485, P = .012). The t test also revealed a significant difference in constriction percentage and velocity scores between TBI patients with and without delirium ( P ≤ .01). CONCLUSION: Our findings suggest that the use of pupillometry in the first 3 days of mechanical ventilation during an ICU stay may help identify TBI patients at risk for delirium after extubation. Although further research is necessary to support its validity, this technological tool may enable ICU nurses to better screen TBI patients for delirium and prevent its development.
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Lesiones Traumáticas del Encéfalo , Delirio , Unidades de Cuidados Intensivos , Reflejo Pupilar , Respiración Artificial , Humanos , Reflejo Pupilar/fisiología , Masculino , Femenino , Lesiones Traumáticas del Encéfalo/complicaciones , Delirio/etiología , Delirio/diagnóstico , Persona de Mediana Edad , Respiración Artificial/efectos adversos , Adulto , Extubación Traqueal/efectos adversosRESUMEN
Outbreaks of corallivorous Crown of Thorns Starfish (Acanthaster spp.; CoTS) cause substantial coral mortality throughout the Indo-Pacific, particularly on the Great Barrier Reef (GBR). Refining CoTS population density modelling and understanding the disparities between real-world observations and model predictions is crucial for developing effective control strategies. Using a spatially explicit ecosystem model of the GBR, we compared CoTS density model predictions to observations and incorporated a new zone-specific mortality rate to account for differences in predation of CoTS between fished and protected reefs. We found high congruence between predictions and observations: â¼81 % of categorical reef level CoTS densities matched or only differed by one category. However, underpredictions increased with higher observed densities. Zone-specific CoTS mortality reduced severe underpredictions from 7.1 % to 5.6 %, which is critical for managers as underpredictions indicate missing outbreaks where targeted culling is necessary, but also lead to underestimated coral loss attributed to CoTS outbreaks. Reef protection status affected prediction accuracy, highlighting the importance of further research on in situ CoTS mortality rates. The location of a reef inside or outside the "initiation box", a speculative area of primary outbreaks (i.e., initial abrupt population increases) on the GBR, also influenced accuracy, with exact predictions more likely outside. Accurately modelling initiation box dynamics is challenging due to limited empirical data on CoTS outbreaks, highlighting the need for focussed research on outbreak dynamics to enhance predictive accuracy. Spatial factors, such as region and shelf position, contributed to the variance between observations and predictions, underscoring the importance of the spatial-temporal context of each observation. Observations of CoTS can help refine model predictions, guide targeted control measures, and contribute to effective ecosystem management for the long-term resilience of the GBR and other reefs targeted by CoTS throughout the Indo-Pacific.
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Traumatic brain injury (TBI) survivors often suffer from agitated behaviors and will most likely receive pharmacological treatments. Choosing an optimal and safe treatment that will not interfere with neurological recovery remains controversial. By interfering with dopaminergic circuits, antipsychotics may impede processes important to cognitive recovery. Despite their frequent use, there have been no large randomized controlled studies of antipsychotics for the management of agitated behaviors during the acute TBI recovery period. We conducted a systematic review and meta-analysis of pre-clinical studies evaluating the effects of antipsychotics post-TBI on both cognitive and motor recovery. MEDLINE and Embase databases were searched up to August 2, 2023. Pre-clinical studies evaluating the effects of antipsychotics on cognitive and motor functions post-TBI were considered. Risk of bias was evaluated with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified 15 studies including a total of 1188 rodents, mostly conducted in male Sprague-Dawley rats using cortical impact injury. The analysis revealed no consistent effect of haloperidol on motor functions, but risperidone was associated with a significant impairment in motor function on day 5 post-injury (7.05 sec; 95% confidence interval [CI]: 1.47, 12.62; I2 = 92%). Other atypical antipsychotics did not result in impaired motor function. When evaluating cognitive function, haloperidol- (23.00 sec; 95% CI: 17.42-28.59; I2 = 7%) and risperidone-treated rats (24.27 sec; 95% CI: 16.18-32.36; I2 = 0%) were consistently impaired when compared to controls. In studies evaluating atypical antipsychotics, no impairments were observed. Clinicians should avoid the regular use of haloperidol and risperidone, and future human studies should be conducted with atypical antipsychotics.
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Cyclic peptides are an important class of molecules that gained significant attention in the field of drug discovery due to their unique pharmacological characteristics and enhanced proteolytic stability. Yet, gastrointestinal degradation remains a major hurdle in the discovery of orally bioavailable cyclic peptides. Soft spot identification (SSID) of the regions in the cyclic peptide sequence susceptible to amide hydrolysis by proteases is used in the discovery stage to guide medicinal chemistry design. SSID can be an arduous task, traditionally performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), often resulting in complex and time-consuming manual analysis, particularly when isomeric linear peptide metabolites chromatographically coelute. Here, we present an alternative orthogonal approach that entails a high-resolution ion mobility (HRIM) system based on Structures for Lossless Ion Manipulation (SLIM) technology interfaced with quadrupole time-of-flight (QTOF) mass spectrometry to address some of the challenges associated with SSID. Two strategies were used to resolve linear isomeric peptide metabolites: labeled and label-free, both utilizing the HRIM platform. The label-free strategy leverages negative polarity to ionize the isomers which achieves better separation of the gas phase ions in the ion mobility (IM) dimension as compared to positive polarity, which is a more conventional approach when studying proteins and peptides. The second approach uses an isotope-labeled dimethyl tag on the terminal amine group, acting as a "shift reagent" to influence the mobility of isomers in the positive mode. This method resulted in baseline separation for the isomers of interest and produced unique product ions in the fragmentation spectra for unambiguous soft spot identification. Both label-free and labeled strategies demonstrated the ability to solve the challenges associated with SSID for cyclic peptides.
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Lasso peptides are a structurally distinct class of biologically active natural products defined by their short sequences with impressively interlocked tertiary structures. Their characteristic peptide [1]rotaxane motif confers marked proteolytic and thermal resiliency, and reports on their diverse biological functions have been credited to their exceptional sequence variability. Because of these unique properties, taken together with improved technologies for their biosynthetic production, lasso peptides are emerging as a designable scaffold for peptide-based therapeutic discovery and development. Although the defined structure of lasso peptides is recognized for its remarkable properties, the role of the motif in imparting bioactivity is less understood. For example, sungsanpin and ulleungdin are natural lasso peptides that similarly exhibit encouraging cell migration inhibitory activities in A549 lung carcinoma epithelial cells, despite sharing only one-third of the sequence homology. We hypothesized that the shape of the lasso motif is beneficial for the preorganization of the conserved residues, which might be partially retained in variants lacking the threaded structure. Herein, we describe solid-phase peptide synthesis strategies to prepare acyclic, head-to-side chain (branched), and head-to-tail (macrocyclic) cyclic variants based on the sungsanpin (Sun) and ulleungdin (Uln) sequences. Proliferation assays and time-lapse cell motility imaging studies were used to evaluate the cell inhibitory properties of natural Sun compared with the synthetic Sun and Uln isomers. These studies demonstrate that the lasso motif is not a required feature to slow cancer cell migration and more generally show that these nonthreaded isomers can retain similar activity to the natural lasso peptide despite the differences in their overall structures.
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Neoplasias Pulmonares , Péptidos , Humanos , Péptidos/farmacología , Péptidos/química , Péptido Hidrolasas , Movimiento CelularRESUMEN
INTRODUCTION: Therapeutic interventions for disorders of consciousness lack consistency; evidence supports non-invasive brain stimulation, but few studies assess neuromodulation in acute-to-subacute brain-injured patients. This study aims to validate the feasibility and assess the effect of a multi-session transcranial alternating current stimulation (tACS) intervention in subacute brain-injured patients on recovery of consciousness, related brain oscillations and brain network dynamics. METHODS AND ANALYSES: The study is comprised of two phases: a validation phase (n=12) and a randomised controlled trial (n=138). Both phases will be conducted in medically stable brain-injured adult patients (traumatic brain injury and hypoxic-ischaemic encephalopathy), with a Glasgow Coma Scale score ≤12 after continuous sedation withdrawal. Recruitment will occur at the intensive care unit of a Level 1 Trauma Centre in Montreal, Quebec, Canada. The intervention includes a 20 min 10 Hz tACS at 1 mA intensity or a sham session over parieto-occipital cortical sites, repeated over five consecutive days. The current's frequency targets alpha brain oscillations (8-13 Hz), known to be associated with consciousness. Resting-state electroencephalogram (EEG) will be recorded four times daily for five consecutive days: pre and post-intervention, at 60 and 120 min post-tACS. Two additional recordings will be included: 24 hours and 1-week post-protocol. Multimodal measures (blood samples, pupillometry, behavioural consciousness assessments (Coma Recovery Scale-revised), actigraphy measures) will be acquired from baseline up to 1 week after the stimulation. EEG signal analysis will focus on the alpha bandwidth (8-13 Hz) using spectral and functional network analyses. Phone assessments at 3, 6 and 12 months post-tACS, will measure long-term functional recovery, quality of life and caregivers' burden. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the Research Ethics Board of the CIUSSS du Nord-de-l'Île-de-Montréal (Project ID 2021-2279). The findings of this two-phase study will be submitted for publication in a peer-reviewed academic journal and submitted for presentation at conferences. The trial's results will be published on a public trial registry database (ClinicalTrials.gov). TRIAL REGISTRATION NUMBER: NCT05833568.
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Trastornos de la Conciencia , Estimulación Transcraneal de Corriente Directa , Humanos , Estimulación Transcraneal de Corriente Directa/métodos , Trastornos de la Conciencia/terapia , Trastornos de la Conciencia/fisiopatología , Trastornos de la Conciencia/etiología , Electroencefalografía , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Cuidados Críticos/métodos , Lesiones Traumáticas del Encéfalo/terapia , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/fisiopatología , Encéfalo/fisiopatología , Lesiones Encefálicas/terapia , Lesiones Encefálicas/fisiopatología , Lesiones Encefálicas/complicaciones , Escala de Coma de Glasgow , Masculino , Femenino , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/fisiopatología , Estado de ConcienciaRESUMEN
Resilience-based management is essential to protect ecosystems in the Anthropocene. Unlike large-scale climate threats to Great Barrier Reef (GBR) corals, outbreaks of coral-eating crown-of-thorns starfish (COTS; Acanthaster cf. solaris) can be directly managed through targeted culling. Here, we evaluate the outcomes of a decade of strategic COTS management in suppressing outbreaks and protecting corals during the 4th COTS outbreak wave at reef and regional scales (sectors). We compare COTS density and coral cover dynamics during the 3rd and 4th outbreak waves. During the 4th outbreak wave, sectors that received limited to no culling had sustained COTS outbreaks causing significant coral losses. In contrast, in sectors that received timely and sufficient cull effort, coral cover increased substantially, and outbreaks were suppressed with COTS densities up to six-fold lower than in the 3rd outbreak wave. In the Townsville sector for example, despite exposure to comparable disturbance regimes during the 4th outbreak wave, effective outbreak suppression coincided with relative increases in sector-wide coral cover (44%), versus significant coral cover declines (37%) during the 3rd outbreak wave. Importantly, these estimated increases span entire sectors, not just reefs with active COTS control. Outbreaking reefs with higher levels of culling had net increases in coral cover, while the rate of coral loss was more than halved on reefs with lower levels of cull effort. Our results also indicate that outbreak wave progression to adjoining sectors has been delayed, probably via suppression of COTS larval supply. Our findings provide compelling evidence that proactive, targeted, and sustained COTS management can effectively suppress COTS outbreaks and deliver coral growth and recovery benefits at reef and sector-wide scales. The clear coral protection outcomes demonstrate the value of targeted manual culling as both a scalable intervention to mitigate COTS outbreaks, and a potent resilience-based management tool to "buy time" for coral reefs, protecting reef ecosystem functions and biodiversity as the climate changes.
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Antozoos , Conservación de los Recursos Naturales , Arrecifes de Coral , Estrellas de Mar , Animales , Estrellas de Mar/fisiología , Antozoos/fisiología , Conservación de los Recursos Naturales/métodos , Ecosistema , Australia/epidemiologíaRESUMEN
BACKGROUND: The goal of this systematic review was to examine the efficacy and safety of proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients. METHODS: We included randomized trials comparing proton-pump inhibitors versus placebo or no prophylaxis in critically ill adults, performed meta-analyses, and assessed certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. To explore the effect of proton-pump inhibitors on mortality based on disease severity, a subgroup analysis was conducted combining within-trial subgroup data from the two largest trials and assessed credibility using the Instrument for Assessing the Credibility of Effect Modification Analyses. RESULTS: Twelve trials that enrolled 9533 patients were included. Proton-pump inhibitors were associated with a reduced incidence of clinically important upper gastrointestinal bleeding (relative risk [RR], 0.51 [95% confidence interval (CI), 0.34 to 0.76]; high certainty evidence). Proton-pump inhibitors may have little or no effect on mortality (RR, 0.99 [95% CI, 0.93 to 1.05]; low certainty). Within-trial subgroup analysis with intermediate credibility suggested that the effect of proton-pump inhibitors on mortality may differ based on disease severity. Subgroup results raise the possibility that proton-pump inhibitors may decrease 90-day mortality in less severely ill patients (RR, 0.89; 95% CI, 0.80 to 0.98) and may increase mortality in more severely ill patients (RR, 1.08; 95% CI, 0.96 to 1.20]. Proton-pump inhibitors may have no effect on pneumonia and little or no effect on Clostridioides difficile infection (low certainty). CONCLUSIONS: High certainty evidence supports the association of proton-pump inhibitors with decreased upper gastrointestinal bleeding. Proton-pump inhibitors may have little or no effect on mortality, although a decrease in mortality in less severely ill patients and an increase in mortality in more severely ill patients remain possible. (PROSPERO number CRD42023461695.).
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Enfermedad Crítica , Hemorragia Gastrointestinal , Inhibidores de la Bomba de Protones , Humanos , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/administración & dosificación , Hemorragia Gastrointestinal/prevención & control , Hemorragia Gastrointestinal/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Surface serology is an important determinant in Spiroplasma systematics. Reciprocal antigen/antibody reactions between spiroplasmas and individual antisera delineate the 38 described groups and species. However, reciprocal serology is impractical for largescale studies. This report describes a successful, streamlined polyvalent screening approach used to examine isolates from an environmental survey.
A sorologia de superfície é um determinante importante na sistemática de Spiroplasma. Reações antígeno-anticorpo entre spiroplasmas e antisoro individuais delineiam os 38 grupos e espécies descritos. No entanto, reações sorológicas são impraticáveis em estudos em larga-escala. Esse relato descreve uma metodologia de triagem bem sucedida a ser empregada no exame de isolados em levantamentos ambientais.