Factors Associated with Fatigue in COVID-19 ICU Survivors.

PURPOSE: Approximately 30% of people infected with COVID-19 require hospitalization and 20% of them are admitted to an intensive care unit (ICU). Most of these patients experience symptoms of fatigue weeks post-ICU, so understanding the factors associated with fatigue in this population is crucial. METHODS: Fifty-nine patients [38-78 yr] hospitalized in ICU for COVID-19 infection for 32 [6-80] days including 23 [3-57] days of mechanical ventilation, visited the laboratory on two separate occasions. The first visit occurred 52 ± 15 days after discharge and was dedicated to questionnaires, blood sampling and cardiopulmonary exercise testing, while measurements of the knee extensors neuromuscular function and performance fatigability were performed in the second visit 7 ± 2 days later. RESULTS: Using the FACIT-F questionnaire, 56% of patients were classified as fatigued. Fatigued patients had worse lung function score than non- fatigued (i.e. 2.9 ± 0.8 L vs 3.6 ± 0.8 L; 2.4 ± 0.7 l vs 3.0 ± 0.7 L for forced vital capacity and forced expiratory volume in one second, respectively) and forced vital capacity was identified as a predictor of being fatigued. Maximal voluntary activation was lower in fatigued patients than non-fatigued patients (82 ± 14% vs 91 ± 3%) and was the only neuromuscular variable that discriminated between fatigued and non-fatigued patients. Patient-reported outcomes also showed differences between fatigued and non-fatigued patients for sleep, physical activity, depression and quality of life (p < 0.05). CONCLUSIONS: COVID-19 survivors showed altered respiratory function 4 to 8 weeks after discharge, that was further deteriorated in fatigued patients. Fatigue was also associated with lower voluntary activation and patient-reported impairments (i.e. sleep satisfaction, quality of life or depressive state). The present study reinforces the importance of exercise intervention and rehabilitation to counteract cardiorespiratory and neuromuscular impairments of COVID-19 patients admitted in ICU, especially individuals experiencing fatigue.

Towards optimization of ceftazidime dosing in obese ICU patients: the end of the 'one-size-fits-all' approach?

BACKGROUND: Ceftazidime is commonly used as a key antibiotic against Pseudomonas aeruginosa in critically ill patients. ICU patients have severely altered and variable antibiotic pharmacokinetics, resulting in lower antimicrobial concentrations and potentially poor outcome. Several factors, including obesity and renal function, may influence pharmacokinetics. Thus, the objective of the study was to evaluate the impact of obesity and renal function on ceftazidime plasma concentrations and dosing regimen in ICU patients. METHODS: All consecutive adult patients from six ICUs, treated with continuous ceftazidime infusion and under therapeutic drug monitoring evaluation, were included. Obesity was defined as BMI ≥30 kg/m². Glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration formula. The ceftazidime recommended target for plasma concentrations was between 35 and 80 mg/L. RESULTS: A total of 98 patients (45 obese), with an average weight of 90 (±25) kg, were included. Mean GFR was 84.1 (±40.4) mL/min/1.73 m2. Recommended ceftazidime plasma concentrations were achieved for only 48.0% of patients, with median dosing regimen of 6 g/day. Obese patients had lower ceftazidime plasma concentrations compared with non-obese patients (37.8 versus 56.3 mg/L; P = 0.0042) despite similar dosing regimens (5.83 g/day versus 5.52 g/day, P = 0.2529). Almost all augmented renal clearance patients were underdosed despite ceftazidime dosing of 6.6 (±0.8) g/day. Weight-based ceftazidime dosing seemed to attenuate such obesity-related discrepancies, regardless of GFR. CONCLUSIONS: Obese ICU patients required significantly greater ceftazidime doses to achieve the target range. A tailored dosing regimen may be considered based on weight and GFR. Future prospective studies should be performed to confirm this individualized dosing approach.

Differential effect of lactate on synovial fibroblast and macrophage effector functions.

Introduction: The synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters. Methods: Synovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets. Results: We show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion. Discussion: In this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.

Management of refractory hypoxemia using recruitment maneuvers and rescue therapies: A comprehensive review.

Refractory hypoxemia in patients with acute respiratory distress syndrome treated with mechanical ventilation is one of the most challenging conditions in human and veterinary intensive care units. When a conventional lung protective approach fails to restore adequate oxygenation to the patient, the use of recruitment maneuvers and positive end-expiratory pressure to maximize alveolar recruitment, improve gas exchange and respiratory mechanics, while reducing the risk of ventilator-induced lung injury has been suggested in people as the open lung approach. Although the proposed physiological rationale of opening and keeping open previously collapsed or obstructed airways is sound, the technique for doing so, as well as the potential benefits regarding patient outcome are highly controversial in light of recent randomized controlled trials. Moreover, a variety of alternative therapies that provide even less robust evidence have been investigated, including prone positioning, neuromuscular blockade, inhaled pulmonary vasodilators, extracorporeal membrane oxygenation, and unconventional ventilatory modes such as airway pressure release ventilation. With the exception of prone positioning, these modalities are limited by their own balance of risks and benefits, which can be significantly influenced by the practitioner's experience. This review explores the rationale, evidence, advantages and disadvantages of each of these therapies as well as available methods to identify suitable candidates for recruitment maneuvers, with a summary on their application in veterinary medicine. Undoubtedly, the heterogeneous and evolving nature of acute respiratory distress syndrome and individual lung phenotypes call for a personalized approach using new non-invasive bedside assessment tools, such as electrical impedance tomography, lung ultrasound, and the recruitment-to-inflation ratio to assess lung recruitability. Data available in human medicine provide valuable insights that could, and should, be used to improve the management of veterinary patients with severe respiratory failure with respect to their intrinsic anatomy and physiology.

Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing.

Fibroblasts, derived from the embryonic mesenchyme, are a diverse array of cells with roles in development, homeostasis, repair, and disease across tissues. In doing so, fibroblasts maintain micro-environmental homeostasis and create tissue niches by producing a complex extracellular matrix (ECM) including various structural proteins. Although long considered phenotypically homogenous and functionally identical, the emergence of novel technologies such as single cell transcriptomics has allowed the identification of different phenotypic and cellular states to be attributed to fibroblasts, highlighting their role in tissue regulation and inflammation. Therefore, fibroblasts are now recognised as central actors in many diseases, increasing the need to discover new therapies targeting those cells. Herein, we review the phenotypic heterogeneity and functionality of these cells and their roles in health and disease.

Cardiorespiratory Fitness and Neuromuscular Function of Mechanically Ventilated ICU COVID-19 Patients.

OBJECTIVES: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration. DESIGN: Prospective nonrandomized study. SETTING: Patients hospitalized in ICU for COVID-19 infection. PATIENTS: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status. CONCLUSIONS: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.

Ultrasonic microrheology for ex vivo skin explants monitoring: A proof of concept.

As an answer to alternative non-animal testing, biosensors dedicated to the ex vivo skin explants monitoring are a challenge to study physiological-like behavior and optimize new topical products. Because of the skin viscoelastic behavior, mechanical tests are commonly based on macroscopic measurement and give global descriptors of its state. Other techniques, including photoacoustic ones, are more focused on the molecular scale. There is a gap to fill in the mesoscopic range to get information about the microstructure of the skin. This article presents the proof-of-concept of a biosensor coupling a thickness shear-mode transducer with human skin explants kept in life-like state for a week. Thanks to a multifrequency analysis of the transducer impedance, this biosensor is able to monitor the viscoelastic properties of the skin. To extract the complex shear modulus and the microstructural evolutions, a mechanical model based on fractional calculus is used. As a preliminary results, the sensitivity of the sensor to probe the skin viscoelasticity in lifelike state and the impact of its culture medium are presented. A suitable microstructural coefficient is also extracted in order to identify mechanical breaches in the skin barrier after the application of peeling products.

Impact of natural disasters on consumer behavior: Case of the 2017 El Niño phenomenon in Peru.

El Niño is an extreme weather event featuring unusual warming of surface waters in the eastern equatorial Pacific Ocean. This phenomenon is characterized by heavy rains and floods that negatively affect the economic activities of the impacted areas. Understanding how this phenomenon influences consumption behavior at different granularity levels is essential for recommending strategies to normalize the situation. With this aim, we performed a multi-scale analysis of data associated with bank transactions involving credit and debit cards. Our findings can be summarized into two main results: Coarse-grained analysis reveals the presence of the El Niño phenomenon and the recovery time in a given territory, while fine-grained analysis demonstrates a change in individuals' purchasing patterns and in merchant relevance as a consequence of the climatic event. The results also indicate that society successfully withstood the natural disaster owing to the economic structure built over time. In this study, we present a new method that may be useful for better characterizing future extreme events.

Pharmacobezoar After Venlafaxine and Oxazepam Overdose: How Pharmacokinetics Could Help?-A Grand Round.

ABSTRACT: The authors present here a case of a pharmacobezoar after drug overdose, diagnosed using multiple blood samples for TDM. This grand round highlights the importance of a dialog between a clinician and a TDM consultant for the optimal care of a patient.

Effect of synthetic colloid administration on hemodynamic and laboratory variables in healthy dogs and dogs with systemic inflammation.

OBJECTIVE: To compare the effects of administering equal volumes of isotonic crystalloids and synthetic colloids on hemodynamic and laboratory variables in healthy dogs and dogs with systemic inflammation. DESIGN: Randomized, placebo-controlled, blinded study. SETTING: Comparative clinical research facility. ANIMALS: Sixteen adult purpose-bred Beagles. INTERVENTIONS: Dogs were first randomized to receive either lipopolysaccharide (LPS; 5 µg/kg, IV) or an equal volume of placebo (0.9% NaCl, IV). Dogs were then randomized into 1 of 2 groups receiving fluid resuscitation with either 40 mL/kg IV isotonic crystalloid (0.9% NaCl) or synthetic colloid (tetrastarch). After a 14-day washout, the study was repeated such that dogs received the opposite treatment (LPS or placebo) and the same resuscitation fluid regimen. Vital signs (heart rate (HR), oscillometric blood pressure) were measured and blood samples were collected for PCV, total plasma protein (TPP), serum lactate concentration, and colloid osmotic pressure (COP) measurements. MEASUREMENTS AND MAIN RESULTS: Healthy (placebo) dogs had similar decreases in PCV and TPP after administration of either fluid. Tetrastarch administration was associated with a larger increase in HR, systolic blood pressure, and mean blood pressure. Dogs with systemic inflammation had similar increases in systolic blood pressure and decreases in PCV, TPP, and lactate after administration of either fluid. Tetrastarch administration caused greater immediate increase in HR and mean blood pressure compared to 0.9% NaCl. In all dogs, 0.9% NaCl administration decreased COP and tetrastarch administration increased COP. CONCLUSIONS: Resuscitation with equal volumes of 0.9% NaCl and tetrastarch caused similar changes in hemodynamic and laboratory variables in dogs with LPS-induced systemic inflammation; however, larger increases in HR and blood pressure were seen within the first 2 hours following tetrastarch administration compared to 0.9% NaCl. Tetrastarch administration increased COP in all dogs, despite a decrease in TPP.

Systematic evaluation of evidence on veterinary viscoelastic testing part 4: Definitions and data reporting.

OBJECTIVE: To systematically examine evidence surrounding definitions and reporting of data for viscoelastic testing in veterinary medicine. DESIGN: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. SETTING: Academic and referral veterinary medical centers. RESULTS: Databases searched included Medline, CAB abstracts, and Google Scholar. CONCLUSIONS: All 4 standard thromboelastography (TEG) and rotational thromboelastometry (ROTEM) variables should be universally reported, and the reporting of shear elastic modulus in addition to maximum amplitude (MA) is encouraged. There is insufficient evidence to support universal usage of the coagulation index at this time. The K value and clot formation time are the most variable of the 4 parameters, with alpha angle, MA, and maximum clot firmness generally the least variable. Individual studies should report sufficient data on patients and institutional controls to enable definitions of hypo- and hypercoagulability to be evaluated post-hoc, and it is recommended that all studies specifically report how these conditions were defined. In reporting data relating to fibrinolysis, the TEG variables LY30, LY60, CL30, CL60, and the ROTEM variables LI30, LI60, ML, LOT, and LT should be documented. Studies should report sufficient data on patients and controls to enable definitions of hyper- and hypofibrinolysis to be evaluated post-hoc, and we suggest that standard TEG/ROTEM assays may be unable to detect hypofibrinolysis in companion animals. We recommend that every center establish reference intervals, which are specific to either TEG or ROTEM. These reference intervals should be established using veterinary clinical pathology guidelines, standardized protocols, and a minimum of 40 healthy animals. There are currently insufficient data in companion animals to suggest a utility for Vcurve variables beyond that of standard TEG variables.

[Six-month outcome of 795 patients admitted to Annecy hospital emergency department for mild traumatic brain injury]. / Devenir à six mois de 795 victimes de traumatisme crânien léger pris en charge aux urgences de l'hôpital d'Annecy.

INTRODUCTION: Mild traumatic brain injuries (mTBI) are common, but their outcomes are not very well known. A prospective study was conducted in Annecy hospital, France (CHRA), to assess the incidence of disorders 6 months after the injury and to identify risk factors for persistent disorders. METHOD: All patients admitted to the emergency department after a mild brain injury between February 2006 and July 2007 were included. They were contacted by telephone 6 months later to detect (by questionnaire) the presence of persistent disorders. Patients reporting disorders were referred to the l ocal brain injury centre for a follow-up check-up. RESULTS: Ninety three of the 795 patients contacted reported disorders: memory disorders (80%), sleep disorders (79%), headaches (65%), irritability (64%), speech disorders (64%) and concentration disorders (62%). Disorders at 6 months were independently associated with age, female gender, presence of headache at the initial examination and CT scan performed in the emergency department. DISCUSSION: The disorders reported in this study were consistent with the results of previous studies. As these disorders are usually nonspecific, a case-control study or an exposed-unexposed study would be necessary to determine whether or not these disorders are linked to mTBI.

Nematodes as a source of total coliforms in a distribution system.

In a distribution system of a large North American city, recurring total coliforms and atypical coliforms were detected at the exit (distribution pumps) of a storage reservoir. The presence of total coliforms and atypical coliforms was noted when the pumps were in operation and the water temperature was higher than 18 degrees C. The total coliform and atypical coliform concentrations at the volute pump casings ranged from 0 to 93.5 colony forming units (cfu)/100 mL. Significant concentrations of nematodes were also detected at this sampling location, averaging 12.0 nematodes/L in 2001 and 17.4 nematodes/L in 2002. The hypothesis that coliforms were released from the nematodes during their transit through the high-pressure pump was tested by recovering nematodes by filtering large volumes of water and grinding the nematodes in the laboratory, using various techniques. Total coliform and heterotrophic bacteria concentrations ranged from 0 to 27 cfu/nematode and 0 to 643 cfu/nematode, respectively. The origin of the nematodes was traced back to the sand filters located at the two water treatment plants. The importance of invertebrates in the distribution system should not be dismissed and the associated health risks, if any, should be assessed.

Assessment of a new technique combining a viability test, whole-cell hybridization and laser-scanning cytometry for the direct counting of viable Enterobacteriaceae cells in drinking water.

A new direct approach, called direct viable count (DVC)-FISH-ScanRDI, combining viability measurement, specific detection and sensitive enumeration of highly diluted Enterobacteriaceae cells, was assessed during the summer in water samples from a North American drinking water treatment plant and its distribution system. Major results of this field investigation show a higher sensitivity of the DVC-FISH-ScanRDI approach in enumerating viable Enterobacteriaceae cells in distributed drinking water, relative to a culture-based method, and the increased concentration of viable but non-culturable (VBNC) Enterobacteriaceae cells in distributed water for temperatures above 18 degrees C.