Dose-response relationships of intravenous and perineural dexamethasone as adjuvants to peripheral nerve blocks: a systematic review and model-based network meta-analysis.

BACKGROUND: Superiority of perineural over intravenous dexamethasone at extending nerve block analgesia has been suggested but without considering the dose-response relationships for each route of administration. METHODS: Randomised control studies that evaluated intravenous or perineural dexamethasone as an adjuvant to unilateral peripheral nerve blocks in adults were searched up to October 2023 in MEDLINE, Central, Google Scholar, and reference lists of previous systematic reviews. The Cochrane Risk-of-Bias tool was used. A maximum effect (Emax) model-based network meta-analysis was undertaken to evaluate the dose-response relationships of dexamethasone. RESULTS: A total of 118 studies were selected (9284 patients; 35 with intravenous dexamethasone; 106 with perineural dexamethasone; dose range 1-16 mg). Studies with unclear or high risk of bias overestimated the effect of dexamethasone. Bias-corrected estimates indicated a maximum fold increase in analgesia duration of 1.7 (95% credible interval (CrI) 1.4-1.9) with dexamethasone, with no difference between perineural and intravenous routes. Trial simulations indicated that 4 mg of perineural dexamethasone increased the mean duration of analgesia for long-acting local anaesthetics from 11.1 h (95% CrI 9.4-13.1) to 16.5 h (95% CrI 14.0-19.3) and halved the rate of postoperative nausea and vomiting. A similar magnitude of effect was observed with 8 mg of intravenous dexamethasone. CONCLUSIONS: Used as an adjuvant for peripheral nerve block, intravenous dexamethasone can be as effective as perineural dexamethasone in prolonging analgesic duration, but is less potent, hence requiring higher doses. The evidence is limited because of the observational nature of the dose-response relationships and the quality of the included studies. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42020141689.

Proton pump inhibitors and risk of severe COVID-19 in older people.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 is a viral respiratory infection that can cause systemic disorders and lead to death, particularly in older people. Proton pump inhibitors (PPIs) increase the risk of enteric and lung infections. Considering the broad use of PPIs in older people, the potential role of PPIs in COVID-19 could be of dramatic significance. The objective of our study was to evaluate the link between PPIs and severe COVID-19 in older people. METHOD: We performed a retrospective cohort study, including all patients aged ≥65, hospitalised for a diagnosis of COVID-19. Epidemiological, clinical and biological data were extracted and we performed an Inverse Probability of Treatment Weighing method based on a propensity score. RESULTS: From March 2020 to February 2021, a total of 834 patients were included, with a median age of 83 and 52.8% were male. A total of 410 patients had a PPIs prescription, 358 (87.3%) were long-term PPIs-users and 52 (12.7%) were recent PPIs-users. Among PPIs-users, 163 (39.8%) patients developed severe COVID-19 versus 113 (26.7%) in PPIs-non users (odds ratio (OR) = 1.59 [1.18-2.14]; P < 0.05). Moreover, the double dose PPI-users had a higher risk of developing severe COVID-19 (OR = 3.36 [1.17-9.66]; P < 0.05) than the full dose PPI-users (OR = 2.15 [1.22-3.76]; P < 0.05) and the half dose PPI-users (OR = 1.64 [1.13-2.37]; P < 0.05). CONCLUSION: Our study reports evidence that the use of PPIs was associated with an increased risk of severe COVID-19 in older people.

Evaluating the Knowledge of and Behavior Toward COVID-19 and the Possibility of Isolating at a City Level: Survey Study.

BACKGROUND: Mass testing campaigns were proposed in France during the first wave of the COVID-19 pandemic to detect and isolate asymptomatic individuals infected by SARS-CoV-2. During mass testing in Saint-Étienne (February 2021), we performed a survey of the general population. OBJECTIVE: We evaluated, on the scale of a city's population, the literacy level about SARS-CoV-2 transmission, barrier gesture respect, and isolation acceptability or possibility in case of SARS-CoV-2 infection. METHODS: We used the validated CovQuest-CC questionnaire. Data were analyzed and correlated with volunteer characteristics and their SARS-CoV-2 screening results using multivariate analysis. RESULTS: In total, 4707 participants completed the CovQuest-CC questionnaire. Multivariate analysis revealed that female sex was a determinant of a higher score of knowledge about SARS-CoV-2 transmission (adjusted ß coefficient=0.14, 95% CI 0.04-0.23; corrected P=.02). Older ages of 50-59 years (adjusted ß coefficient=0.25, 95% CI 0.19-0.31; corrected P<.001) and ≥60 years (adjusted ß coefficient=0.25, 95% CI 0.15-0.34; corrected P<.001) were determinants of a higher score on barrier gesture respect compared to ages 20-49 years considered as reference. Female sex was also a determinant of a higher score on barrier gesture respect (adjusted ß coefficient=0.10, 95% CI 0.02-4.63; corrected P<.001). The knowledge score was correlated with the score on barrier gesture respect measures (adjusted ß coefficient=0.03, 95% CI 0.001-0.004; corrected P=.001). Older ages of 50-59 years (adjusted ß coefficient=0.21, 95% CI 0.13-0.29; corrected P<.001) and ≥60 years (adjusted ß coefficient=0.25, 95% CI 0.1-0.38; corrected P<.001) were determinants of a higher score on isolation acceptability or possibility compared to the age of 20-49 years considered as reference. Finally, the knowledge score regarding SARS-CoV-2 transmission was significantly associated with a lower risk of RT-PCR (reverse transcriptase-polymerase chain reaction) positivity (adjusted odds ratio 0.80, 95% CI 0.69-0.94; corrected P<.03), implying that a 1-point increase in the knowledge score lowers the risk of positivity by 20% on average. CONCLUSIONS: This study identified factors associated with health literacy regarding SARS-CoV-2 infection in asymptomatic individuals in a large French city's population. We can confirm that in the context of the COVID-19 pandemic, the determinants of better health literacy are not the same as those in other contexts. It seems critical to obtain a more detailed understanding of the determinants of individual citizens' behavior, as part of a strategy to combat the large-scale spread of the virus. The harsh experience of this pandemic should teach us how to nurture research to structure customized interventions to encourage the adoption of ad hoc behaviors to engage citizens in adapting behaviors more favorable to their health.

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass.

BACKGROUND: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies. METHODS: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered. RESULTS: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates. CONCLUSIONS: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation.

Classification Performance of the Ages and Stages Questionnaire: Influence of Maternal Education Level.

(1) Background: The Ages and Stages Questionnaire-Third Edition (ASQ-3) is a parental screening questionnaire increasingly being used to evaluate the development of preterm children. We aimed to assess the classification performance of the ASQ-3 in preterm infant follow-up. (2) Methods: In this cross-sectional study, we included 185 children from the SEVE longitudinal cohort born <33 weeks of gestational age between November 2011 and January 2018, who had both an ASQ-3 score at 24 months of corrected age (CA) and a revised Brunet-Lézine (RBL) scale score at 30 months of CA. The ASQ-3 overall score and sub-scores were compared to the RBL developmental quotient (DQ) scores domain by domain. The diagnostic performance of the ASQ-3 was evaluated with the RBL as the reference method by calculating sensitivity, specificity, and positive and negative likelihood ratios. A multivariate analysis assessed the association between low maternal education level and incorrect evaluation with the ASQ-3. (3) Results: The ASQ-3 overall score had a specificity of 91%, a sensitivity of 34%, a positive likelihood ratio of 3.82, and a negative likelihood ratio of 0.72. Low maternal education level was a major risk factor for incorrectly evaluating children with the ASQ-3 (odds ratio 4.16, 95% confidence interval 1.47-12.03; p < 0.01). (4) Conclusions: Regarding the low sensitivity and the impact of a low maternal education level on the classification performance of the ASQ-3, this parental questionnaire should not be used alone to follow the development of preterm children.

Robust K-PD model for activated clotting time prediction and UFH dose individualisation during cardiopulmonary bypass.

BACKGROUND AND OBJECTIVE: Activated clotting time (ACT) is a point-of-care test used to monitor the effect of unfractionated heparin (UFH) during cardiopulmonary bypass (CPB). This test sometimes returns aberrant values, which can lead to the administration of an inappropriate dosing regimen. The development of a population-robust K-PD model of UFH could allow the individualisation and automation of UFH therapy during CPB. METHODS: We conducted a prospective observational study to collect ACT measurements from patients undergoing surgery using CPB. The ACT data were split into a development and validation cohort. The development cohort was used to estimate a standard and robust population K-PD model characterised by a residual error following a normal distribution and student's t-distribution. The ACT prediction performance using Bayesian estimates of individual K-PD parameters was evaluated by comparing predicted versus observed ACTs. Using estimates of the robust K-PD model, a Bayesian individualisation strategy to automate UFH administration was proposed and evaluated using Monte Carlo simulations. RESULTS: A total of 295 patients were included in the study, and 1561 ACTs were collected. In patients without outlier values, Bayesian estimates (based on four ACT measurements) from both standard and robust K-PD models had similar performances, with a median prediction bias close to 0 s. In patients with outlier measurements, the use of the robust K-PD model greatly improved the prediction bias and root-mean-square error (RMSE), with a mean prediction bias of 3.25 s, IQR = [-19.9; 46.03] versus -86 s IQR = [-135.7; -63.8] for the standard model. Monte Carlo simulations showed that the robust Bayesian individualisation strategy allowed the ACT to be maintained above the target using only two to three ACT measurements. CONCLUSIONS: The use of a robust K-PD model reduced prediction bias and RMSE in patients with outlier ACT measurements. The Bayesian individualisation strategy using robust estimates of individual parameters may help automate UFH dosing regimens. Proper clinical validation is warranted before its use in daily clinical practice.

Development and Validation of the COVID-19 Knowledges and Behavior Questionnaire in a French Population (CoVQuest-CC).

BACKGROUND: The SARS-CoV-2 pandemic has led most countries to take restrictive measures affecting social activities and individual freedoms to limit viral transmission. It was shown that practical, motivational and social barriers impact on adherence to the isolation and social distancing measures advocated by the health authorities. The purpose of this study was to develop and validate a COVID-19 Knowledges and Behavior Questionnaire adapted to a teenager and adult French population. METHODS: CoVQuest-CC was developed by a multidisciplinary team made of infectious diseases physicians, medical virologist, specialists of infectious control, experts of the questionnaires methodology, experts in public health and prevention, and statisticians. CoVQuest-CC was responded to by a big cohort from the general population during their participation in a massive SARS-CoV-2 screening campaign in 2021 in Saint-Etienne, France. RESULTS: The confirmatory factorial analysis yielded good results (CFI = 0.94, TLI = 0.94, RMSEA = 0.04), and confirmed the five-dimensional structure of the questionnaire. Each dimension had a satisfying internal consistency, with Cronbach alphas of 0.83, 0.71, 0.65, 0.72 and 0.83 for transmission knowledge, barrier gesture respect, tests acceptability, home isolation possibility and test practicability, respectively. CONCLUSIONS: According to our knowledge, CoVQuest-CC is the first validated, consistent and reliable self-administrated French-specific questionnaire investigating the general population's knowledge and attitudes towards COVID-19. It shows acceptable psychometric properties and can be use by Public Health teams or caregivers for public health and research purposes. TRIAL REGISTRATION: The study protocol was approved by the IRB ILE-DE-FRANCE 1 (No. IRB: I ORG0009918). All participants were given written and verbal information about the study and gave informed consent to participate. CLINICALTRIALS: gov identifier (NCT number): NCT04859023.

Body surface area capping may not improve cytotoxic drugs tolerance.

Capping body surface area (BSA) at 2 m2 is a routine clinical practice. It aims at reducing toxicities in over 2 m2 BSA patients. 455,502 computerized chemotherapy prescriptions made between 2011 and 2017 were taken from BPC software. Chemotherapy computerized order entry is created by a senior physician prescribers before patient consultation. Only prescriptions with dose calculation involving BSA were selected. 51,179 chemotherapy prescriptions were analyzed; corresponding to 7206 patients who received intravenous chemotherapy. The number of chemotherapy prescriptions in over 2 m2 BSA patients was nearly the same in the hematology as in the oncology departments. But, 79.1% of prescriptions were capped at 2 m2 in the oncology department contrary to 21.9% in the hematology department. Practices analysis showed more dose limitation in palliative situations in both departments. Unexpectedly, 6.53% of capped prescriptions were performed in patients with normal BMI. The patients who received capped doses of chemotherapy had neither fewer dose reductions due to toxicity nor deterioration of their general condition. Capping did not induce fewer dose reductions in patients with BSA greater than 2 m2. Prospective studies in this population are needed to standardize chemotherapy administration in population with BSA > 2 m2.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

Automated Control of Codes Accuracy in Case-Mix Databases by Evaluating Coherence with Available Information in the Electronic Health Record.

Coding accuracy in case-mix databases enables efficient funding of health facilities and accurate epidemiological statistics based on patients' stays information. We assume that the data collected in the electronic health record, especially drug prescriptions and medical reports are relevant for checking the consistency of the coding of diagnoses. We evaluated a new coding control tool, "TOLBIAC control", embedded in the Web100T coding assistant. This tool interacts with the Vidal Application Programming Interface and the electronic health record of the University Hospital of Saint-Etienne. The micro-average F-measure was 0.76 for drug prescriptions and 0.55 for free text medical reports. This initial evaluation has revealed that drug prescriptions in EHRs can successfully be used to develop an automated ICD-10 code-control tool. Nevertheless the "TOLBIAC control" tool is not yet fully effective for widespread use because of its limited performance in text analysis, a feature that is currently undergoing improvements.

Parathyroid hormone 1-84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy.

Bone vessel functions during bone remodeling are poorly understood. They depend on both vessel network structure and vasomotor regulation. Parathyroid hormone (PTH) is a systemic vasodilator that may modulate microvascularization. Moreover, although intermittent PTH is anti-osteoporotic, continuous PTH administration can be catabolic for bone. Finally, ovariectomy (OVX) reduces bone perfusion and vessel density in mice. We reasoned that the effects of PTH on bone vascularization might depend on its administration regimen and be impacted by ovariectomy. A 100-µg/kg PTH 1-84 daily dose was administered for 15 days to 4-month-old female C57BL/6 mice, either as daily sc injection (iPTH) or continuously (cPTH; ALZET minipump). Blood pressure (BP) and tibia bone perfusion were measured in vivo with a laser Doppler device. Histomorphometry of bone and barium-contrasted vascular network were performed on the same tibia. Compared with untreated controls, both iPTH and cPTH increased bone formation but had opposite effects on resorption. Both iPTH and cPTH were slightly angiogenic. Intermittent PTH increased microvessel size (+48%, p < 0.001), whereas cPTH decreased it (-29%, p = 0.009). iPTH increased bone perfusion (27%, p < 0.001) with no change in BP, whereas cPTH did not. The vascular effects of a 15-day iPTH treatment were analyzed in OVX mice and compared with sham-operated and OVX untreated controls. Two other anti-osteoporotic drugs, zoledronate (one injection, 70 µg/kg) and propranolol, (5 mg/kg/d) were tested in OVX mice. Although no change in bone mass was observed, iPTH stimulated bone formation and prevented the OVX-induced reduction in bone perfusion and vessel density. Both zoledronate and propranolol strongly lowered bone turnover, but surprisingly, zoledronate prevented OVX-induced reduction in bone perfusion but propranolol did not. Our integrative approach thus demonstrates that the effects of PTH on bone vessel structure and function depend on its mode of administration as well as on the HPG-axis hormonal status, and that OVX-induced vascular changes are prevented by iPTH.