Change in stroke volume during alveolar recruitment maneuvers through transient continuous positive airway pressure or stepwise increase in positive end expiratory pressure in anesthetized patients: a prospective randomized double-blind study.

PURPOSE: Intraoperative alveolar recruitment maneuvers (ARM) used during protective ventilation strategy may have severe adverse hemodynamic effects, reported mainly during abrupt continuous positive airway pressure (CPAP). Stepwise increase and decrease in positive end expiratory pressure (PEEP) may be used. We compared the hemodynamic effects of these two maneuvers. METHODS: We enrolled patients scheduled for intermediate to high-risk surgery with continuous arterial pressure and stroke volume (esophageal Doppler) monitoring in a prospective, single-centre, randomized, double-blind study. After induction of anesthesia, we ensured preload independence of stroke volume before an ARM was randomly performed: 30 cm H2O CPAP for 30 sec (CPAP group) or stepwise increase in PEEP from 8 to 20 cm H2O with inspiratory pressure of 10 cm H2O followed by a stepwise decrease in PEEP from 20 to 8 cm H2O (STEP group). The primary outcome was the relative variation in stroke volume. RESULTS: Thirty-five patients were included in the CPAP and STEP groups. Mean (standard deviation) relative variation in stroke volume was -57 (24)% in the CPAP group and -32 (24)% in the STEP group (difference, -25; 95% confidence interval, -37 to -14; P < 0.001). Changes in systolic, mean, and diastolic arterial pressure over time were not different between groups. The ARM was stopped because of a systolic arterial pressure < 70 mm Hg in four patients in the CPAP group and in one patient in the STEP group. CONCLUSIONS: Alveolar recruitment maneuvers through stepwise increase and decrease in PEEP have a better hemodynamic tolerance than transient CPAP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04802421); first submitted 15 March 2021.

RéSUMé: OBJECTIF: Les manœuvres de recrutement alvéolaire (MRA) peropératoire utilisées pendant les stratégies de ventilation protectrice peuvent avoir des effets hémodynamiques indésirables graves, rapportés principalement lors d'une ventilation en pression positive continue (PPC ou CPAP en anglais) abrupte. L'augmentation et la diminution par étapes de la pression expiratoire positive (PEP) peuvent être utilisées. Nous avons comparé les effets hémodynamiques de ces deux manœuvres. MéTHODE: Nous avons recruté des patient·es devant bénéficier d'une chirurgie à risque intermédiaire à élevé avec monitorage continu de la tension artérielle et du volume d'éjection (Doppler œsophagien) dans le cadre d'une étude prospective, monocentrique, randomisée et à double insu. Après induction de l'anesthésie, nous nous sommes assurés de l'indépendance de précharge du volume d'éjection avant qu'une MRA ne soit effectuée au hasard : 30 cm H2O PPC pendant 30 secondes (groupe PPC) ou augmentation progressive de la PEP de 8 à 20 cm H2O avec pression inspiratoire de 10 cm H2O, suivie d'une diminution progressive de la PEP de 20 à 8 cm H2O (groupe STEP). Le critère d'évaluation principal était la variation relative du volume d'éjection. RéSULTATS: Trente-cinq personnes ont été incluses dans les groupes PPC et STEP. La variation relative moyenne (écart type) du volume d'éjection était de −57 (24) % dans le groupe PPC et de −32 (24) % dans le groupe STEP (différence, −25; intervalle de confiance à 95 %, −37 à −14; P < 0,001). Les changements dans la tension artérielle systolique, moyenne et diastolique au fil du temps n'étaient pas différents entre les groupes. Les MRA ont été arrêtées en raison d'une tension artérielle systolique < 70 mm Hg chez quatre patient·es du groupe PPC et chez une personne du groupe STEP. CONCLUSION: Les manœuvres de recrutement alvéolaire par augmentation et diminution par étapes de la PEP ont une meilleure tolérance hémodynamique que la PPC transitoire. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04802421); soumis pour la première fois le 15 mars 2021.

Effects of a 20-Week High-Intensity Strength Training Program on Muscle Strength Gain and Cardiac Adaptation in Untrained Men: Preliminary Results of a Prospective Longitudinal Study.

BACKGROUND: As strength sports gain popularity, there is a growing need to explore the impact of sustained strength training on cardiac biventricular structure and function, an area that has received less attention compared to the well-established physiological cardiac adaptation to endurance training. OBJECTIVE: This study aims to implement a 20-week high-intensity strength training program to enhance maximal muscle strength and evaluate its impact on cardiac biventricular adaptation in healthy, untrained men. METHODS: A total of 27 healthy and untrained young men (mean age 22.8, SD 3.2 years) participated in a strength training program designed to increase muscle strength. The training program involved concentric, eccentric, and isometric exercise phases, conducted over a consecutive 20-week time frame with a frequency of 3 weekly training sessions. Participants were evaluated before and after 12 and 20 weeks of training through body composition analysis (bioelectrical impedance), a 12-lead resting electrocardiogram, 3D transthoracic echocardiography, cardiopulmonary exercise testing, and muscle isokinetic dynamometry. The progression of strength training loads was guided by 1-repetition maximum (RM) testing during the training program. RESULTS: Of the initial cohort, 22 participants completed the study protocol. No injuries were reported. The BMI (mean 69.8, SD 10.8 kg/m² vs mean 72, SD 11 kg/m²; P=.72) and the fat mass (mean 15.3%, SD 7.5% vs mean 16.5%, SD 7%; P=.87) remained unchanged after training. The strength training program led to significant gains in 1-RM exercise testing as early as 4 weeks into training for leg extension (mean 69.6, SD 17.7 kg vs mean 96.5, SD 31 kg; P<.001), leg curl (mean 43.2, SD 9.7 kg vs mean 52.8, SD 13.4 kg; P<.001), inclined press (mean 174.1, SD 41.1 kg vs mean 229.2, SD 50.4 kg; P<.001), butterfly (mean 26.3, SD 6.2 kg vs mean 32.5, SD 6.6 kg; P<.001), and curl biceps on desk (mean 22.9, SD 5.2 kg vs mean 29.6, SD 5.2 kg; P<.001). After 20 weeks, the 1-RM leg curl, bench press, pullover, butterfly, leg extension, curl biceps on desk, and inclined press showed significant mean percentage gains of +40%, +41.1%, +50.3%, +63.5%, +80.1%, +105%, and +106%, respectively (P<.001). Additionally, the isokinetic evaluation confirmed increases in maximal strength for the biceps (+9.2 Nm), triceps (+11.6 Nm), quadriceps (+46.8 Nm), and hamstrings (+25.3 Nm). In this paper, only the training and muscular aspects are presented; the cardiac analysis will be addressed separately. CONCLUSIONS: This study demonstrated that a short-term high-intensity strength training program was successful in achieving significant gains in muscle strength among previously untrained young men. We intend to use this protocol to gain a better understanding of the impact of high-intensity strength training on cardiac physiological remodeling, thereby providing new insights into the cardiac global response in strength athletes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04187170; https://clinicaltrials.gov/study/NCT04187170.

Are unknown co-medications, over-the-counter and off-label drug use still problems among people living with HIV? Results from a transversal survey in 23 centres in France.

INTRODUCTION: Polypharmacy can lead to drug-drug interactions (DDIs), especially with ART. The burden of co-medications, including over-the-counter (OTC) drugs and self-medications, could be underestimated. We aimed to investigate the proportion of people living with HIV (PLHIV) with declared and undeclared co-medications, as well as their potential burden. METHODS: We conducted a national, multicentre, 1 week cross-sectional study between 10 December and 16 December 2019 in 23 French hospitals amongst consecutive adult PLHIV presenting for a routine outpatient visit. A standardized questionnaire filled in by the physicians assessed all medications and other active chemical substances taken by the PLHIV. RESULTS: Overall we enrolled 496 participants from 23 centres. Median age was 50.6 years; ART regimens included an integrase inhibitor in 61% (n = 302), an NNRTI in 34% (n = 169) and a PI in 14% (n = 70) of the cases. Co-medications involved 392 (79%) PLHIV, among which 85 (17%) received polypharmacy (≥5 medications). Previously unknown co-medications or other active substances were found for 32% (n = 159) of the participants. Corticosteroids (9%, n = 46) and proton pump inhibitors (10%, n = 50) were frequently administered. These co-medications did not differ according to age range. Illegal drug use was declared by 11% (n = 54) and OTC drugs by 23% (n = 113) of PLHIV. Potential DDIs were discovered for 11% (n = 53), leading to treatment modifications in 47% (25/53) of cases. CONCLUSIONS: Potential DDIs that lead to therapeutic modifications remain significant whatever the age of PLHIV. More devoted time to identify co-medications and OTC treatment is needed in all PLHIV.

Long-term weight loss outcomes after bariatric surgery: a propensity score study among patients with psychiatric disorders.

INTRODUCTION: To analyze the safety and long-term result of bariatric surgery in patients with psychiatric disorders. MATERIAL AND METHODS: From January 2009 to December 2018, n = 961 patients underwent bariatric surgery in a tertiary center. Among them, two groups of patients were created: a group of patients with psychiatric disorders (PG) and a group without psychiatric disorders (CG), using a propensity score matched (PSM). Primary endpoint was long-term outcomes and secondary endpoints were the postoperative morbidity 90 days after surgery, late morbidity, occurrence of psychiatric adverse events, and resolution of obesity-related comorbidities. RESULTS: Analysis with PSM permitted to compare 136 patients in each group, with a ratio 1:1. TWL% at 2 years in the PG was 32.7% versus 36.6% in the CG (p = 0.002). Overall surgical morbidity was higher in the PG than the CG (28% vs 17%, p = 0.01). Severe surgical complications were not statistically significant (4% vs 3%, p = 0.44). Psychiatric adverse events were significantly more frequent in the PG than in the CG. The resolution of obesity comorbidities was equivalent for both groups at 2 years. CONCLUSION: Substantial weigh loss was reported among patients with psychiatric disorders receiving bariatric surgery at the cost of more non-severe surgical complications. Further, a psychiatric postoperative follow-up visit may be warranted for patients with preoperative psychiatric disorders, given the incidence of psychiatric adverse events.

Compensating patients in trials: Perspectives from an ethical committee versus sponsor.

BACKGROUND: According to European clinical research legislation, no undue influence, including financial incentives, should be used to encourage participation in clinical trials. Financial compensation should be based on the inconvenience experienced by patients and is determined by the sponsor. OBJECTIVES: The objective of this study was to assess the adequacy of patients' financial compensation by obtaining an external ethical opinion compared to the actual compensation provided. METHODS: We randomly selected and reviewed 50 clinical drug trials, including 25 academic and 25 industry-sponsored studies. An external ethics group consisting of three members from French ethics committees, blinded to the actual compensation and the sponsor, retrospectively reviewed the study characteristics and assessed whether financial compensation was appropriate. Cohen's Kappa test measured agreement between actual compensation and the ethics group's opinion, and the McNemar test measured discrepancies. RESULTS: There was no agreement between the actual financial compensation and the ethics group's opinion (K = -.07; 95% CI = [-.16-.02]). More discrepancies were found in favour of financial compensation according to the ethics group than provided by sponsors (12 vs. 2, p = .016). The ethics group recommended financial compensation in 12 out of 50 studies (24%), which were studies with a higher number of additional visits (p = .004) and were more frequently sponsored by industry (p = .008). Sponsors only provided financial compensation in 2 out of 50 studies (4%). CONCLUSION: Patients are rarely compensated despite the perceived inconvenience. Both sponsors and ethics members struggle to determine the need for financial compensation, indicating a need for more precise recommendations for both parties.

Comparison of landiolol and amiodarone for the treatment of new-onset atrial fibrillation after cardiac surgery (FAAC) trial: study protocol for a randomized controlled trial.

BACKGROUND: Postoperative atrial fibrillation (PoAF) after cardiac surgery has a high incidence of 30%, but its management is controversial. Two strategies are recommended without evidence of a superiority of one against the other: rate control with beta-blocker or rhythm control with amiodarone. Landiolol is a new-generation beta-blocker with fast onset and short half-life. One retrospective, single-center study compared landiolol to amiodarone for PoAF after cardiac surgery with a better hemodynamic stability and a higher rate of reduction to sinus rhythm with landiolol, justifying the need for a multicenter randomized controlled trial. Our aim is to compare landiolol to amiodarone in the setting of PoAF after cardiac surgery with the hypothesis of a higher rate of reduction to sinus rhythm with landiolol during the 48 h after the first episode of POAF. METHODS: The FAAC trial is a multicenter single-blind two parallel-arm randomized study, which planned to include 350 patients with a first episode of PoAF following cardiac surgery. The duration of the study is 2 years. The patients are randomized in two arms: a landiolol group and an amiodarone group. Randomization (Ennov Clinical®) is performed by the anesthesiologist in charge of the patient if PoAF is persistent for at least 30 min after correction of hypovolemia, dyskalemia, and absence of pericardial effusion on a transthoracic echocardiography done at bedside. Our hypothesis is an increase of the percentage of patients in sinus rhythm from 70 to 85% with landiolol in less than 48 h after onset of PoAF (alpha risk = 5%, power = 90%, bilateral test). DISCUSSION: The FAAC trial was approved by the Ethics Committee of EST III with approval number 19.05.08. The FAAC trial is the first randomized controlled trial comparing landiolol to amiodarone for PoAF after cardiac surgery. In case of higher rate of reduction with landiolol, this beta-blocker could be the drug of choice used in this context as to reduce the need for anticoagulant therapy and reduce the risk of complications of anticoagulant therapy for patients with a first episode of postoperative atrial fibrillation after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04223739. Registered on January 10, 2020.

Comparison of diagnostic performance of a deep learning algorithm, emergency physicians, junior radiologists and senior radiologists in the detection of appendicular fractures in children.

BACKGROUND: Advances have been made in the use of artificial intelligence (AI) in the field of diagnostic imaging, particularly in the detection of fractures on conventional radiographs. Studies looking at the detection of fractures in the pediatric population are few. The anatomical variations and evolution according to the child's age require specific studies of this population. Failure to diagnose fractures early in children may lead to serious consequences for growth. OBJECTIVE: To evaluate the performance of an AI algorithm based on deep neural networks toward detecting traumatic appendicular fractures in a pediatric population. To compare sensitivity, specificity, positive predictive value and negative predictive value of different readers and the AI algorithm. MATERIALS AND METHODS: This retrospective study conducted on 878 patients younger than 18 years of age evaluated conventional radiographs obtained after recent non-life-threatening trauma. All radiographs of the shoulder, arm, elbow, forearm, wrist, hand, leg, knee, ankle and foot were evaluated. The diagnostic performance of a consensus of radiology experts in pediatric imaging (reference standard) was compared with those of pediatric radiologists, emergency physicians, senior residents and junior residents. The predictions made by the AI algorithm and the annotations made by the different physicians were compared. RESULTS: The algorithm predicted 174 fractures out of 182, corresponding to a sensitivity of 95.6%, a specificity of 91.64% and a negative predictive value of 98.76%. The AI predictions were close to that of pediatric radiologists (sensitivity 98.35%) and that of senior residents (95.05%) and were above those of emergency physicians (81.87%) and junior residents (90.1%). The algorithm identified 3 (1.6%) fractures not initially seen by pediatric radiologists. CONCLUSION: This study suggests that deep learning algorithms can be useful in improving the detection of fractures in children.

Perioperative individualized hemodynamic optimization according to baseline mean arterial pressure in cardiac surgery patients: Rationale and design of the OPTIPAM randomized trial.

BACKGROUND: Postoperative morbidity and mortality after cardiac surgery with cardiopulmonary bypass (CPB) remain high despite recent advances in both anesthesia and perioperative management. Among modifiable risk factors for postoperative complications, optimal arterial pressure during and after surgery has been under debate for years. Recent data suggest that optimizing arterial pressure to the baseline of the patient may improve outcomes. We hypothesize that optimizing the mean arterial pressure (MAP) to the baseline MAP of the patient during cardiac surgery with CPB and during the first 24 hours postoperatively may improve outcomes. STUDY DESIGN: The OPTIPAM trial (NCT05403697) will be a multicenter, randomized, open-label controlled trial testing the superiority of optimized MAP management as compared with a MAP of 65 mm Hg or more during both the intraoperative and postoperative periods in 1,100 patients scheduled for cardiac surgery with CPB. The primary composite end point is the occurrence of acute kidney injury, neurological complications including stroke or postoperative delirium, and death. The secondary end points are hospital and intensive care unit lengths of stay, Day 7 and Day 90 mortality, postoperative cognitive dysfunction on Day 7 and Day 90, and quality of life at Day 7 and Day 90. Two interim analyses will assess the safety of the intervention. CONCLUSION: The OPTIPAM trial will assess the effectiveness of an individualized target of mean arterial pressure in cardiac surgery with CPB in reducing postoperative morbidity. CLINICAL TRIAL REGISTRATION: NCT05403697.

Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

INTRODUCTION: Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. METHODS: We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. RESULTS: Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12 months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent. CONCLUSION: These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab. CLINICAL TRIALS: gov identifier (NCT04580381).

Development and validation of a multivariable model predicting the required catheter dwell time among mechanically ventilated critically ill patients in three randomized trials.

BACKGROUND: The anatomic site for central venous catheter insertion influences the risk of central venous catheter-related intravascular complications. We developed and validated a predictive score of required catheter dwell time to identify critically ill patients at higher risk of intravascular complications. METHODS: We retrospectively conducted a cohort study from three multicenter randomized controlled trials enrolling consecutive patients requiring central venous catheterization. The primary outcome was the required catheter dwell time, defined as the period between the first catheter insertion and removal of the last catheter for absence of utility. Predictors were identified in the training cohort (3SITES trial; 2336 patients) through multivariable analyses based on the subdistribution hazard function accounting for death as a competing event. Internal validation was performed in the training cohort by 500 bootstraps to derive the CVC-IN score from robust risk factors. External validation of the CVC-IN score were performed in the testing cohort (CLEAN, and DRESSING2; 2371 patients). RESULTS: The analysis was restricted to patients requiring mechanical ventilation to comply with model assumptions. Immunosuppression (2 points), high creatinine > 100 micromol/L (2 points), use of vasopressor (1 point), obesity (1 point) and older age (40-59, 1 point; ≥ 60, 2 points) were independently associated with the required catheter dwell time. At day 28, area under the ROC curve for the CVC-IN score was 0.69, 95% confidence interval (CI) [0.66-0.72] in the training cohort and 0.64, 95% CI [0.61-0.66] in the testing cohort. Patients with a CVC-IN score ≥ 4 in the overall cohort had a median required catheter dwell time of 24 days (versus 11 days for CVC-IN score < 4 points). The positive predictive value of a CVC-IN score ≥ 4 was 76.9% for > 7 days required catheter dwell time in the testing cohort. CONCLUSION: The CVC-IN score, which can be used for the first catheter, had a modest ability to discriminate required catheter dwell time. Nevertheless, preference of the subclavian site may contribute to limit the risk of intravascular complications, in particular among ventilated patients with high CVC-IN score. Trials Registration NCT01479153, NCT01629550, NCT01189682.

Validation of an anti-α-Gal IgE fluoroenzyme-immunoassay for the screening of patients at risk of severe anaphylaxis to cetuximab.

BACKGROUND: The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-α-1,3-galactose (α-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-α-Gal IgE before treatment. METHODS: This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts. RESULTS: Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a ≥ 0.525 kUA/L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%). CONCLUSION: Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-α-Gal IgE screening before treatment.

Prevalence of anemia at diagnosis of pediatric chronic myeloid leukemia and prognostic impact on the disease course.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

Bioavailability of dissolved and crushed single tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC randomized crossover study.

BACKGROUND: Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. METHODS: A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference. RESULTS: Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively. CONCLUSIONS: Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.

ESPNIC clinical practice guidelines: intravenous maintenance fluid therapy in acute and critically ill children- a systematic review and meta-analysis.

PURPOSE: Intravenous maintenance fluid therapy (IV-MFT) prescribing in acute and critically ill children is very variable among pediatric health care professionals. In order to provide up to date IV-MFT guidelines, the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) undertook a systematic review to answer the following five main questions about IV-MFT: (i) the indications for use (ii) the role of isotonic fluid (iii) the role of balanced solutions (iv) IV fluid composition (calcium, magnesium, potassium, glucose and micronutrients) and v) and the optimal amount of fluid. METHODS: A multidisciplinary expert group within ESPNIC conducted this systematic review using the Scottish Intercollegiate Guidelines Network (SIGN) grading method. Five databases were searched for studies that answered these questions, in acute and critically children (from 37 weeks gestational age to 18 years), published until November 2020. The quality of evidence and risk of bias were assessed, and meta-analyses were undertaken when appropriate. A series of recommendations was derived and voted on by the expert group to achieve consensus through two voting rounds. RESULTS: 56 papers met the inclusion criteria, and 16 recommendations were produced. Outcome reporting was inconsistent among studies. Recommendations generated were based on a heterogeneous level of evidence, but consensus within the expert group was high. "Strong consensus" was reached for 11/16 (69%) and "consensus" for 5/16 (31%) of the recommendations. CONCLUSIONS: Key recommendations are to use isotonic balanced solutions providing glucose to restrict IV-MFT infusion volumes in most hospitalized children and to regularly monitor plasma electrolyte levels, serum glucose and fluid balance.