Antimicrobial resistance in Enterobacterales infections among children in sub-Saharan Africa: a systematic review and meta-analysis.

Background: The burden of antimicrobial resistance (AMR) has been estimated to be the highest in sub-Saharan Africa (SSA). The current study estimated the proportion of drug-resistant Enterobacterales causing infections in SSA children. Methods: We searched MEDLINE/PubMed, Embase and the Cochrane Library to identify retrospective and prospective studies published from 01/01/2005 to 01/06/2022 reporting AMR of Enterobacterales causing infections in sub-Saharan children (0-18 years old). Studies were excluded if they had unclear documentation of antimicrobial susceptibility testing methods or fewer than ten observations per bacteria. Data extraction and quality appraisal were conducted by two authors independently. The primary outcome was the proportion of Enterobacterales resistant to antibiotics commonly used in paediatrics. Proportions were combined across studies using mixed-effects logistic regression models per bacteria and per antibiotic. Between-study heterogeneity was assessed using the I2 statistic. The protocol was registered with PROSPERO (CRD42021260157). Findings: After screening 1111 records, 122 relevant studies were included, providing data on more than 30,000 blood, urine and stool isolates. Escherichia coli and Klebsiella spp. were the predominant species, both presenting high proportions of resistance to third-generation cephalosporins, especially in blood cultures: 40.6% (95% CI: 27.7%-55%; I2: 85.7%, number of isolates (n): 1032) and 84.9% (72.8%-92.2%; I2: 94.1%, n: 2067), respectively. High proportions of resistance to other commonly used antibiotics were also observed. E. coli had high proportions of resistance, especially for ampicillin (92.5%; 95% CI: 76.4%-97.9%; I2: 89.8%, n: 888) and gentamicin (42.7%; 95% CI: 30%-56.5%; I2: 71.9%, n: 968). Gentamicin-resistant Klebsiella spp. were also frequently reported (77.6%; 95% CI: 65.5%-86.3%; I2: 91.6%, n: 1886). Interpretation: High proportions of resistance to antibiotics commonly used for empirical treatment of infectious syndromes were found for Enterobacterales in sub-Saharan children. There is a critical need to better identify local patterns of AMR to inform and update clinical guidelines for better treatment outcomes. Funding: No funding was received.

Carriage of third-generation cephalosporin-resistant and carbapenem-resistant Enterobacterales among children in sub-Saharan Africa: a systematic review and meta-analysis.

Background: The increasing resistance of Enterobacterales to third-generation cephalosporins and carbapenems in sub-Saharan Africa (SSA) is a major public health concern. We did a systematic review and meta-analysis of studies to estimate the carriage prevalence of Enterobacterales not susceptible to third-generation cephalosporins or carbapenems among paediatric populations in SSA. Methods: We performed a systematic literature review and meta-analysis of cross-sectional and cohort studies to estimate the prevalence of childhood (0-18 years old) carriage of extended-spectrum cephalosporin-resistant Enterobacterales (ESCR-E) or carbapenem-resistant Enterobacterales (CRE) in SSA. Medline, EMBASE and the Cochrane Library were searched for studies published from 1 January 2005 to 1 June 2022. Studies with <10 occurrences per bacteria, case reports, and meta-analyses were excluded. Quality and risk of bias were assessed using the Newcastle-Ottawa scale. Meta-analyses of prevalences and odds ratios were calculated using generalised linear mixed-effects models. Heterogeneity was assessed using I2 statistics. The protocol is available on PROSPERO (CRD42021260157). Findings: Of 1111 studies examined, 40 met our inclusion criteria, reporting on the carriage prevalence of Enterobacterales in 9408 children. The pooled carriage prevalence of ESCR-E was 32.2% (95% CI: 25.2%-40.2%). Between-study heterogeneity was high (I2 = 96%). The main sources of bias pertained to participant selection and the heterogeneity of the microbiological specimens. Carriage proportions were higher among sick children than healthy ones (35.7% vs 16.9%). The pooled proportion of nosocomial acquisition was 53.8% (95% CI: 32.1%-74.1%) among the 922 children without ESCR-E carriage at hospital admission. The pooled odds ratio of ESCR-E carriage after antibiotic treatment within the previous 3 months was 3.20 (95% CI: 2.10-4.88). The proportion of pooled carbapenem-resistant for Enterobacterales was 3.6% (95% CI: 0.7%-16.4%). Interpretation: This study suggests that ESCR-E carriage among children in SSA is frequent. Microbiology capacity and infection control must be scaled-up to reduce the spread of those multidrug-resistant microorganisms. Funding: There was no funding source for this study.

Clinical investigations to evaluate high-risk orthopaedic devices: a systematic review of the peer-reviewed medical literature.

Purpose: The objective of this systematic review was to give an overview of clinical investigations regarding hip and knee arthroplasty implants published in peer-reviewed scientific medical journals before entry into force of the EU Medical Device Regulation in May 2021. Methods: We systematically reviewed the medical literature for a random selection of hip and knee implants to identify all peer-reviewed clinical investigations published within 10 years before and up to 20 years after regulatory approval. We report study characteristics, methodologies, outcomes, measures to prevent bias, and timing of clinical investigations of 30 current implants. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: We identified 2912 publications and finally included 151 papers published between 1995 and 2021 (63 on hip stems, 34 on hip cups, and 54 on knee systems). We identified no clinical studies published before Conformité Européene (CE)-marking for any selected device, and no studies even up to 20 years after CE-marking in one-quarter of devices. There were very few randomized controlled trials, and registry-based studies generally had larger sample sizes and better methodology. Conclusion: The peer-reviewed literature alone is insufficient as a source of clinical investigations of these high-risk devices intended for life-long use. A more systematic, efficient, and faster way to evaluate safety and performance is necessary. Using a phased introduction approach, nesting comparative studies of observational and experimental design in existing registries, increasing the use of benefit measures, and accelerating surrogate outcomes research will help to minimize risks and maximize benefits.

Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source.

BACKGROUND: Improved tools are required to detect bacterial infection in children with fever without source (FWS), especially when younger than 3 years old. The aim of the present study was to investigate the diagnostic accuracy of a host signature combining for the first time two viral-induced biomarkers, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon γ-induced protein-10 (IP-10), with a bacterial-induced one, C-reactive protein (CRP), to reliably predict bacterial infection in children with fever without source (FWS) and to compare its performance to routine individual biomarkers (CRP, procalcitonin (PCT), white blood cell and absolute neutrophil counts, TRAIL, and IP-10) and to the Labscore. METHODS: This was a prospective diagnostic accuracy study conducted in a single tertiary center in children aged less than 3 years old presenting with FWS. Reference standard etiology (bacterial or viral) was assigned by a panel of three independent experts. Diagnostic accuracy (AUC, sensitivity, specificity) of host individual biomarkers and combinatorial scores was evaluated in comparison to reference standard outcomes (expert panel adjudication and microbiological diagnosis). RESULTS: 241 patients were included. 68 of them (28%) were diagnosed with a bacterial infection and 5 (2%) with invasive bacterial infection (IBI). Labscore, ImmunoXpert, and CRP attained the highest AUC values for the detection of bacterial infection, respectively 0.854 (0.804-0.905), 0.827 (0.764-0.890), and 0.807 (0.744-0.869). Labscore and ImmunoXpert outperformed the other single biomarkers with higher sensitivity and/or specificity and showed comparable performance to one another although slightly reduced sensitivity in children < 90 days of age. CONCLUSION: Labscore and ImmunoXpert demonstrate high diagnostic accuracy for safely discriminating bacterial infection in children with FWS aged under and over 90 days, supporting their adoption in the assessment of febrile patients.

Outdoor Cold Air Versus Room Temperature Exposure for Croup Symptoms: A Randomized Controlled Trial.

OBJECTIVES: Croup is the most common cause of acute upper airway obstruction in children. The benefits of treating croup with steroids are well established, with an onset of effect 30 minutes after administration. We investigated whether a 30-minute exposure to outdoor cold air might improve mild to moderate croup symptoms before the onset of action of steroids. METHODS: This open-label, single-center, randomized controlled trial, enrolled children aged 3 months to 10 years with croup and a Westley Croup Score (WCS) ≥2 attending a tertiary pediatric emergency department. Participants were randomized (1:1) to either a 30-minute exposure to outdoor cold (<10°C) atmospheric air or to indoor ambient room air immediately after triage and administration of a single-dose oral dexamethasone. The primary endpoint was a decrease in WCS ≥2 points from baseline at 30 minutes. Analyses were intention to treat. RESULTS: A total of 118 participants were randomly assigned to be exposed to outdoor cold air (n = 59) or indoor room temperature (n = 59). Twenty-nine of 59 children (49.2%) in the outdoor group and 14 of 59 (23.7%) in the indoor group showed a decrease in WCS ≥2 points from baseline at 30 minutes after triage (risk difference 25.4% [95% confidence interval 7.0-43.9], P = .007). Patients with moderate croup benefited the most from the intervention at 30 minutes (risk difference 46.1% [20.6-71.5], P < .001). CONCLUSIONS: A 30-minute exposure to outdoor cold air (<10°C), as an adjunct to oral dexamethasone, is beneficial for reducing the intensity of clinical symptoms in children with croup, especially when moderate.

Adjustment for baseline characteristics in randomized trials using logistic regression: sample-based model versus true model.

BACKGROUND: Adjustment for baseline prognostic factors in randomized clinical trials is usually performed by means of sample-based regression models. Sample-based models may be incorrect due to overfitting. To assess whether overfitting is a problem in practice, we used simulated data to examine the performance of the sample-based model in comparison to a "true" adjustment model, in terms of estimation of the treatment effect. METHODS: We conducted a simulation study using samples drawn from a "population" in which both the treatment effect and the effect of the potential confounder were specified. The outcome variable was binary. Using logistic regression, we compared three estimates of the treatment effect in each situation: unadjusted, adjusted for the confounder using the sample, adjusted for the confounder using the true effect. Experimental factors were sample size (from 2 × 50 to 2 × 1000), treatment effect (logit of 0, 0.5, or 1.0), confounder type (continuous or binary), and confounder effect (logit of 0, - 0.5, or - 1.0). The assessment criteria for the estimated treatment effect were bias, variance, precision (proportion of estimates within 0.1 logit units), type 1 error, and power. RESULTS: Sample-based adjustment models yielded more biased estimates of the treatment effect than adjustment models that used the true confounder effect but had similar variance, accuracy, power, and type 1 error rates. The simulation also confirmed the conservative bias of unadjusted analyses due to the non-collapsibility of the odds ratio, the smaller variance of unadjusted estimates, and the bias of the odds ratio away from the null hypothesis in small datasets. CONCLUSIONS: Sample-based adjustment yields similar results to exact adjustment in estimating the treatment effect. Sample-based adjustment is preferable to no adjustment.

Viremia as a predictor of absence of serious bacterial infection in children with fever without source.

Most children with fever without source (FWS) require diagnostic laboratory tests to exclude a serious bacterial infection (SBI), often followed by admission and empirical antibiotics. As febrile children with a viral infection are less likely to have a SBI, identifying patients with systemic viral infection could contribute to exclude SBI. We evaluated whether the presence of virus in the blood could be used as a biomarker to rule out SBI. Children < 3 years old with FWS were prospectively enrolled and had real-time (reverse-transcription) PCR performed on the blood for adenovirus, enterovirus, parechovirus, and HHV6. 20/135 patients had SBI, and in 47/135, at least one virus was detected in the blood. Viremia had a higher sensitivity and negative predictive value (90% and 96%) to rule out SBI compared to CRP (65% and 93%) and PCT (55% and 90%). The odds ratio (OR) for the presence of SBI among non-viremic patients was 5.8 (p = 0.0225), compared to 5.5 for CRP ≥ 40 mg/l (p = 0.0009) and 3.7 for PCT ≥ 0.5 ng/mL (0.0093). This remained significant after adjusting for CRP and PCT (OR 5.6 and 5.9, respectively; p = 0.03 for both). Area under the ROC curve for CRP and PCT were 0.754 and 0.779, respectively, but increased to 0.803 and 0.832, respectively, when combined with viremia. CONCLUSION: The presence of viremia had a better performance than commonly used biomarkers to rule-out SBI and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS. Larger studies should evaluate the role of point-of-care testing of viruses by (revere-transcription) PCR in the plasma in management algorithms of children with FWS. WHAT IS KNOWN: • Most children with FWS have a viral infection, but up to 15% have a SBI; most require laboratory tests, and many admission and empirical antibiotics. • Children with a viral infection are less likely to have a SBI. WHAT IS NEW: • Children with a systemic viral infection are less likely to have an SBI. • Viremia is a better predictor of absence of SBI than commonly used biomarkers and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS.

Management of injuries in Swiss primary care practices: a cross-sectional study within the Sentinella surveillance system.

INTRODUCTION: Injuries are amongst the most frequent causes of morbidity and mortality worldwide. Our aim was to describe the frequency, type of injury and care provided in primary care in Switzerland. METHODS: We used anonymous data from 14,307 injury-related consultations of all ages, with a representative sample of 160 primary care physicians from the Sentinella network throughout the year 2017. Descriptive information about patients presenting with one or multiple injuries and the type of care provided were collected in a weekly questionnaire. Data about the primary care physicians including their experience, postgraduate training, equipment and skills were obtained using a single anonymous questionnaire. Negative binomial regression models with mixed effects were used to examine the association between primary care physicians' characteristics, the proportion represented by injured patients in their total activity and independent management in primary care (without referral). With these models, the associations are expressed as a ratio of prevalence (PR). RESULTS: The median proportion (prevalence) of injury-related consultations was 2.0% (range 0.0-19.8%), with a significant difference between paediatricians and general practitioners (median 1.2% vs 2.1%). Nearly 60% of consultations for injuries involved men, 21.0% were for patients <18 years and 15.3% for those above 65. Sprains and dislocations (31.2%) were the most frequent diagnoses followed by cutaneous injuries (23.0%), contusions (20.1%) and fractures (18.8%). Of the injuries presenting directly to primary care, 87.0% were managed by the primary care physician without referral to external services. Fractures were the main diagnosis motivating referral, yet 67.9% of them were entirely managed within primary care. Multivariable analyses showed that training as a paediatrician and a longer experience in primary care were associated with having a lower prevalence of injury-related consultations (adjusted PR [adjPR] 0.49, 95% confidence interval [CI] 0.31-0.78 and adjPR 0.41, 95% CI 0.23-0.75, respectively), whereas the ability to offer wound care including sutures and both splints and casts were associated with a much higher prevalence of injury-related consultations (adjPR 9.36, 95% CI 3.42-25.61 and adjPR 2.38, 95% CI 1.43-3.97, respectively). CONCLUSION: The proportion represented by injured patients in a primary care physician's total activity is heterogeneous. Most patients with mild to moderate injuries could be managed in primary care without referral to secondary care. Further studies could explore factors associated with patients' decision to consult their primary care physician or emergency services for injuries. Exploring outcomes of primary care and patients' satisfaction is another future research priority.

Harms and benefits of cervical cancer screening among non-attenders in Switzerland: The transition towards HPV-based screening.

Human papillomavirus (HPV) testing is replacing cytological screening for cervical cancer. Our aim was to assess the expected benefits and harms of different cervical screening strategies. This study is sub-analysis of a previous cost-effectiveness study with a target population of unscreened women without cervical cancer aged ≥ 25 years. A recursive decision-tree with one-year cycles was used to model the life-long natural HPV history. Markov cohort simulations were used to assess the expected outcomes from the model. The outcomes of three strategies were compared with the absence of screening: HPV-testing on self-collected vaginal samples (Self-HPV) followed by colposcopy (Self-HPV/colpo), Self-HPV and triage with cytology (Self-HPV/PAP), cytology and triage with HPV (PAP/HPV). All screening strategies resulted in reductions in cancer cases and deaths. Self-HPV strategies were associated with a lower cancer incidence and mortality life-long, not only when performed every 3 years but also when Self-HPV was performed every 5 years vs cytology every 3 years. The gain in life expectancy obtained was 82 days with Self-HPV/colpo, 81 days with Self-HPV/PAP and 75 days with PAP/HPV compared to no screening. The number of lifetime total visits was greater with PAP/HPV compared with the Self-HPV strategies (13.13 vs < 3). The number of conizations remained relatively stable with the change of screening frequency and strategy. Self-HPV may represent a reasonable balance of harms and benefits when performed every 5 years compared to cytology every 3 years. Self-HPV/PAP yielded the most efficient harm to benefit ratio when using colposcopy as a proxy for harms.

A systematic review and meta-analysis of three risk factors for chronic postsurgical pain: age, sex and preoperative pain.

INTRODUCTION: Chronic postsurgical pain (CPSP) is a common and disabling postoperative complication. Several risk factors for CPSP have been established, but it is unclear whether they are significant for any type of surgery. This systematic review aimed to assess the risk of CPSP related to three known preoperative risk factors "age, sex and preoperative pain" in the adult population after any type of elective non-obstetrical surgery. EVIDENCE ACQUISITION: We conducted a systematic literature search using PubMed and EMBASE databases retrieving 1458 abstracts; 320 publications were screened and 71 papers were included. Odds ratios were combined across studies and quality of evidence graded using GRADE. Sub-groups comparisons were conducted for type of surgery, time point for CPSP and definition of CPSP. EVIDENCE SYNTHESIS: The pooled unadjusted ORs were 1.34 for female sex, 2.43 for preoperative pain at surgical site, 1.75 for preoperative pain elsewhere and 3.95 for preoperative pain at an unspecified site. The pooled unadjusted OR for age was 2.04 in the younger (age midpoint <40 years) compared with the older population of patients (age midpoint >62.5 years). In the subgroup analysis, preoperative pain was a more important risk factor for orthopedic surgery and age for breast surgery. CONCLUSIONS: This systematic review confirms that younger age, female sex, and preoperative pain are associated with higher risk of developing CPSP in any type of elective non-obstetrical surgery. However, effect sizes are small and quality of evidence low-moderate only, limiting comparisons of different types of surgery.

Kinetics of disappearance and appearance of isoagglutinins A and B after ABO-incompatible hematopoietic stem cell transplantation.

ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT) can be complicated by poor red cell engraftment and hemolysis, both mediated by isoagglutinins. Anecdotally, isoagglutinins indicates an activation of donor's immunity or even relapse. Consequently, the routine monitoring of isoagglutinins could help physicians to predict the risk of complications. The purpose of this study is to investigate the time to disappearance and appearance of isoagglutinins after ABO-incompatible allogeneic HSCT. In a one-year follow-up, data of 136 ABO-incompatible hematopoietic stem cell (HSC) allogeneic transplanted patients were studied, of which 60 had major, 61 minor and 15 bidirectional incompatibility. Survival analyses were conducted and association with hematological diseases, HLA-compatibility and transplantation strategy was investigated. We observed a disappearance of isoagglutinin A in 82.0% of cases at one year with a median and 75th percentile of 38.4 and 138.6 days, respectively. For isoagglutinin B, these same values were 96.4%, 15.9 and 29.1 days, respectively. The appearance of isoagglutinin A occurred in 10.7% of cases. Disappearance of isoagglutinin A was significantly slower in patients with myeloid diseases compared to other diseases. The results of this study provide useful values to detect early risks of preventable immunohematological complications and possibly, in exceptional cases, relapse.

LOw-dose CT Or Lung UltraSonography versus standard of care based-strategies for the diagnosis of pneumonia in the elderly: protocol for a multicentre randomised controlled trial (OCTOPLUS).

INTRODUCTION: Pneumonia is a leading cause of mortality and a common indication for antibiotic in elderly patients. However, its diagnosis is often inaccurate. We aim to compare the diagnostic accuracy, the clinical and cost outcomes and the use of antibiotics associated with three imaging strategies in patients >65 years old with suspected pneumonia in the emergency room (ER): chest X-ray (CXR, standard of care), low-dose CT scan (LDCT) or lung ultrasonography (LUS). METHODS AND ANALYSIS: This is a multicentre randomised superiority clinical trial with three parallel arms. Patients will be allocated in the ER to a diagnostic strategy based on either CXR, LDCT or LUS. All three imaging modalities will be performed but the results of two of them will be masked during 5 days to the patients, the physicians in charge of the patients and the investigators according to random allocation. The primary objective is to compare the accuracy of LDCT versus CXR-based strategies. As secondary objectives, antibiotics prescription, clinical and cost outcomes will be compared, and the same analyses repeated to compare the LUS and CXR strategies. The reference diagnosis will be established a posteriori by a panel of experts. Based on a previous study, we expect an improvement of 16% of the accuracy of pneumonia diagnosis using LDCT instead of CXR. Under this assumption, and accounting for 10% of drop-out, the enrolment of 495 patients is needed to prove the superiority of LDCT over CRX (alpha error=0.05, beta error=0.10). ETHICS AND DISSEMINATION: Ethical approval: CER Geneva 2019-01288. TRIAL REGISTRATION NUMBER: NCT04978116.

Therapeutic anticoagulation to prevent thrombosis, coagulopathy, and mortality in severe COVID-19: The Swiss COVID-HEP randomized clinical trial.

Background: Hospitalized patients with COVID-19 suffered initially from high rates of venous thromboembolism (VTE), with possible associations between therapeutic anticoagulation and better clinical outcomes in observational studies. Objective: To test whether therapeutic anticoagulation improves clinical outcomes in severe COVID-19. Patients/Methods: In this multicenter, open-label, randomized controlled trial, we recruited acutely ill medical COVID-19 patients with D-dimer >1000 ng/ml or critically ill COVID-19 patients in four Swiss hospitals, from April 2020 until June 2021, with a 30-day follow-up. Participants were randomized to in-hospital therapeutic anticoagulation versus low-dose anticoagulation in acutely ill participants/intermediate-dose anticoagulation in critically ill participants, with enoxaparin or unfractionated heparins. The primary outcome was a centrally adjudicated composite of 30-day all-cause mortality, VTE, arterial thrombosis, and disseminated intravascular coagulopathy (DIC), with screening for proximal deep vein thrombosis. Results: Among 159 participants, 55.3% were critically ill and 94.3% received corticosteroids. Before study inclusion, pulmonary embolism had been excluded in 71.7%. The primary outcome occurred in 4/79 participants randomized to therapeutic anticoagulation and 4/80 to low/intermediate anticoagulation (5.4% vs. 5.0%; risk difference +0.4%; adjusted hazard ratio 0.76, 95% confidence interval 0.18-3.21), including three deaths in each group. All primary outcomes and major bleeding (n = 3) occurred in critically ill participants. There was no asymptomatic proximal deep vein thrombosis and no difference in major bleeding. Conclusions: Among patients with severe COVID-19 treated with corticosteroids and with exclusion of pulmonary embolism at hospital admission for most, risks of mortality, thrombotic outcomes, and DIC were low at 30 days. The lack of benefit of therapeutic anticoagulation was too imprecise for definite conclusions.

Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting.

Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug−drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC0−6h of fexofenadine, respectively. Relevant CYP3A and ABCB1 genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (p < 0.001) and creatinine clearance (CrCl) (p = 0.01) significantly affected apixaban AUC0−6h. P-gp activity (p < 0.001) also significantly impacted rivaroxaban AUC0−6h. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC0−6h by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment.

Usability Testing and Technology Acceptance of an mHealth App at the Point of Care During Simulated Pediatric In- and Out-of-Hospital Cardiopulmonary Resuscitations: Study Nested Within 2 Multicenter Randomized Controlled Trials.

BACKGROUND: Mobile apps are increasingly being used in various domains of medicine. Few are evidence-based, and their benefits can only be achieved if end users intend to adopt and use them. To date, only a small fraction of mobile apps have published data on their field usability and end user acceptance results, especially in emergency medicine. OBJECTIVE: This study aims to determine the usability and acceptance of an evidence-based mobile app while safely preparing emergency drugs at the point of care during pediatric in- and out-of-hospital cardiopulmonary resuscitations by frontline caregivers. METHODS: In 2 multicenter randomized controlled parent trials conducted at 6 pediatric emergency departments from March 1 to December 31, 2017, and 14 emergency medical services from September 3, 2019, to January 21, 2020, the usability and technology acceptance of the PedAMINES (Pediatric Accurate Medication in Emergency Situations) app were evaluated among skilled pediatric emergency nurses and advanced paramedics when preparing continuous infusions of vasoactive drugs and direct intravenous emergency drugs at pediatric dosages during standardized, simulation-based, pediatric in- and out-of-hospital cardiac arrest scenarios, respectively. Usability was measured using the 10-item System Usability Scale. A 26-item technology acceptance self-administered survey (5-point Likert-type scales), adapted from the Unified Theory of Acceptance and Use of Technology model, was used to measure app acceptance and intention to use. RESULTS: All 100% (128/128) of nurses (crossover trial) and 49.3% (74/150) of paramedics (parallel trial) were assigned to the mobile app. Mean total scores on the System Usability Scale were excellent and reached 89.5 (SD 8.8; 95% CI 88.0-91.1) for nurses and 89.7 (SD 8.7; 95% CI 87.7-91.7) for paramedics. Acceptance of the technology was very good and rated on average >4.5/5 for 5 of the 8 independent constructs evaluated. Only the image construct scored between 3.2 and 3.5 by both participant populations. CONCLUSIONS: The results provide evidence that dedicated mobile apps can be easy to use and highly accepted at the point of care during in- and out-of-hospital cardiopulmonary resuscitations by frontline emergency caregivers. These findings can contribute to the implementation and valorization of studies aimed at evaluating the usability and acceptance of mobile apps in the field by caregivers, even in critical situations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03021122; https://clinicaltrials.gov/ct2/show/NCT03021122. ClinicalTrials.gov NCT03921346; https://clinicaltrials.gov/ct2/show/NCT03921346. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-019-3726-4.

Eight versus 28-point lung ultrasonography in moderate acute heart failure: a prospective comparative study.

Lung ultrasonography (LUS) is an accurate method of estimating lung congestion but there is ongoing debate on the optimal number of scanning points. The aim of the present study was to compare the reproducibility (i.e. interobserver agreement) and the feasibility (i.e. time consumption) of the two most practiced protocols in patients hospitalized for acute heart failure (AHF). This prospective trial compared 8- and 28-point LUS protocols. Both were performed by an expert-novice pair of sonographers at admission and after 4 to 6 days on patients admitted for AHF. A structured bio-clinical evaluation was simultaneously carried out by the treating physician. The primary outcome was expert-novice interobserver agreement estimated by kappa statistics. Secondary outcomes included time spent on image acquisition and interpretation. During the study period, 43 patients underwent a total of 319 LUS exams. Expert-novice interobserver agreement was moderate at admission and substantial at follow-up for 8-point protocol (weighted kappa of 0.54 and 0.62, respectively) with no significant difference for 28-point protocol (weighted kappa of 0.51 and 0.41; P value for comparison 0.74 at admission and 0.13 at follow-up). The 8-point protocol required significantly less time for image acquisition at admission (mean time difference - 3.6 min for experts, - 5.1 min for novices) and interpretation (- 6.0 min for experts and - 6.3 min for novices; P value < 0.001 for all time comparisons). Similar differences were observed at follow-up. In conclusion, an 8-point LUS protocol was shown to be timesaving with similar reproducibility when compared with a 28-point protocol. It should be preferred for evaluating lung congestion in AHF inpatients.

Diffusion-magnetic resonance imaging predicts decline of kidney function in chronic kidney disease and in patients with a kidney allograft.

Kidney cortical interstitial fibrosis is highly predictive of kidney prognosis and is currently assessed by evaluation of a biopsy. Diffusion-weighted magnetic resonance imaging is a promising non-invasive tool to evaluate kidney fibrosis. We recently adapted diffusion-weighted imaging sequence for discrimination between the kidney cortex and medulla and found that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) correlated with histological interstitial fibrosis. Here, we assessed whether ΔADC as measured with diffusion-weighted magnetic resonance imaging is predictive of kidney function decline and dialysis initiation in chronic kidney disease (CKD) and patients with a kidney allograft in a prospective study encompassing 197 patients. We measured ΔADC in 43 patients with CKD (estimated GFR (eGFR) 55ml/min/1.73m2) and 154 patients with a kidney allograft (eGFR 53ml/min/1.73m2). Patients underwent a kidney biopsy and diffusion-weighted magnetic resonance imaging within one week of biopsy; median follow-up of 2.2 years with measured laboratory parameters. The primary outcome was a rapid decline of kidney function (eGFR decline over 30% or dialysis initiation) during follow up. Significantly, patients with a negative ΔADC had 5.4 times more risk of rapid decline of kidney function or dialysis (95% confidence interval: 2.29-12.58). After correction for kidney function at baseline and proteinuria, low ADC still predicted significant kidney function loss with a hazard ratio of 4.62 (95% confidence interval 1.56-13.67) independent of baseline age, sex, eGFR and proteinuria. Thus, low ΔADC can be a predictor of kidney function decline and dialysis initiation in patients with native kidney disease or kidney allograft, independent of baseline kidney function and proteinuria.

Influence of chemotherapy on postural control and quality of life in women with gynaecological cancer: a protocol of a prospective observational study.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy is a frequent side effect of some chemotherapies that can cause postural control disorders and has a serious impact on quality of life (QoL). An enhanced understanding of postural control dysfunction could help build a systematic and accurate assessment as well as specific exercises to limit the impact on QoL. This study aims to assess the influence of chemotherapy on postural control and the QoL for women with gynaecological cancer. METHODS AND ANALYSIS: This prospective observational study will include 37 participants with cancer treated using neurotoxic chemotherapy. Their postural control in various conditions (rigid and foam surfaces, eyes open and closed, with and without tendon vibration, and dual tasks), limits of stability, QoL and modified Total Neuropathy Score will be assessed. A linear mixed model will compare postural control pre-chemotherapy and post-chemotherapy. ETHICS AND DISSEMINATION: This study was approved by an ethical review board in Geneva (CCER-2020-01639). The study findings will be disseminated through conference presentations and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04692168.

Predicting recurrence of hepatocellular carcinoma after liver transplantation using a novel model that incorporates tumor and donor-related factors.

Evidence suggests that liver graft quality impacts on posttransplant recurrence of hepatocellular carcinoma (HCC). As of today, selection criteria only use variables related to tumor characteristics. Within the Scientific Registry of Transplant Recipients, we identified patients with HCC who underwent liver transplantation between 2004 and 2016 (development cohort, n = 10 887). Based on tumor recurrence rates, we fitted a competing-risk regression incorporating tumor- and donor-related factors, and we developed a prognostic score. Results were validated both internally and externally in the Australia and New Zealand Liver Transplant Registry. Total tumor diameter (subhazard ratio [sub-HR] 1.52 [1.28-1.81]), alpha-feto protein (sub-HR 1.27 [1.23-1.32], recipient male gender (sub-HR 1.43 [1.18-1.74]), elevated donor body mass index (sub-HR 1.26 [1.01-1.58]), and shared graft allocation policy (sub-HR 1.20 [1.01-1.43]) were independently associated with tumor recurrence. We next developed the Darlica score (sub-HR 2.72 [2.41-3.08] P < 0.001) that allows identifying risky combinations between a given donor and a given recipient. Results were validated internally (n = 3 629) and externally in the Australia and New Zealand Liver Transplant Registry (n = 370). The current score is based on variables that are readily available at the time of graft offer. It allows identifying hazardous donor-recipient combinations in terms of risk of tumor recurrence and overall survival.