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In studies of disease states and their relation to evolution, data on the state are usually obtained at in frequent time points during follow-up. Moreover in many applications, there are measured covariates on each individual under study and interest centres on the relationship between these covariates and the disease evolution. We developed a continuous-time Markov model with use of time-dependent covariates and a Markov model with piecewise constant intensities to model asthma evolution. Methods to estimate the effect of covariates on transition intensities, to test the assumption of time homogeneity and to assess goodness-of-fit are proposed. We apply these methods to asthma control. We consider a three-state model and we discuss in detail the analysis of asthma control evolution. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Peritonsillar abscess (PTA) is relatively common but challenging to diagnose clinically. Several clinical signs may be used, with unknown performances. We evaluated and compared the diagnostic performance of individual and combined clinical signs ( trismus , edema , pharynx immobility , uvula deviation , hot potato voice , and overall clinical impression ) assessed by an otolaryngologist and of contrast-enhanced computed tomography (CT) to detect acute PTA. Methods: Prospective study in 133 consecutive adult patients (77 males, mean age = 33 years) with suspected clinical PTA and CT obtained in the emergency setting of a tertiary care hospital between November 2020 and October 2022. The standard of reference consisted of surgically proven pus within 24 h of CT or a favorable clinical evolution at 48 h without surgical intervention. Results: PTA was present in 117/133 (88%) patients, with no difference between mean age or sex distribution between the groups with and without PTA. None of the evaluated clinical signs were associated with PTA (OR = 1.26-5.43, p > 0.05), whereas the CT finding "abscess" was significantly associated with PTA (OR = 67.2, p < 0.0001). The sensitivity of individual clinical signs varied between 19.7% and 73.5%, and the sensitivity of CT was significantly higher for all clinical signs (95.7%, p < 0.0001) except for overall clinical impression (97.4%, p = 0.7266). The specificity of clinical signs varied between 12.5% and 93.8%, and the specificity of CT was significantly higher (75%, p < 0.05) for overall clinical impression and edema . All clinical signs together yielded an area under the curve (AUC) = 0.677. Conclusions: In adults, clinical assessment alone using independent clinical signs and overall clinical impression does not allow a reliable diagnosis of PTA, even when performed by an otolaryngologist. CT is reliable in diagnosing PTA and, whenever available, should be the examination method of choice for diagnosing PTA, especially by a non-specialist.

Background and Purpose: International variation exists in the types of shoulder replacement used for treatment of specific diseases. Implant choice continues to evolve without high-quality evidence. Our aim was to evaluate trends in incidence rates of shoulder replacement and assess any recent changes in practice between countries by using registry data., Methods: Patient characteristics, indication and year of surgery, type of replacement, and collection methods of patient-reported outcomes (PROMs) was extracted from 11 public joint registries. Meta-analyses examined use of reverse total shoulder replacement (RTSR) for osteoarthritis, cuff tear arthropathy, and acute fracture; use of anatomical total shoulder replacement (TSR) for osteoarthritis; and use of humeral hemiarthroplasty for fracture., Results: The annual growth rate of shoulder replacements performed is 6-15% (2011-2019). The use of RTSR has almost doubled (93%). RTSR is now universally performed for cuff tear arthropathy (97.3%, 95% confidence interval [CI] 96.0-98.1). Its use for avascular necrosis, trauma, and inflammatory arthropathy is increasing. The use of RTSR was similar (43.1%, CI 30.0-57.2) versus TSR (44.7%, CI 31.1-59.1) for osteoarthritis. The types of PROMs used, collection time points, and response rates lack standardization. COVID-19 had a varying inter-registry impact on incidence rates., Conclusion: The incidence of shoulder replacements has grown. Use of RTSR has increased for all disease indications despite limited high-quality evidence driving this change in indications outside of cuff arthropathy. Consequently, less variation is observed in international practice. Existing differences now relate to use of newer implant types and methodology of PROMs collection, which prevents international comparison and outcome 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 I 2 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 (I 2  = 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., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

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 I 2 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%; I 2 : 85.7%, number of isolates (n): 1032) and 84.9% (72.8%-92.2%; I 2 : 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%; I 2 : 89.8%, n: 888) and gentamicin (42.7%; 95% CI: 30%-56.5%; I 2 : 71.9%, n: 968). Gentamicin-resistant Klebsiella spp. were also frequently reported (77.6%; 95% CI: 65.5%-86.3%; I 2 : 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., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

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., Competing Interests: The financial support received by AG from MeMed as well as the commercial affiliation of authors NM, LE, LS, ES, EB, RN, TG, KO, EE with MeMed does not alter our adherence to all PLOS ONE policies on sharing data and materials. Other authors had no relationship relating to employment, consultancy, patents, products in development, marketed products, etc. with any of the funding organizations., (Copyright: © 2023 Lacroix et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

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., (Copyright © 2023 by the American Academy of Pediatrics.)

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., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)

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.

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

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., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

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., Competing Interests: Competing interests: WH has received research funding from the European Union, the Swiss National Science foundation, Zoll foundation, Dräger Medical Germany, Mundipharma Research UK, MDI International Australia, Roche Diagnostics Germany, all outside the submitted work. WH has provided paid consultancies to AO foundation Switzerland and MDI International Australia, all outside the submitted work. WH has received financial support for a congress he chaired from EBSCO Germany, Isabel Healthcare UK, Mundipharma Medical Switzerland, VisualDx USA, all outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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/1.73m 2 ) and 154 patients with a kidney allograft (eGFR 53ml/min/1.73m 2 ). 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., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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.

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., (©Johan N Siebert, Laëtitia Gosetto, Manon Sauvage, Laurie Bloudeau, Laurent Suppan, Frédérique Rodieux, Kevin Haddad, Florence Hugon, Alain Gervaix, Christian Lovis, Christophe Combescure, Sergio Manzano, Frederic Ehrler, PedAMINES Trial Group, PedAMINES Prehospital Group. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 01.03.2022.)

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., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Out-of-hospital cardiac arrests (OHCAs) are stressful, high-stake events that are associated with low survival rates. Acute stress experienced in this situation is associated with lower cardiopulmonary resuscitation performance in calculating drug dosages by emergency medical services. Children are particularly vulnerable to such errors. To date, no app has been validated to specifically support emergency drug preparation by paramedics through reducing the stress level of this procedure and medication errors., Objective: This study aims to determine the effectiveness of an evidence-based mobile app compared with that of the conventional preparation methods in reducing acute stress in paramedics at the psychological and physiological levels while safely preparing emergency drugs during simulated pediatric OHCA scenarios., Methods: In a parent, multicenter, randomized controlled trial of 14 emergency medical services, perceived and physiologic stress of advanced paramedics with drug preparation autonomy was assessed during a 20-minute, standardized, fully video-recorded, and highly realistic pediatric OHCA scenario in an 18-month-old child. The primary outcome was participants' self-reported psychological stress perceived during sequential preparations of 4 intravenous emergency drugs (epinephrine, midazolam, 10% dextrose, and sodium bicarbonate) with the support of the PedAMINES (Pediatric Accurate Medication in Emergency Situations) app designed to help pediatric drug preparation (intervention) or conventional methods (control). The State-Trait Anxiety Inventory and Visual Analog Scale questionnaires were used to measure perceived stress. The secondary outcome was physiologic stress, measured by a single continuous measurement of the participants' heart rate with optical photoplethysmography., Results: From September 3, 2019, to January 21, 2020, 150 advanced paramedics underwent randomization. A total of 74 participants were assigned to the mobile app (intervention group), and 76 did not use the app (control group). A total of 600 drug doses were prepared. Higher State-Trait Anxiety Inventory-perceived stress increase from baseline was observed during the scenario using the conventional methods (mean 35.4, SD 8.2 to mean 49.8, SD 13.2; a 41.3%, 35.0 increase) than when using the app (mean 36.1, SD 8.1 to mean 39.0, SD 8.4; a 12.3%, 29.0 increase). This revealed a 30.1% (95% CI 20.5%-39.8%; P<.001) lower relative change in stress response in participants who used the app. On the Visual Analog Scale questionnaire, participants in the control group reported a higher increase in stress at the peak of the scenario (mean 7.1, SD 1.8 vs mean 6.4, SD 1.9; difference: -0.8, 95% CI -1.3 to -0.2; P=.005). Increase in heart rate during the scenario and over the 4 drugs was not different between the 2 groups., Conclusions: Compared with the conventional method, dedicated mobile apps can reduce acute perceived stress during the preparation of emergency drugs in the prehospital setting during critical situations. These findings can help advance the development and evaluation of mobile apps for OHCA management and should be encouraged., Trial Registration: ClinicalTrials.gov NCT03921346; https://clinicaltrials.gov/ct2/show/NCT03921346., International Registered Report Identifier (irrid): RR2-10.1186/s13063-019-3726-4., (©Matthieu Lacour, Laurie Bloudeau, Christophe Combescure, Kevin Haddad, Florence Hugon, Laurent Suppan, Frédérique Rodieux, Christian Lovis, Alain Gervaix, Frédéric Ehrler, Sergio Manzano, Johan N Siebert, PedAMINES Prehospital Group. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 07.10.2021.)

Background: The usefulness of D-dimer measurement to rule out venous thromboembolism (VTE) during pregnancy is debated., Objectives: We performed a systematic review and meta-analysis to investigate the safety of D-dimer to rule out acute VTE in pregnant women with suspected pulmonary embolism and/or deep vein thrombosis., Methods: Two reviewers independently identified studies through PubMed and Embase until June 2021, week 1. We supplemented our search by manually reviewing reference lists of all retrieved articles, clinicalTrials.gov, and reference literature. Prospective or retrospective studies in which a formal diagnostic algorithm was used to evaluate the ability of D-dimer to rule out VTE during pregnancy were eligible., Results: We identified 665 references through systematic database and additional search strategies; 45 studies were retrieved in full, of which four were included, after applying exclusion criteria. Three studies were prospective, and one had a retrospective design. The 3-month thromboembolic rate in pregnant women left untreated after a negative D-dimer was 1/312 (0.32%; 95% CI, 0.06-1.83). The pooled estimate values were 99.5% for sensitivity (95% CI, 95.0-100.0; I², 0%) and 100% for negative predictive value (95% CI, 99.19-100.0; I², 0%). The prevalence of VTE and the yield of D-dimer were 7.4% (95% CI, 3.8-12; I², 83%) and 34.2% (95% CI, 15.9-55.23; I², 89%) respectively., Conclusion: Our results suggest that D-dimer allows to safely rule out VTE in pregnant women with suspected VTE and a disease prevalence consistent with a low/intermediate or unlikely pretest probability., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Aims of the Study: The Swiss healthcare system is highly ranked, given its unrestricted access to specialised care and short waiting lists for surgery. However, the need for anaesthetic and surgical care is escalating owing to the increasing size and ageing of the Swiss population. In addition, to address the persistent and recurrent SARS-CoV-2 pandemic crisis, the speciality of anaesthesia is under tremendous pressure to maintain an effective workforce in order to address population needs. The current number, characteristics and future evolution of the physician anaesthesia workforce in Switzerland are currently unknown. The purpose of this study was to assess the size and professional and sociodemographic characteristics of the current anaesthesia workforce in Switzerland and to forecast its development up to 2034., Methods: We performed a cross-sectional study using a 150-item questionnaire prepared by the National Anaesthesia Workforce Study Group (NAWOS). We included all physicians (trainees and certified) practising anaesthesia in Switzerland. We collected demographic and professional information, such as the current position, hospital characteristics, workload, number of shifts and future life plans. We built a computer-based Markov model with Monte Carlo simulations to project both supply and demand for physician anaesthesia provider positions., Results: Of the 2661 distributed questionnaires, 1985 (74.2%) were completed and returned. We found that the average age of anaesthesiologists practising in Switzerland was 45.2 years, with 44.3% of them being women and 76.9% holding a Swiss specialist title. Only 59.6% of respondents worked full time. The forecasting model showed a steady increase in the number of anaesthesiologists retiring by 2034, with 27% of full-time equivalent jobs being lost in the next 8 years. Even if existing full-time equivalent training positions are all filled, a gradual deficit of anaesthesiologists is to be expected after 2022, and the deficit should culminate in 2034 with a deficit ratio of 0.87., Conclusions: Due to the upcoming high retirement rate of anaesthesiologists, Switzerland is likely to face a shortage of anaesthesiologists in the near future. To compensate for the shortage, the country will likely increase its reliance on medical staff trained abroad. Southern and eastern cantons of Switzerland are particularly at risk, given that they already heavily rely on foreign anaesthesia workforce. This reliance should be considered a national priority because anaesthesiologists are heavily involved in both the treatment of patients with respiratory complications of SARS-CoV2 infection and the care of surgical patients, the number of which is expected to rise steadily in upcoming years.

Importance: Medication errors are a leading cause of injury and avoidable harm, affecting millions of people worldwide each year. Children are particularly susceptible to medication errors, but innovative interventions for the prevention of these errors in prehospital emergency care are lacking., Objective: To assess the efficacy of an evidence-based mobile app in reducing the occurrence of medication errors compared with conventional preparation methods during simulated pediatric out-of-hospital cardiac arrest scenarios., Design, Setting, and Participants: This nationwide, open-label, multicenter, randomized clinical trial was conducted at 14 emergency medical services centers in Switzerland from September 3, 2019, to January 21, 2020. The participants were 150 advanced paramedics with drug preparation autonomy. Each participant was exposed to a 20-minute, standardized, fully video-recorded, realistic pediatric out-of-hospital cardiac arrest cardiopulmonary resuscitation scenario concerning an 18-month-old child. Participants were tested on sequential preparations of 4 intravenous emergency drugs of varying degrees of preparation difficulty (epinephrine, midazolam, 10% dextrose, and sodium bicarbonate)., Intervention: Participants were randomized (1:1 ratio) to the support of an app designed to assist with pediatric drug preparation (intervention; n = 74) or to follow conventional drug preparation methods without assistance (control; n = 76)., Main Outcomes and Measures: The primary outcome was the rate of medication errors, defined as a failure in drug preparation according to predefined, expert consensus-based criteria. Logistic regression models with mixed effects were used to assess the effect of the app on binary outcomes. Secondary outcomes included times to drug preparation and delivery, assessed with linear regression models with mixed effects., Results: In total, 150 advanced paramedics (mean [SD] age, 35.6 [7.2] years; 101 men [67.3%]; mean [SD] time since paramedic certification, 8.0 [6.2] years) participated in the study and completed 600 drug preparations. Of 304 preparations delivered using the conventional method, 191 (62.8%; 95% CI, 57.1%-68.3%) were associated with medication errors compared with 17 of 296 preparations delivered using the app (5.7%; 95% CI, 3.4%-9.0%). When accounting for repeated measures, with the app, the proportion of medication errors decreased in absolute terms by 66.5% (95% CI, 32.6%-83.8%; P < .001), the mean time to drug preparation decreased by 40 seconds (95% CI, 23-57 seconds; P < .001), and the mean time to drug delivery decreased by 47 seconds (95% CI, 27-66 seconds; P < .001). The risk of medication errors varied across drugs with conventional methods (19.7%-100%) when compared with the app (4.1%-6.8%)., Conclusions and Relevance: Compared with conventional methods, the use of a mobile app significantly decreased the rate of medication errors and time to drug delivery for emergency drug preparation in a prehospital setting. Dedicated mobile apps have the potential to improve medication safety and change practices in pediatric emergency medicine., Trial Registration: ClinicalTrials.gov Identifier: NCT03921346.

Objective: Patient's work of breathing may vary between different neonatal nasal continuous positive airway pressure (NCPAP) devices. Therefore, we aimed to compare the inspiratory effort of three variable-flow NCPAP delivery systems used in preterm infants., Design: Cross-over study., Patients/setting: From June 2015 to August 2016, 20 preterm infants weighing ≤2500 g requiring NCPAP for mild respiratory distress syndrome were enrolled., Interventions: Each patient was successively supported by three randomly assigned variable-flow NCPAP systems (MedinCNO, Infant Flow and Servo-i) for 20 min while maintaining the same continuous positive airway pressure level as the patient was on before the study period., Main Outcome Measures: Patients' inspiratory effort was estimated by calculating the sum of the difference between maximal inspiratory and baseline electrical activity of the diaphragm (∆EAdi) for 30 consecutive breaths, and after normalising this obtained value for the timing of the 30 breaths., Results: Physiological parameters (oxygen saturation measured by pulse oximetry, respiratory rate, heart beat, transcutaneous partial pressure CO 2 ) and oxygen requirements remained identical between the three NCPAP systems. Although a wide variability in inspiratory effort could be observed, there were no statistically significant differences between the three systems for the sum of ∆EAdi for 30 breaths: CNO, 262 (±119) µV; IF, 352 (±262) µV; and SERVO-i, 286 (±126) µV, and the ∆EAdi reported on the timing of 30 breaths (sum ∆EAdi/s): CNO, 6.1 (±2.3) µV/s; IF, 7.9 (±4.9) µV/s; SERVO-i, 7.6 (±3.6) µV/s., Conclusion: In a neonatal population of preterm infants, inspiratory effort is comparable between the three tested modern variable-flow NCPAP devices., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is a large controversy as to whether nitrous oxide (N 2 O) added to the anaesthetic gas mixture is harmful or harmless for postoperative cognitive function recovery. We performed a nested study in the ENIGMA-II trial and compared postoperative neurocognitive recovery of patients randomly receiving N 2 O (70%) or Air (70%) in 30% O 2 during anesthesia. We included adults having non cardiac surgery. We compared recovery scores for episodic memory, decision making/processing speed and executive functions measured with the computerised Cambridge Neuropsychological Test Automated Battery (CANTAB). Assessments were performed at baseline, seven and ninety days. At first interim analysis, following recruitment of 140 participants, the trial was suspended. We found that the mean (95%CI) changes of scores for episodic memory were in the Pocock futility boundaries. Decision making/processing speed did not differ either between groups (P > 0.182). But for executive functions at seven days, the mean number (95% CI) of problems successfully solved and the number of correct box choices made was higher in the N2O group, P = 0.029. N 2 O with the limitations of an interim analysis appears to have no harmful effect on cognitive functions (memory/processing speed). It may improve the early recovery process of executive functions. This preliminary finding warrants further investigations.

Background and purpose - A challenge comparing outcomes from total hip arthroplasty between countries is variation in preoperative characteristics, particularly comorbidity. Therefore, we investigated between-country variation in comorbidity in patients based on ASA class distribution, and determined any variation of ASA class to mortality risk between countries.Patients and methods - All arthroplasty registries collecting ASA class and mortality data in patients with elective primary THAs performed 2012-2016 were identified. Survival analyses of the influence of ASA class on 1-year mortality were performed by individual registries, followed by meta-analysis of aggregated data.Results - 6 national registries and 1 US healthcare organization registry with 418,916 THAs were included. There was substantial variation in the proportion of ASA class III/IV, ranging from 14% in the Netherlands to 39% in Finland. Overall, 1-year mortality was 0.93% (95% CI 0.87-1.01) and increased from 0.2% in ASA class I to 8.9% in class IV. The association between ASA class and mortality measured by hazard ratios (HR) was strong in all registries even after adjustment for age and sex, which reduced them by half in all registries. Combined adjusted HRs were 2.0, 6.1, and 22 for ASA class II-IV vs. I, respectively. Associations were moderately heterogeneous across registries.Interpretation - We observed large variation in ASA class distribution between registries, possibly explained by differences in background morbidity and/or international variation in access to surgery. The similar, strong mortality trends by ASA class between countries enhance the relevance of its use as an indicator of comorbidity in international registry studies.

Importance: Rectal cancers occupy the eighth position worldwide for new cases and deaths for both men and women. These cancers have a high tendency to form metastases in the mesorectum but also in the lateral lymph nodes. The therapeutic approach for the involved lateral lymph nodes remains controversial., Objective: We performed a systematic review and meta-analysis to assess the prevalence of metastatic lateral lymph nodes in patients with lateral lymph node dissection (LLND) for rectal cancer, which seems to be a fundamental and necessary criterion to discuss any possible indications for LLND., Methods: Data sources-study selection-data extraction and synthesis-main outcome and measures. We searched MEDLINE, EMBASE and COCHRANE from November 1, 2018, to November 19, 2018, for studies reporting the presence of metastatic lateral lymph nodes (iliac, obturator and middle sacral nodes) among patients undergoing rectal surgery with LLND. Pooled prevalence values were obtained by random effects models, and the robustness was tested by leave-one-out sensitivity analyses. Heterogeneity was assessed using the Q-test, quantified based on the I2 value and explored by subgroup analyses., Results: Our final analysis included 31 studies from Asian countries, comprising 7599 patients. The pooled prevalence of metastatic lateral lymph nodes was 17.3% (95% CI: 14.6-20.5). The inter-study variability (heterogeneity) was high (I 2  = 89%). The pooled prevalence was, however, robust and varied between 16.6% and 17.9% according to leave-one-out sensitivity analysis. The pooled prevalence of metastatic lymph nodes was not significantly different when pooling only studies including patients who received neoadjuvant treatment or those without neoadjuvant treatment (p = 0.44). Meta-regression showed that the pooled prevalence was associated with the sample size of studies (p < 0.05), as the prevalence decreased when the sample size increased., Conclusion: The pooled prevalence of metastatic lateral lymph nodes was 17.3% among patients who underwent rectal surgery with LLND in Asian countries. Further studies are necessary to determine whether this finding could impact the therapeutic strategy (total mesorectal excision with LLND versus total mesorectal excision with neoadjuvant radiochemotherapy).

Many variables impact islet isolation, including pancreas ischemia time. The ischemia time upper limit that should be respected to avoid a negative impact on the isolation outcome is not well defined. We have performed a retrospective analysis of all islet isolations in our center between 2008 and 2018. Total ischemia time, cold ischemia time, and organ removal time were analyzed. Isolation success was defined as an islet yield ≥200 000 IEQ. Of the 452 pancreases included, 288 (64%) were successfully isolated. Probability of isolation success showed a significant decrease after 8 hours of total ischemia time, 7 hours of cold ischemia time, and 80 minutes of organ removal time. Although we observed an impact of ischemia time on islet yield, a probability of isolation success of 50% was still present even when total ischemia time exceeds 12 hours. Posttransplantation clinical outcomes were assessed in 32 recipients and no significant difference was found regardless of ischemia time. These data indicate that although shorter ischemia times are associated with better islet isolation outcomes, total ischemia time >12 hours can provide excellent results in appropriately selected donors., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Emergence of molecular methods to screen stools could provide a more complete picture of pathogens causing gastroenteritis, allowing to adequately treat patients whenever required but, so far, no aggregate data have been released. Our objective was to report pathogens identified in patients suffering from gastroenteritis using a multiplex molecular array., Design: Medline and Embase were searched for original publications reporting pathogens identified with FilmArray GI panel in patients suffering from gastroenteritis. Proportions of pathogens were extracted and pooled using a model with random effects., Results: Fourteen studies (17,815 patients) were included in the analysis. Among the 7,071 patients (39.7%) with positive FilmArray, identified pathogens were EPEC (27.5%), Clostridium difficile (19.3%), Norovirus (15.1%), EAEC (15%), Campylobacter spp (11.8%), Salmonella spp (8.1%), ETEC (7.3%), Rotavirus (7.3%), Sapovirus (7.1%), STEC (5.2%), Shigella/EIEC (4.9%), Giardia lamblia (4%), Adenovirus (3.8%), Cryptosporidium spp (3.8%), Astrovirus (2.8%), Yersinia enterocolitica (1.7%), Escherichia coli O157 (1.1%), Plesiomonas shigelloides (1.1%), Cyclospora cayetanensis (0.7%), Vibrio spp (0.5%), Vibrio cholerae (0.3%) and Entamoeba histolytica (0.3%). When considering only studies with control group (microbiological examination of the stools performed by other methods), FilmArray identified at least one pathogen in 48.2% of patients versus 16.7% when using comparative diagnostic methods., Conclusions: FilmArray GI panel was positive in 39.7% of patients suffering from gastroenteritis. This proportion has to be mitigated by the carriage rates of identified organisms. Ultimately, restricted ordering of molecular panels to those patients who might benefit from specific treatment could provide medical value by swift identification of the pathogen and more targeted therapy.

Background: MD-PhD programs confer degrees that empower medical doctors with in-depth scientific skills to contribute to biomedical research and academic medicine, alongside clinical practice. Whilst the career options and research opportunities related to graduates following these programs in the US are well documented, little is known about their European counterparts. In this article, we studied graduates who had completed the MD-PhD program at the University of Geneva between 2010 and 2019., Methods: A cross-sectional survey was performed in April 2019, targeting all medical doctors who had obtained the MD-PhD degree from the University of Geneva since 2010. Demographics, opinions, and career outcomes of the MD-PhD graduates were assessed through an online anonymous questionnaire., Results: Twenty-one questionnaires were collected from 31 MD-PhD graduates (response rate 65.5%). Most respondents (57.1%) had performed an MD-PhD training in basic sciences; however, only 14.3% had pursued this type of research thereafter. Most of the respondents held a position at a University hospital (90.5%), although a significant number of them were no longer involved in research in their current position (28.6%). 85.7% mentioned obstacles and challenges in combining clinical duties with research. Despite this, the majority (85.7%) declared that the MD-PhD degree had given them advantages in their career path, granting access to clinical and academic positions, as well as funding., Conclusions: Graduates from the MD-PhD program in Geneva were for the most part, satisfied with their training. However, because of the challenges and obstacles in combining clinical duties with research, the implementation of research activities in their current position proved difficult.

Objectives: The objective of the study is to estimate the proportion of statistically significant survival improvements reported in randomized trials of cancer treatments that are also compatible with a clinically negligible benefit., Study Design and Setting: This is a cross-sectional study of reports of randomized clinical trials of cancer treatments that reported a statistically significant increase in overall survival, published in leading journals between 2009 and 2019. The main outcome variable was the hazard ratio (HR) for overall survival and its upper 95% confidence limit. An HR of 0.95 implies an absolute survival gain ≤1.9%, and an HR of 0.90 implies an absolute survival gain ≤3.8%; we reasoned that such survival gains can be considered clinically negligible, given the potential toxicity of oncologic treatments., Results: Among 234 trial results, the mean point estimate of the HR was 0.664, and all HRs were below 0.90. The mean upper 95% confidence limit for the HR was 0.897, but 37.6% of the values were ≥0.95, and 59.0% were ≥0.90. These proportions were lower when overall survival was the primary outcome of the trial (29.9% ≥ 0.95 and 51.3% ≥ 0.90)., Conclusions: Considering only point estimates of HRs, all trials reported clinically meaningful improvements in overall survival. However, the upper confidence limits of a large proportion of HRs were also compatible with clinically negligible survival gains. Acknowledging the uncertainty regarding treatment benefits presents a challenge for the reporting of trial results and for clinical decision-making., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pediatric Index of Mortality (PIM) 2 score is used in pediatric intensive care unit (PICU) to predict the patients' risk of death. The performance of this model has never been assessed in Switzerland. The aim of this study was to evaluate the performance of the PIM2 score in the whole cohort and in pre-specified diagnostic subgroups of patients admitted to PICUs in Switzerland. All children younger than 16 years admitted to any PICU in Switzerland between January 1, 2012 and December 31, 2017 were included in the study. A total of 22,382 patients were analyzed. Observed mortality was 2%, whereas mortality predicted by PIM2 was 4.2% (SMR = 0.47, 95% CI, 0.42-0.52). Calibration was also poor across the deciles of mortality risks (p < 0.001). The AUC-ROC for the entire cohort was 0.88 (95% CI, 0.87-0.90). Calibration varied significantly according to primary diagnosis.Conclusion: The performance of the PIM 2 score in a cohort of Swiss patients is poor with adequate discrimination and poor calibration. The PIM 2 score tends to under predict the number of deaths among septic patients and in patients admitted after a cardiorespiratory arrest. What is Known: •PIM2 score is a widely used mortality prediction model in PICU. •PIM2 performance among uncommon but clinically relevant diagnostic subgroups of patients is unknown. •The performance of PIM2 score has never been assessed in Switzerland. What is New: •The performance of the PIM 2 score in a cohort of Swiss patients is poor with adequate discrimination and poor calibration. •Calibration varies significantly according to primary diagnosis. The PIM 2 score under predict the number of deaths among septic patients and in patients admitted after a cardiorespiratory arrest.

Background: Infections are an important complication after allogeneic hematopoietic cell transplantation (allo-HCT). The present study aimed at determining the landscape of infections occurring in a large cohort of allo-HCT patients, as well as associated risk factors for infections and for one-year non-relapse mortality., Methods: This is a retrospective cohort study using STCS and EBMT databases to assess the one-year incidence rate of infection, as well as risk factors for infections and for one-year non-relapse mortality among adult allo-HCT patients transplanted between 2010 and 2014 in Switzerland. Univariable and multivariable quasi-Poisson and multivariable Cox regression models were used., Results: Of 553 patients included, 486 had an infection with a global incidence rate of 3.66 infections per patient-year. Among a total of 1534 infections analyzed, viral infections were predominant (n = 1138, 74.2%), followed by bacterial (n = 343, 22.4%) and fungal (n = 53, 3.5%) infections. At one year, the cumulative incidence of relapse and non-relapse mortality was 26% and 16%, respectively. 195 (35.3%) of patients had at least one episode of severe graft-versus-host-disease (GvHD). A center effect was observed, and underlying disease, donor type, cytomegalovirus serological constellation, and GvHD were also associated with the incidence rate of infections. There was an increased risk for one-year non-relapse mortality associated with all pathogens, specifically within two months of infection, and this remained true beyond 2 months of a fungal infection., Conclusion: Despite advances to limit infections in this population, they still occur in most allo-HCT patients with a major impact on survival at 1 year., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS., Materials and Methods: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one., Results: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS., Conclusion: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)