title: Dual-room twin-CT scanner in multiple trauma care: first results after implementation in a level one trauma centre

text: PURPOSE: The trauma centre of the Wuerzburg University Hospital has integrated a pioneering dual-room twin-CT scanner in a multiple trauma pathway. For concurrent treatment of two trauma patients, two carbon CT examination and intervention tables are positioned head to head with one sliding CT-Gantry in the middle. The focus of this study is the process of trauma care with the time to CT (tCT) and the time to operation (tOR) as quality indicator. METHODS: All patients with suspected multiple trauma, who required emergency surgery and who were initially diagnosed by the CT trauma protocol between 05/2018 and 12/2018 were included. Data relating to time spans (tCT and tOR), severity of injury and outcome was obtained. RESULTS: 110 of the 589 screened trauma patients had surgery immediately after finishing primary assessment in the ER. The ISS was 17 (9–34) (median and interquartile range, IQR). tCT was 15 (11–19) minutes (median and IQR) and tOR was 96.5 (75–119) minutes (median and IQR). In the first 30 days, seven patients died (6.4%) including two within the first 24 h (2%). There were two ICU days (1–6) (median and IQR) and one (0–1) (median and IQR) ventilator day. CONCLUSION: The twin-CT technology is a fascinating tool to organize high-quality trauma care for two multiple trauma patients simultaneously.


title: Exploring Lassa Virus Proteome to Design a Multi-epitope Vaccine Through Immunoinformatics and Immune Simulation Analyses

text: Lassa virus (LASV) is responsible for a type of acute viral haemorrhagic fever referred to as Lassa fever. Lack of adequate treatment and preventive measures against LASV resulted in a high mortality rate in its endemic regions. In this study, a multi-epitope vaccine was designed using immunoinformatics as a prophylactic agent against the virus. Following a rigorous assessment, the vaccine was built using T-cell (N(CTL) = 8 and N(HTL) = 6) and B-cell (N(LBL) = 4) epitopes from each LASV-derived protein in addition with suitable linkers and adjuvant. The physicochemistry, immunogenic potency and safeness of the designed vaccine (~ 68 kDa) were assessed. In addition, chosen CTL and HTL epitopes of our vaccine showed 97.37% worldwide population coverage. Besides, disulphide engineering also improved the stability of the chimeric vaccine. Molecular docking of our vaccine protein with toll-like receptor 2 (TLR2) showed binding efficiency followed by dynamics simulation for stable interaction. Furthermore, higher levels of cell-mediated immunity and rapid antigen clearance were suggested by immune simulation and repeated-exposure simulation, respectively. Finally, the optimized codons were used in in silico cloning to ensure higher expression within E. coli K12 bacterium. With further assessment both in vitro and in vivo, we believe that our proposed peptide-vaccine would be potential immunogen against Lassa fever. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10989-019-10003-8) contains supplementary material, which is available to authorized users.


title: Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE)

text: BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3−14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.


title: A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery

text: mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with IC(50) values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 (GI(50) = 4.66 μM) and HCT116 (GI(50) = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.


Focus on paediatrics


title: The possible regions to design Human Papilloma Viruses vaccine in Iranian L1 protein

text: Human Papilloma Virus (HPV) genome encodes several proteins, as L1is major capsid protein and L2 is minor capsid protein. Among all HPV types HPV-16 and HPV-18 are the most common high-risk HPV (HR-HPV) types globally and the majority of cases are infected with these types. HPV entry and the initial interaction with the host cell are mainly related to the L1 protein which is the main component of HPV vaccines. The aim of this research was comparison analysis among all Iranian L1 protein sequences submitted in NCBI GenBank to find the major substitutions as well as structural and immune properties of this protein. All sequences HPV L1 protein from Iranian isolates from 2014 to 2016 were selected and obtained from NCBI data bank. “CLC Genomics Workbench” was used to translate alignment. To predict B cell epitopes, we employed several programs. Modification sites such as phosphorylation, glycosylation, and disulfide bonds were determined. Secondary and tertiary structures of all sequences were analyzed. Several mutations were found and major mutations were in amino acid residues 102, 202, 207, 292, 379, and 502. The mentioned mutations showed the minor effect on B cell and physicochemical properties of the L1 protein. Six disulfide bonds were determined in L1 protein and also in several N-link glycosylation and phosphorylation sites. Five L1 loops were determined, which had great potential to be B cell epitopes with high antigenic properties. All in all, this research as the first report from Iran described the tremendous potential of two L1 loops (BC and FG) to induce immune system which can be used as the descent candidate to design a new vaccine against HPV in the Iranian population. In addition, some differences between the reference sequence and Iranian patients’ sequences were determined. It is essential to consider these differences to monitor the effectiveness and efficacy of the vaccine for the Iranian population. Our results provide a vast understanding of L1 protein that can be useful for further studies on HPV infections and new vaccine generations.


title: Pre-clinical Stress Management Workshops Increase Medical Students’ Knowledge and Self-awareness of Coping with Stress

text: OBJECTIVES: To investigate the effects of a stress management workshop on medical students’ knowledge of stress and potential coping strategies. METHODS: A panel discussion with small group breakouts on stress in clinical medicine, learning challenges, competition with colleagues, handling stressful events, and recognizing burnout symptoms was conducted with medical students entering clerkships. A longitudinal survey design was utilized to measure pre-, post-, and long-term (3-month) changes in knowledge (impact of stress on personal health, learning, and patient care), confidence, perceived skills, and attitude (towards utilizing adaptive coping strategies) among participating students (N = 135). Paired t test and multivariate analyses were performed to assess the differences between survey responses on a 5-point Likert scale. RESULTS: Survey response rates were pre-90.4%, post-77%, and long-term post-71.1%. Compared to pre-workshop, students reported significant improvement in all four domains immediately post-workshop: knowledge (4.4 vs. 4.7, p < 0.05), confidence (3.6 vs. 3.9, p < 0.05), perceived skills (3.3 vs. 3.7, p < 0.05), and attitude (2.6 vs. 2.8, p < 0.05). Compared to immediate post-workshop, students’ scores slightly decreased at 3 months but were overall significantly higher than the pre-workshop scores. CONCLUSIONS: A stress management workshop can improve medical students’ knowledge of the impact of stress as well as the use of adaptive stress coping strategies.


title: Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial

text: PURPOSE: Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation. METHODS: The MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality. RESULTS: A total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82–2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1–3. However, during days 4–28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4–28 (p = 0.007). CONCLUSION: We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05913-6) contains supplementary material, which is available to authorized users.


Family reflections: our family’s journey with Wolfram syndrome


title: “She is Like a Sister to Me.” Gender-Affirming Services and Relationships are Key to the Implementation of HIV Care Engagement Interventions with Transgender Women of Color

text: We present findings from qualitative interviews (N = 67) with 36 staff and 31 participants of nine distinct individual and/or group level interventions to engage transgender women of color (TWOC) in HIV care in the U.S. We examine the commonalities amongst the intervention services (addressing unmet basic needs, facilitating engagement in HIV care, health system navigation, improving health literacy, emotional support), and the relationships formed during implementation of the interventions (between interventionists and participants, among participants in intervention groups, between participants and peers in the community). Interventionists, often TWOC themselves, who provided these services developed caring relationships, promoted personal empowerment, and became role models for participants and the community. Intervention groups engaged participants to reinforce the importance of health and HIV care and provided mutual support. Gender affirming services and caring relationships may be two key characteristics of interventions that address individual and structural-level barriers to engage TWOC in HIV care.


title: Immunogenicity of the inactivated influenza vaccine in children who have undergone allogeneic haematopoietic stem cell transplant

text: Influenza vaccination is recommended for children following allogeneic haematopoietic stem cell transplant (HSCT), however there is limited evidence regarding its benefit. A prospective multicentre study was conducted to evaluate the immunogenicity of the inactivated influenza vaccine in children who have undergone HSCT compared with healthy age-matched controls. Participants were vaccinated between 2013 and 2016 according to Australian guidelines. Influenza-specific hemagglutinin inhibition antibody titres were performed prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on participants that developed influenza-like illness. There were 86 children recruited; 43 who had undergone HSCT and 43 controls. For the HSCT group, seroprotection and seroconversion rates were 81.4% and 60.5% for H3N2, 41.9% and 32.6% for H1N1, and 44.2% and 39.5% for B strain respectively. There was a significant geometric mean fold increase to the H3N2 (GMFI 5.80, 95% CI 3.68–9.14, p < 0.001) and B (GMFI 3.44, 95% CI 2.36–5.00, p = 0.048) strains. Serological response was superior in age-matched controls to all vaccine strains. There were no serious adverse events following vaccination. For children who underwent HSCT, incidence of laboratory-proven influenza infection was 2.3%. Overall, this study provides evidence to support annual inactivated influenza vaccine administration to children following HSCT.


title: Incidence, Risk Factors, and Outcomes of Ventilator-Associated Pneumonia in Traumatic Brain Injury: A Meta-analysis

text: Ventilator-associated pneumonia (VAP) is one of the most severe complications in patients with traumatic brain injury (TBI) and is considered a risk factor for poor outcomes. However, the incidence of VAP among patients with TBI reported in studies varies widely. What is more, the risk factors and outcomes of VAP are controversial. This study estimates the incidence, risk factors, and outcomes of VAP in patients with TBI and provides evidence for prevention and treatment. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched from the earliest records to May 2018. Data involving the incidence, risk factors, and outcomes were extracted for meta-analysis. The results showed that the incidence of VAP was 36% (95% confidence interval (CI) 31–41%); risk factors analyses showed that smoking [odds ratio (OR) 2.13; 95% CI 1.16–3.92], tracheostomy (OR 9.55; 95% CI 3.24–28.17), blood transfusion on admission (OR 2.54; 95% CI 1.24–5.18), barbiturate infusion (OR 3.52; 95% CI 1.68–7.40), injury severity score (OR 4.65; 95% CI 1.96–7.34), and head abbreviated injury scale (OR 2.99; 95% CI 1.66–5.37) were related to the occurrence of VAP. When patients developed VAP, mechanical ventilation time (OR 5.45; 95% CI 3.78–7.12), ICU length of stay (OR 6.85; 95% CI 4.90–8.79), and hospital length of stay (OR 10.92; 95% CI 9.12–12.72) were significantly increased. However, VAP was not associated with an increased risk of mortality (OR 1.28; 95% CI 0.74–2.21). VAP is common in patients with TBI. It is affected by a series of factors and has a poor prognosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12028-019-00773-w) contains supplementary material, which is available to authorized users.


title: Non-immune Hydrops in Neonates: A Tertiary Care Center Experience

text: OBJECTIVE: To evaluate the clinical profile and outcome of neonates with non-immune hydrops (NIH). METHODS: Data of all the NIH cases admitted to neonatal intensive care unit at our center, New Delhi from January, 2010 to October, 2017 were extracted from hospital records, which included clinical profile and outcomes. RESULTS: Of the 17,299 total births, 27 neonates were identified to have NIH. Antenatal interventions were undertaken in five (18.5%) cases. The most common etiology of NIH was cardiac (n=5; 18.5%). Two babies with chylothorax were successfully managed with octreotide infusions. Overall survival rate of NIH was 70.3% (n=19). All neonates with a suspected genetic syndrome died. CONCLUSION: Multidisciplinary team including obstetricians, pediatric surgeons, geneticists and neonatologists can improve outcome in neonates with NIH.


The harm of high-frequency oscillatory ventilation (HFOV) in ARDS is not related to a high baseline risk of acute cor pulmonale or short-term changes in hemodynamics


title: Protocol for two-arm pragmatic cluster randomized hybrid implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation

text: BACKGROUND: COPD is the fourth leading cause of death in the US, and COPD exacerbations result in approximately 700,000 hospitalizations annually. Patients with acute respiratory failure due to severe COPD exacerbation are treated with invasive (IMV) or noninvasive mechanical ventilation (NIV). Although IMV reverses hypercapnia/hypoxia, it causes significant morbidity and mortality. There is strong evidence that patients treated with NIV have better outcomes, and NIV is recommended as first line therapy in these patients. Yet, several studies have demonstrated substantial variation in the use of NIV across hospitals, leading to preventable morbidity and mortality. Through a series of mixed-methods studies, we have found that successful implementation of NIV requires physicians, respiratory therapists (RTs), and nurses to communicate and collaborate effectively, suggesting that efforts to increase the use of NIV in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, we propose to compare two educational strategies: online education (OLE) and interprofessional education (IPE) which targets complex team-based care in NIV delivery. METHODS AND DESIGN: Twenty hospitals with low baseline rates of NIV use will be randomized to either the OLE or IPE study arm. The primary outcome of the trial is change in the hospital rate of NIV use among patients with COPD requiring ventilatory support. In aim 1, we will compare the uptake change over time of NIV use among patients with COPD in hospitals enrolled in the two arms. In aim 2, we will explore mediators’ role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and implementation effectiveness. Finally, in aim 3, through interviews with providers, we will assess acceptability and feasibility of the educational training. DISCUSSIONS: This study will be among the first to carefully test the impact of IPE in the inpatient setting. This work promises to change practice by offering approaches to facilitate greater uptake of NIV and may generalize to other interventions directed to seriously-ill patients. TRIAL REGISTRATION: Name of registry: ClinicalTrials.gov Trial registration number: NCT04206735 Date of Registration: December 20, 2019


title: Progress in research and application development of surface display technology using Bacillus subtilis spores

text: Bacillus subtilis is a widely distributed aerobic Gram-positive species of bacteria. As a tool in the lab, it has the advantages of nonpathogenicity and limited likelihood of becoming drug resistant. It is a probiotic strain that can be directly used in humans and animals. It can be induced to produce spores under nutrient deficiency or other adverse conditions. B. subtilis spores have unique physical, chemical, and biochemical characteristics. Expression of heterologous antigens or proteins on the surface of B. subtilis spores has been successfully performed for over a decade. As an update and supplement to previously published research, this paper reviews the latest research on spore surface display technology using B. subtilis. We have mainly focused on the regulation of spore coat protein expression, display and application of exogenous proteins, and identification of developing research areas of spore surface display technology.


title: Effectiveness of adjunctive nebulized antibiotics in critically ill patients with respiratory tract infections

text: The purpose of the study was to analyze the effectiveness of adding nebulized antibiotics to systemic antimicrobials in critically ill patients with respiratory tract infections (pneumonia or tracheobronchitis) and the effect on renal function. A retrospective observational cohort study including critically ill patients with respiratory tract infections during a 2-year period was conducted. Intervention group included patients that received nebulized and systemic antimicrobials. Patients in the control group received only systemic antimicrobials. Clinical resolution was the primary endpoint. Secondary outcomes included change in fever, inflammatory parameters, and creatinine clearance; length of hospital stay, systemic therapy, and mechanical ventilation; hospital readmission; and mortality. Regression models were performed to estimate the effect of nebulized antibiotics on outcome variables adjusted by potential confounders. A total of 136 patients were included (93 in control group and 43 in intervention group). The intervention group had higher odds of clinical resolution (adjusted odds ratio (OR): 7.1; 95% confidence interval (95% CI): 1.2, 43.3). Nebulized antibiotic therapy was independently associated with reduction in procalcitonin (adjusted OR: 12.4; 95% CI: 1.4, 109.7). There were no significant differences in the rest of the secondary outcomes or in creatinine clearance reduction. Adding nebulized antibiotics for the management of respiratory tract infections has a positive impact on clinical resolution without increasing the risk of renal toxicity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10096-019-03733-6) contains supplementary material, which is available to authorized users.


title: Ventilator-associated pneumonia diagnosis: a prioritization exercise based on multi-criteria decision analysis

text: The aim was to provide global experts ranking on priorities in diagnostic tools for VAP in clinical practice. A multiple criteria decision analysis (MCDA) was performed to identify diagnosis tools for VAP diagnosis. Priority factors were identified after literature review. An international, multidisciplinary expert panel reviewed variables and ranked diagnostic tools. Experts from ten European hospitals participated. Regarding bedside clinical practices, seven required chest X-ray use in all patients, whereas six reported the use of blood cultures and endotracheal aspirate in all patients. Invasive techniques were routinely performed in seven sites. CRP, PCT, and Gram stains were performed in all patients by 5, 2, and 8, respectively. Impact on patient outcomes, safety, and impact on the decision to start antibiotic therapy were ranked as the top three relevant concerns (7.7/10, 7/10, and 6.9/10, respectively). Chest X-ray was ranked as the most important imaging technique to diagnose VAP (score 251.7). Apart from blood cultures, endotracheal aspirate culture was identified as the main collection method for the microbiological testing (scores of 274.8 and 246.8, respectively). Mini-BAL was the preferred invasive technique with a score of 208. Top three biomarkers were CRP (score 184.3), PCT (181.3), and WBC (166.4). Gram stain (192.5) was prioritized among laboratory diagnostic techniques. Using MCDA, it is recommended to perform a combination of diagnostic techniques including images (chest X-ray), culture of clinical specimens (blood cultures and endotracheal aspirate), and biomarkers (CRP or PCT) for VAP diagnosis at the bedside. Gram stain was ranked as the preferred laboratory technique. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10096-019-03720-x) contains supplementary material, which is available to authorized users.


title: Acute normovolemic hemodilution reduced allogeneic blood transfusion without increasing perioperative complications in patients undergoing free-flap reconstruction of the head and neck

text: PURPOSE: The present case–control study was conducted to evaluate whether acute normovolemic hemodilution (ANH) can reduce the need for perioperative allogeneic blood transfusion (ABT) and affect the incidence of perioperative complications in free-flap reconstruction of the head and neck. METHODS: This single-center, retrospective, observational study included the perioperative data of 123 patients who underwent free-flap reconstruction of the head and neck following oncological surgery. Patients were divided into the following two groups according to whether they received ANH: ANH group and non-ANH group. We investigated whether ANH can reduce the need for perioperative ABT using propensity score-adjusted logistic regression analysis. RESULTS: Of the 123 patients, 113 patients were assessed; 57 patients were in the ANH group and 56 patients were in the non-ANH group. The rate [ANH group vs. non-ANH group, n (%): 2 (3.5%) vs. 23 (41.1%), p < 0.0001] and amount [median (IQR): 0 mL (0, 0) vs. 0 mL (0, 280), p < 0.0001] of ABT were significantly lower in the ANH group than in the non-ANH group. Propensity score-adjusted multivariate logistic regression analysis indicated that ANH use [odds ratio (OR): 0.040; 95% confidence interval (CI) 0.005, 0.320; p = 0.0024)] was one of the independent predictors of perioperative ABT. There were no significant differences in the incidences of post-operative complications between the two groups. CONCLUSION: ANH use can reduce the need for perioperative ABT in patients undergoing free-flap reconstruction of the head and neck without increasing the incidence of post-operative complications.


title: Involvement of fat mass and obesity gene (FTO) in the anti-obesity action of Annona muricata Annonaceae: in silico and in vivo studies

text: BACKGROUND: Annona muricata (Annonaceae) known as soursop is a common tropical plant species known for its numerous medicinal properties including obesity. The underlying mechanism of anti-obesity effect of A. muricata was investigated. The fat mass and obesity associated protein (FTO) is a validated potential target for anti-obesity drugs. METHODS: The interaction of compounds previously characterized from A. muricata was investigated against FTO using Autodock Vina. Also, modulation of FTO and STAT-3 mRNA expression by A. muricata was investigated in high fat diet induced obese rats (HFDR) using RT-PCR. RESULTS: A significant up-regulation of FTO gene was observed in HFDR when compared to control rats, while administration of A. muricata (200 mg/kg) significantly (p < 0.05) down-regulated FTO gene expression when compared to HFDR group. The effect of obesity on STAT-3 gene expression was also reversed by A. muricata (200 mg/kg). In silico study revealed annonaine and annonioside (−9.2 kcal/mol) exhibited the highest binding affinity with FTO, followed by anonaine and isolaureline (−8.6 kcal/mol). Arg-96 is a critical amino acid enhancing anonaine, isolaureline-FTO binding. CONCLUSION: This study suggests the possible anti-obesity mechanism of A. muricata is via down-regulation of FTO with concomitant up-regulation of STAT-3 genes. This study confirmed the use of this plant in the management of obesity and the probable compounds responsible for its antiobesity effect are annonaine and annonioside.


title: Do-not-intubate orders in patients with acute respiratory failure: a systematic review and meta-analysis

text: PURPOSE: To assess the rates and variability of do-not-intubate orders in patients with acute respiratory failure. METHODS: We conducted a systematic review of observational studies that enrolled adult patients with acute respiratory failure requiring noninvasive ventilation or high-flow nasal cannula oxygen from inception to 2019. RESULTS: Twenty-six studies evaluating 10,755 patients were included. The overall pooled rate of do-not-intubate orders was 27%. The pooled rate of do-not-intubate orders in studies from North America was 14% (range 9–22%), from Europe was 28% (range 13–58%), and from Asia was 38% (range 9–83%), p = 0.001. Do-not-intubate rates were higher in studies with higher patient age and in studies where do-not-intubate decisions were made without reported patient/family input. There were no significant differences in do-not-intubate orders according to illness severity, observed mortality, malignancy comorbidity, or methodological quality. Rates of do-not-intubate orders increased over time from 9% in 2000–2004 to 32% in 2015–2019. Only 12 studies (46%) reported information about do-not-intubate decision-making processes. Only 4 studies (15%) also reported rates of do-not-resuscitate. CONCLUSIONS: One in four patients with acute respiratory failure (who receive noninvasive ventilation or high-flow nasal cannula oxygen) has a do-not-intubate order. The rate of do-not-intubate orders has increased over time. There is high inter-study variability in do-not-intubate rates—even when accounting for age and illness severity. There is high variability in patient/family involvement in do-not-intubate decision making processes. Few studies reported differences in rates of do-not-resuscitate and do-not-intubate—even though recovery is very different for acute respiratory failure and cardiac arrest. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05828-2) contains supplementary material, which is available to authorized users.


title: Transient protein expression in tobacco BY-2 plant cell packs using single and multi-cassette replicating vectors

text: KEY MESSAGE: This is the first evidence that replicating vectors can be successfully used for transient protein expression in BY-2 plant cell packs. ABSTRACT: Transient recombinant protein expression in plants and recently also plant cell cultures are of increasing interest due to the speed, safety and scalability of the process. Currently, studies are focussing on the design of plant virus-derived vectors to achieve higher amounts of transiently expressed proteins in these systems. Here we designed and tested replicating single and multi-cassette vectors that combine elements for enhanced replication and hypertranslation, and assessed their ability to express and particularly co-express proteins by Agrobacterium-mediated transient expression in tobacco BY-2 plant cell packs. Substantial yields of green and red fluorescent proteins of up to ~ 700 ng/g fresh mass were detected in the plant cells along with position-dependent expression. This is the first evidence of the ability of replicating vectors to transiently express proteins in BY-2 plant cell packs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00299-020-02544-w) contains supplementary material, which is available to authorized users.


title: Next-generation influenza vaccines: opportunities and challenges

text: Seasonal influenza vaccines lack efficacy against drifted or pandemic influenza strains. Developing improved vaccines that elicit broader immunity remains a public health priority. Immune responses to current vaccines focus on the haemagglutinin head domain, whereas next-generation vaccines target less variable virus structures, including the haemagglutinin stem. Strategies employed to improve vaccine efficacy involve using structure-based design and nanoparticle display to optimize the antigenicity and immunogenicity of target antigens; increasing the antigen dose; using novel adjuvants; stimulating cellular immunity; and targeting other viral proteins, including neuraminidase, matrix protein 2 or nucleoprotein. Improved understanding of influenza antigen structure and immunobiology is advancing novel vaccine candidates into human trials.


title: Effects of a Single Head Exposure to GSM-1800 MHz Signals on the Transcriptome Profile in the Rat Cerebral Cortex: Enhanced Gene Responses Under Proinflammatory Conditions

text: Mobile communications are propagated by electromagnetic fields (EMFs), and since the 1990s, they operate with pulse-modulated signals such as the GSM-1800 MHz. The biological effects of GSM-EMF in humans affected by neuropathological processes remain seldom investigated. In this study, a 2-h head-only exposure to GSM-1800 MHz was applied to (i) rats undergoing an acute neuroinflammation triggered by a lipopolysaccharide (LPS) treatment, (ii) age-matched healthy rats, or (iii) transgenic hSOD1(G93A) rats that modeled a presymptomatic phase of human amyotrophic lateral sclerosis (ALS). Gene responses were assessed 24 h after the GSM head-only exposure in a motor area of the cerebral cortex (mCx) where the mean specific absorption rate (SAR) was estimated to be 3.22 W/kg. In LPS-treated rats, a genome-wide mRNA profiling was performed by RNA-seq analysis and revealed significant (adjusted p value < 0.05) but moderate (fold changes < 2) upregulations or downregulations affecting 2.7% of the expressed genes, including genes expressed predominantly in neuronal or in glial cell types and groups of genes involved in protein ubiquitination or dephosphorylation. Reverse transcription-quantitative PCR analyses confirmed gene modulations uncovered by RNA-seq data and showed that in a set of 15 PCR-assessed genes, significant gene responses to GSM-1800 MHz depended upon the acute neuroinflammatory state triggered in LPS-treated rats, because they were not observed in healthy or in hSOD1(G93A) rats. Together, our data specify the extent of cortical gene modulations triggered by GSM-EMF in the course of an acute neuroinflammation and indicate that GSM-induced gene responses can differ according to pathologies affecting the CNS.


title: Decreasing radiographs in neonates through targeted quality improvement interventions

text: OBJECTIVE: Our aim was to decrease radiograph use for monitoring placement of peripherally inserted central catheters (PICC) and endotracheal tubes (ETT) in neonates admitted to the neonatal intensive care unit (NICU) by 20% from November 2017 to November 2018. STUDY DESIGN: We carried out three Plan-Do-Study-Act (PDSA) cycles: (1) implementation of a radiograph protocol emphasizing ideal patient positioning, standard radiograph views and frequency, (2) standardizing ETT depth using the NRP guidelines, and (3) implementation of an institution specific ETT depth guideline. RESULTS: The pre-intervention radiographs per PICC day was 0.86 versus a post-intervention value of 0.46 (P = 0.004). The pre-intervention radiographs per ETT day was 1.45 versus a post-intervention value of 1.07 (P = 0.002). CONCLUSIONS: Our multidisciplinary NICU team performed a QI project, which resulted in more than a 20% decrease in the number of radiographs used for monitoring placement of PICCs and ETTs.


A review of approaches for resolving disputes between physicians and families on end-of-life care for newborns


title: Effect of edaravone therapy in Korean amyotrophic lateral sclerosis (ALS) patients

text: Oxidative stress caused by free radicals has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone (also known as MCI-186), a free radical scavenger, was approved as an ALS treatment in 2015 in Japan. However, the therapeutic effects of edaravone on patients with ALS outside of Japan are not yet reported. This study aims to investigate effects of edaravone on ALS patients in the Korean population. The study included 22 patients with ALS who were treated with edaravone. Of the 16 patients who finished six cycles of treatment, a mean decline of ALSFRS-R after the treatments was 5.75 ± 6.07 points and the average change of FVC was − 8.7 ± 17.0%. Patients experienced only minor adverse events. This study reports on the open-label study of edaravone on patients in Korea for ALS patients, which showed a modest effect of edaravone in this population of ALS patients.


title: Evidence-based impact by clinical engineers on global patients outcomes

text: The intersection of technological changes and societal evolution has transformed every aspect of human life. Technological advancements are transforming how healthcare knowledge is expanding and accelerating the outreach of critical medical services delivery (Jamal et al. in Health Information Management Journal 38(3):26–37, 2009). While this transformation facilitates new opportunities simultaneously it also introduces challenges (Jacobzone and Oxley, 2001). Appropriate Health Technology (HT) is vital to new and existing global health care programs. Therefore, qualified professionals who can safely guide the development, evaluation, installation, integration, performance assurance, and risk mitigation of HT must be in position to lead. Trained Clinical Engineers (CE) and Biomedical Engineers (BE) have been recognized by the World Health Organization (WHO) as the essential practitioners to providing this critically needed guidance. Over the past four years, a senior professional group participated in an international project that seeks evidence for the hypothesis - that the engagement of CE and BE in guiding HT - impacts positively on patient outcomes, while the alternative is that there is no difference. The group collected published data that was subjected to peer review screening; additional data qualification conditions are described in this paper. The project was initiated at the Global CE Summit during the first International Clinical Engineering and Health Technology Management Congress (ICEHTMC) in Hangzhou, China in October 2015 (Global Clinical Engineering Summit at the First International Clinical Engineering and Health Technology Management Congress, 2015). Following the adoption of a resolution to investigate CE contributions to the improvement of world health status, an international survey and literature survey were initiated. During the first two years of this project 150 case studies from 90 countries were identified covering the previous ten years. The results of this survey were presented to health leaders at the World Health Organization (WHO) World Health Assembly in 2016. Last year, 250 case studies were added including 35 more countries covering the 2016–2017 period. The combined project contains 400 qualified submissions from 125 countries. The conclusion was that engagement of CE and BME is critical for successful investment in HT and for achieving intended patient outcomes. This paper describes the project’s plan, the results of the literature review performed, and the evidence identified during the process.


The Janus faces of bicarbonate therapy in the ICU: not sure!


title: Addressing Diversity in PTSD Treatment: Clinical Considerations and Guidance for the Treatment of PTSD in LGBTQ Populations

text: PURPOSE OF REVIEW: Trauma exposure is widespread but is especially common among lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals. LGBTQ individuals also experience higher rates of discrimination, victimization, and minority stress which can complicate posttraumatic stress disorder (PTSD) treatment but also represent independent intervention targets. In this review, we highlight existing evidence-based practices, current limitations, and provide recommendations for care in the absence of established guidelines for treatment PTSD among LGBTQ patients. RECENT FINDINGS: Trauma-focused therapies (e.g., CPT, PE) and medications (e.g., SSRIs, SNRIs) have shown benefit for people with PTSD. However, evaluations of these interventions have failed to examine the role of LGBTQ identities in recovery from trauma, and existing PTSD treatments do not account for ongoing threat to safety or the pervasive minority stress experienced by LGBTQ patients. In addition, many LGBTQ patients report negative experiences with healthcare, necessitating increased education and cultural awareness on the part of clinicians to provide patient-centered care and, potentially, corrective mental health treatment experiences. SUMMARY: Providers should routinely assess trauma exposure, PTSD, and minority stress among LGBTQ patients. We provide assessment and screening recommendations, outline current evidence-based treatments, and suggest strategies for integrating existing treatments to treat PTSD among LGBTQ patients.


title: Metagenomic next-generation sequencing in the diagnosis of severe pneumonias caused by Chlamydia psittaci

text: PURPOSE: Chlamydia psittaci infection in humans can lead to serious clinical manifestations, including severe pneumonia, adult respiratory distress syndrome, and, rarely, death. Implementation of metagenomic next-generation sequencing (mNGS) gives a promising new tool for diagnosis. The clinical spectrum of severe psittacosis pneumonia is described to provide physicians with a better understanding and to highlight the rarity and severity of severe psittacosis pneumonia. METHODS: Nine cases of severe psittacosis pneumonia were diagnosed using mNGS. Retrospective analysis of the data on disease progression, new diagnosis tool, treatments, and outcomes, and the findings were summarised. RESULTS: Frequent symptoms included chills and remittent fever (100%), cough and hypodynamia (100%), and headache and myalgia (77.8%). All patients were severe psittacosis pneumonia developed respiratory failure, accompanied by sepsis in 6/9 patients. mNGS takes 48–72 h to provide the results, and help to identify diagnosis of psittacosis. Laboratory data showed normal or slightly increased leucocytes, neutrophils, and procalcitonin but high C-reactive protein levels. Computed tomography revealed air-space consolidation and ground-glass opacity, which began in the upper lobe of one lung, and spread to both lungs, along with miliary, nodular, or consolidated shadows. One patient died because of secondary infection with Klebsiella pneumoniae, while the other eight patients experienced complete recoveries. CONCLUSIONS: The use of mNGS can improve accuracy and reduce the delay in diagnosis of psittacosis. Severe psittacosis pneumonia responds well to the timely use of appropriate antibiotics.


title: MiR-802 alleviates lipopolysaccharide-induced acute lung injury by targeting Peli2

text: INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a life-threatening medical condition. It is characterized by serious lung inflammation or injury. Characterizing novel miRNAs implicated in ARDS pathogenesis may provide new therapeutic strategy for managing ARDS. METHODS: We employed LPS-induced lung injury model to profile miRNAs associated with ARDS. We isolated one miRNA candidate and characterized its role in lipopolysaccharide (LPS)-induced proinflammatory cytokine production in lung macrophages. We further evaluated its functional role in ARDS model by assessing histological change, neutrophil activation, tissue permeability and tumor necrosis factor alpha (TNFα) production. We also characterized its downstream target using luciferase assay, Western blotting, enzyme-linked immunosorbent assay and cell inflammation assay. RESULTS: Microarray profiling revealed miR-802 was significantly downregulated in ARDS mouse model. LPS-induced miR-802 downregulation was confirmed in lung macrophages. Overexpression of miR-802 significantly suppressed LPS-induced inflammatory cytokine production in vitro and alleviates LPS-induced acute lung injury in vivo. Peli2 was identified as a downstream target of miR-802 and found upregulated in ARDS model. Overexpressing Peli2 abolished the antagonizing effect of miR-802 on LPS-mediated inflammatory response. CONCLUSION: MiR-802 carried a protective role against LPS-induced acute lung injury by downregulating Peli2. MiR-802/Peli2 axis may act as intervening targets to manage ARDS.


title: Incidence and complications of cannula changes in long-term tracheotomized patients: a prospective observational study

text: STUDY DESIGN: Prospective, monocentric observational study. OBJECTIVE: Investigation of incidence and complication rate of cannula changes in long-term tracheotomized patients suffering spinal cord injury. SETTING: University hospital in Bochum, Germany. METHODS: Prospective data collection of all cannula changes between September 2016 and September 2017. Physicians recorded mechanical complications and techniques to solve them, and/or complications resulting in patient-threatening condition. RESULTS: There were 149 cannula changes during 3191 observation days. Overall, urgent cannula changes occurred 2.1 times per 100 observation days. Within the first 8 weeks after tracheostomy, urgent cannula changes were necessary four times per 100 observation days, and were mandatory less than two times per 100 observation days thereafter. Overall, mechanical complications occurred in 12% of cannula changes, and 8% of cannula changes were accompanied by patient-threatening complications. Accidental decannulation (AD) occurred in 0.97 of 100 observation days. Recannulation after AD was accompanied by 29% of mechanical complications during reinsertion, and 16% led to patient-threatening complications. The major risk factors for mechanical complications were the time lag between cannula change and tracheostomy, and the urgency of the procedure while the thyroid cartilage–jugular distance was significantly associated with patient-threatening complications. CONCLUSION: AD and the requirement for urgent cannula changes are common and often related with mechanical and patient-threatening complications. Even weeks after tracheostomy, caregivers need to be aware of serious events, and therefore provide monitoring, knowledge, and appropriate resources to handle these events.


title: Response Measures to Infection Outbreaks During the Second Year of Sustenance Phase of Infection Control Quality Improvement

text: OBJECTIVE: To analyze the infection outbreaks, control measures and outcomes of the outbreak in the NICU of a tertiary care centre in the year 2018. METHODS: This study was conducted in a 30 bedded tertiary care NICU from January 2018 through December 2018. The study design was an Outbreak investigation, based on a program of prospective surveillance for nosocomial infection. All neonates admitted to the NICU formed part of the the study. An Infection Control Quality Improvement (QI) team was available to analyze the infection and initiate response action to outbreaks. RESULTS: Three outbreaks were reported in the year 2018. The first was in May 2018 and comprised of colonization with rectal Multi-drug resistant gram negative bacilli (MDR GNB). The outbreak was controlled by using Aseptic non-touch technique (ANTT) for fortification of milk and using distilled water for cleaning of diaper area. The second outbreak in August 2018 was Methicillin resistant Staphylococcus aureus (MRSA) whose source was a maternal Lower segment cesarean section (LSCS) wound. The third outbreak in October 2018 was MDR Acinetobacter. The source was from an outborn having the same organism. All infants were in close proximity to the index case. This outbreak was controlled with cohorting, hand hygiene and strengthening of bundle care. CONCLUSIONS: Surveillance aids in early detection and successful control of outbreaks. A systematic search for the source and meticulous containment of spread can successfully control an outbreak.


title: Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

text: Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.


title: Neurally adjusted ventilatory assist preserves cerebral blood flow velocity in patients recovering from acute brain injury

text: Neurally adjusted ventilatory assist (NAVA) has never been applied in patients recovering from acute brain injury (ABI) because neural respiratory drive could be affected by intracranial disease with detrimental effects on cerebral blood flow (CBF) velocity. Our primary aim was to assess the impact of NAVA and pressure support ventilation (PSV) on CBF velocity. In fifteen adult patients recovering from ABI and undergoing invasive assisted ventilation, PSV and NAVA were applied over 30-min-lasting trials, in the following sequence: PSV(1), NAVA, and PSV(2). While PSV was set to deliver a tidal volume ranging between 6 and 8 ml kg(−1) of predicted body weight, in NAVA the level of assistance was chosen to achieve the same inspiratory peak airway pressure as PSV. At the end of each trial, a sonographic evaluation of CBF mean velocity was bilaterally obtained on the middle cerebral artery and an arterial blood gas sample was taken for analysis. CBF mean velocity was 51.8 [41.9,75.2] cm s(−1) at baseline, 51.9 [43.4,71.0] cm s(−1) in PSV(1), 53.6 [40.7,67.7] cm s(−1) in NAVA, and 49.5 [42.1,70.8] cm s(−1) in PSV(2) (p = 0.0514) on the left and 50.2 [38.0,77.7] cm s(−1) at baseline, 47.8 [41.7,68.2] cm s(−1) in PSV(1), 53.9 [40.1,78.5] cm s(−1) in NAVA, and 55.6 [35.9,74.1] cm s(−1) in PSV(2) (p = 0.8240) on the right side. No differences were detected for pH (p = 0.0551), arterial carbon dioxide tension (p = 0.8142), and oxygenation (p = 0.0928) over the entire study duration. NAVA and PSV preserved CBF velocity in patients recovering from ABI. Trial registration: The present trial was prospectively registered at www.clinicatrials.gov (NCT03721354) on October 18th, 2018. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10877-020-00523-w) contains supplementary material, which is available to authorized users.


title: SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA

text: HBV infection initiates hepatitis B and promotes liver cirrhosis and hepatocellular carcinoma. IFN-α is commonly used in hepatitis B therapy, but how it inhibits HBV is not fully understood. We screened 285 human interferon-stimulated genes (ISGs) for anti-HBV activity using a cell-based assay, which revealed several anti-HBV ISGs. Among these ISGs, SAMD4A was the strongest suppressor of HBV replication. We found the binding site of SAMD4A in HBV RNA, which was a previously unidentified Smaug recognition region (SRE) sequence conserved in HBV variants. SAMD4A binds to the SRE site in viral RNA to trigger its degradation. The SAM domain in SAMD4A is critical for RNA binding and the C-terminal domain of SAMD4A is required for SAMD4A anti-HBV function. Human SAMD4B is a homolog of human SAMD4A but is not an ISG, and the murine genome encodes SAMD4. All these SAMD4 proteins suppressed HBV replication when overexpressed in vitro and in vivo. We also showed that knocking out the Samd4 gene in hepatocytes led to a higher level of HBV replication in mice and AAV-delivered SAMD4A expression reduced the virus titer in HBV-producing transgenic mice. In addition, a database analysis revealed a negative correlation between the levels of SAMD4A/B and HBV in patients. Our data suggest that SAMD4A is an important anti-HBV ISG for use in IFN therapy of hepatitis B and that the levels of SAMD4A/B expression are related to HBV sensitivity in humans.


title: Blood Component Transfusion in a Tertiary Care Hospital

text: OBJECTIVES: To study the rational use of the blood components in pediatric and neonatal wards. METHODS: It was a retrospective study conducted by department of pediatrics of a tertiary care centre in western part of India. The patients were included from the pediatric ward, pediatric surgery ward, neonatal intensive care unit (NICU), pediatric intensive care unit (PICU) over a period of three months. All the patients below 12 y of age receiving blood components, admitted in general pediatric wards, pediatric intensive care unit, neonatal intensive care unit and pediatric surgery ward were included in the study. Each transfusion episode was assessed as per predetermined guidelines. RESULTS: Of the total 336 episodes of blood component transfusions, 244 episodes were appropriate and 92 episodes were inappropriate. Among these, platelets had highest inappropriate (36.84%) episodes followed by fresh frozen plasma (FFP) (28.95%) and packed red blood cell transfusions (PRBC) (21.21%). Majority inappropriate transfusions were seen in intensive care settings. CONCLUSIONS: Almost one-third of blood component transfusions (FFP, platelets and PRBC) were given without any definitive indication. Judicious use of various blood products by following recommended guidelines may help in decreasing the inappropriate use of blood components.


2019: Archives of Virology celebrates its eightieth birthday with a scientific symposium


title: Worldwide Organization of Neurocritical Care: Results from the PRINCE Study Part 1

text: INTRODUCTION: Neurocritical care focuses on the care of critically ill patients with an acute neurologic disorder and has grown significantly in the past few years. However, there is a lack of data that describe the scope of practice of neurointensivists and epidemiological data on the types of patients and treatments used in neurocritical care units worldwide. To address these issues, we designed a multicenter, international, point-prevalence, cross-sectional, prospective, observational, non-interventional study in the setting of neurocritical care (PRINCE Study). METHODS: In this manuscript, we analyzed data from the initial phase of the study that included registration, hospital, and intensive care unit (ICU) organizations. We present here descriptive statistics to summarize data from the registration case report form. We performed the Kruskal–Wallis test followed by the Dunn procedure to test for differences in practices among world regions. RESULTS: We analyzed information submitted by 257 participating sites from 47 countries. The majority of those sites, 119 (46.3%), were in North America, 44 (17.2%) in Europe, 34 (13.3%) in Asia, 9 (3.5%) in the Middle East, 34 (13.3%) in Latin America, and 14 (5.5%) in Oceania. Most ICUs are from academic institutions (73.4%) located in large urban centers (44% > 1 million inhabitants). We found significant differences in hospital and ICU organization, resource allocation, and use of patient management protocols. The highest nursing/patient ratio was in Oceania (100% 1:1). Dedicated Advanced Practiced Providers are mostly present in North America (73.7%) and are uncommon in Oceania (7.7%) and the Middle East (0%). The presence of dedicated respiratory therapist is common in North America (85%), Middle East (85%), and Latin America (84%) but less common in Europe (26%) and Oceania (7.7%). The presence of dedicated pharmacist is highest in North America (89%) and Oceania (85%) and least common in Latin America (38%). The majority of respondents reported having a dedicated neuro-ICU (67% overall; highest in North America: 82%; and lowest in Oceania: 14%). CONCLUSION: The PRINCE Study results suggest that there is significant variability in the delivery of neurocritical care. The study also shows it is feasible to undertake international collaborations to gather global data about the practice of neurocritical care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12028-019-00750-3) contains supplementary material, which is available to authorized users.


Defining patient–ventilator asynchrony severity according to recurrence


title: Prevalence, Clinical Characteristics, and Outcomes Related to Ventilator-Associated Events in Neurocritically Ill Patients

text: BACKGROUND: The prevalence, characteristics, and outcomes related to the ventilator-associated event(s) (VAE) in neurocritically ill patients are unknown and examined in this study. METHODS: A retrospective study was performed on neurocritically ill patients at a 413-bed level 1 trauma and stroke center who received three or more days of mechanical ventilation to describe rates of VAE, describe characteristics of patients with VAE, and examine the association of VAE on ventilator days, mortality, length of stay, and discharge to home. RESULTS: Over a 5-year period from 2014 through 2018, 855 neurocritically ill patients requiring mechanical ventilation were identified. A total of 147 VAEs occurred in 130 (15.2%) patients with an overall VAE rate of 13 per 1000 ventilator days and occurred across age, sex, BMI, and admission Glasgow Coma Scores. The average time from the start of ventilation to a VAE was 5 (range 3–48) days after initiation of mechanical ventilation. Using Centers for Disease Control and Prevention definitions, VAEs met criteria for a ventilator-associated condition in 58% of events (n = 85), infection-related VAE in 22% of events (n = 33), and possible ventilator-associated pneumonia in 20% of events (n = 29). A most common trigger for VAE was an increase in positive end-expiratory pressure (84%). Presence of a VAE was associated with an increase in duration of mechanical ventilation (17.4[IQR 20.5] vs. 7.9[8.9] days, p < 0.001, 95% CI 7.86–13.92), intensive care unit (ICU) length of stay (20.2[1.1] vs. 12.5[0.4] days, p < 0.001 95% CI 5.3–10.02), but not associated with in-patient mortality (34.1 vs. 31.3%. 95% CI 0.76–1.69) or discharge to home (12.7% vs. 16.3%, 95% 0.47–1.29). CONCLUSIONS: VAE are prevalent in the neurocritically ill. They result in an increased duration of mechanical ventilation and ICU length of stay, but may not be associated with in-hospital mortality or discharge to home. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12028-019-00910-5) contains supplementary material, which is available to authorized users.


title: New-Onset Refractory Status Epilepticus with Underlying Autoimmune Etiology: a Case Report

text: Management of new-onset refractory status epilepticus and the approach to burst suppression variable is often challenging. We present the unusual case of a previously healthy 18-year-old male with new-onset status epilepticus admitted to the neurologic intensive care unit for 70 days. Despite treatment with multiple anti-epileptic drugs in addition to IV anesthetics, burst suppression was initially unsustainable and the patient remained in super-refractory status epilepticus. Extensive evaluation revealed an underlying autoimmune-mediated etiology with positivity for glutamic acid decarboxylase-65 antibody. Clinical response with a goal of 1–2 bursts per screen on EEG monitor was eventually achieved after a course of rituximab and plasma exchange therapy as well as a 7-day barbiturate coma with a regimen of clobazam, lacosamide, Keppra, and oxcarbazepine followed by a slow taper of phenobarbital and the addition of fosphenytoin. Remarkably, the patient was subsequently discharged to a rehabilitation facility with complete neurologic recovery. We discuss treatment strategies for new-onset refractory status epilepticus and highlight the role of rapid initiation of burst suppression with high-dose IV anesthetics to ensure neuroprotection while the underlying etiology is addressed with immune-modulating therapy.


title: Post-Marketing Pooled Safety Analysis for CT-P13 Treatment of Patients with Immune-Mediated Inflammatory Diseases in Observational Cohort Studies

text: BACKGROUND: At EU marketing authorisation, safety data for CT-P13 (biosimilar infliximab) were limited, particularly in some indications, and uncommon adverse events (AEs) could not be evaluated among relatively small analysis populations. OBJECTIVES: Our objective was to investigate the overall safety profile and incidence rate of AEs of special interest (AESIs), including serious infections and tuberculosis, in CT-P13-treated patients. METHODS: Data were pooled from six observational studies representing authorised indications of CT-P13 (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, adult and paediatric Crohn’s disease and ulcerative colitis). Patients were analysed by indication and treatment (patients who received CT-P13 or those who switched from reference infliximab to CT-P13 ≤ 6 months prior to enrolment or during the study). RESULTS: Overall, 4393 patients were included (n = 3677 CT-P13 group; n = 716 switched group); 64.03% of patients had inflammatory bowel disease and 6.31% of patients were antidrug antibody positive. Overall, 32.94% and 9.58% of patients experienced treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs, respectively. Across indications, TEAEs were more frequent with CT-P13 than with the switched group. Infections including tuberculosis were the most frequent serious AESI overall (2.48%) and by treatment group or indication. In total, 14 patients (0.32%) reported active tuberculosis. Overall incidence rates per 100 patient-years (95% confidence interval) were 3.40 (2.788–4.096) for serious infections including tuberculosis and 0.44 (0.238–0.732) for active tuberculosis. Infusion-related reactions were the second most frequent AESI following infection including tuberculosis. CONCLUSION: The CT-P13 safety profile appears consistent with previous studies for CT-P13 and reference infliximab, supporting the favourable risk/benefit balance for CT-P13 treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40259-020-00421-2) contains supplementary material, which is available to authorized users.


title: Dear Mental Health Practitioners, Take Care of Yourselves: a Literature Review on Self-Care

text: Stress, burnout, and professional impairment are prevalent among mental health professionals and can have a negative impact on their clinical work, whilst engagement in self-care can help promote therapist well-being. This literature review examines the role of self-care in the promotion of well-being among mental health practitioners. Specifically, empirical research is presented in relation to specific domains of self-care practice, including awareness, balance, flexibility, physical health, social support, and spirituality. Findings from this review underscore the importance of taking a proactive approach to self-care and, in particular, integrating self-care directly into clinical training programs and into the quality assurance processes of professional organizations within the field of mental health.


title: Bloodstream infections in critically ill patients: an expert statement

text: Bloodstream infection (BSI) is defined by positive blood cultures in a patient with systemic signs of infection and may be either secondary to a documented source or primary—that is, without identified origin. Community-acquired BSIs in immunocompetent adults usually involve drug-susceptible bacteria, while healthcare-associated BSIs are frequently due to multidrug-resistant (MDR) strains. Early adequate antimicrobial therapy is a key to improve patient outcomes, especially in those with criteria for sepsis or septic shock, and should be based on guidelines and direct examination of available samples. Local epidemiology, suspected source, immune status, previous antimicrobial exposure, and documented colonization with MDR bacteria must be considered for the choice of first-line antimicrobials in healthcare-associated and hospital-acquired BSIs. Early genotypic or phenotypic tests are now available for bacterial identification and early detection of resistance mechanisms and may help, though their clinical impact warrants further investigations. Initial antimicrobial dosing should take into account the pharmacokinetic alterations commonly observed in ICU patients, with a loading dose in case of sepsis or septic shock. Initial antimicrobial combination attempting to increase the antimicrobial spectrum should be discussed when MDR bacteria are suspected and/or in the most severely ill patients. Source identification and control should be performed as soon as the hemodynamic status is stabilized. De-escalation from a broad-spectrum to a narrow-spectrum antimicrobial may reduce antibiotic selection pressure without negative impact on mortality. The duration of therapy is usually 5–8 days though longer durations may be discussed depending on the underlying illness and the source of infection. This narrative review covers the epidemiology, diagnostic workflow and therapeutic aspects of BSI in ICU patients and proposed up-to-date expert statements.


title: Event-triggered averaging of electrical impedance tomography (EIT) respiratory waveforms as compared to low-pass filtering for removal of cardiac related impedance changes

text: Electrical impedance tomography (EIT) is used for bedside ventilation monitoring; cardiac related impedance changes represent a source of noise superimposed on the ventilation signal, commonly removed by low-pass filtering (LPF). We investigated if an alternative approach, based on an event-triggered averaging (ETA) process, is more effective at preserving the actual ventilation waveform. Ten paralyzed patients undergoing volume-controlled ventilation were studied; 30 breaths for each patient were identified to compare LPF and ETA. For ETA the identified breaths were temporally aligned on the beginning of inspiration; the values of the thirty curves at each time point were averaged. The analysis was conducted on the global EIT signal and on four ventral-to-dorsal regions of interest. Global tidal variations by ETA resulted higher than LPF (average difference 139 ± 88 arbitrary units, p = 0.004). Both for global and regional waveforms, minimum and maximum EIT slopes were steeper by ETA as compared to LPF (average difference respectively − 57 ± 60 mL/s and 144 ± 96 mL/s for global signal, p < 0.05); ventilator inspiratory peak airflow correlated with maximum slope measured by ETA (r = 0.902, p < 0.001), but not LPF (p = 0.319). Beginning of inspiration identified on the ventilator waveform and on the global EIT signal by ETA occurred simultaneously, (+ 0.04 ± 0.07 s, p = 0.081), while occurred earlier by LPF (− 0.26 ± 0.1 s, p < 0.001). Removal of cardiac related impedance changes by ETA results in a ventilation signal more similar to the waveforms recorded by the ventilator, particularly regarding the slope of impedance changes and time at the minimum values as compared to LPF. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10877-019-00348-2) contains supplementary material, which is available to authorized users.


title: The changing face of neurosurgery for the older person

text: Increased life expectancy and illness prevention and treatment have led to a growing population of older patients. These changes in patient population are apparent in neurosurgery; however, relatively little is reported about specific outcomes and prognostication in this group. This review summarises the challenges and management changes occurring in the treatment of three common neurosurgical pathologies; aneurysmal subarachnoid haemorrhage, head injury, and haemorrhagic stroke. A move towards less invasive neurosurgical techniques has implications on the risk–benefit profile of interventions. This creates the opportunity to intervene in older patients with greater co-morbidity, as long as improved outcomes can be evidenced. A critical part of assessing appropriateness for surgical intervention in older patients may be to change from a mindset of age to one of frailty and growing interest in scales assessing this may aid treatment decisions in the future.


title: Respiratory and Blood Stream Infections are Associated with Subsequent Venous Thromboembolism After Primary Intracerebral Hemorrhage

text: BACKGROUND: Infection and venous thromboembolism (VTE) are associated with worse outcomes after intracerebral hemorrhage (ICH). The relationship between infection and VTE in ICH patients is unclear. We hypothesized that infection would be associated with subsequent VTE after ICH. METHODS: We retrospectively studied consecutively admitted spontaneous primary ICH patients from 2009 to 2018 surviving beyond 24 h. The primary predictor variable was infection, diagnosed prior to VTE. The primary outcome was VTE. We used multivariable logistic regression models to estimate the odds ratios and 95% confidence intervals (OR, 95% CI) for VTE risk after infection of any type, after adjusting for ICH score, length of stay and days to deep venous thrombosis (DVT) prophylaxis. Similar analysis was done to estimate the association of infection subtypes, including respiratory and urinary and blood stream infections (BSI) with VTE. RESULTS: There were 414 patients (mean age 65 years, 47% female) that met were analyzed. Infection was diagnosed in 181 (44%) patients. Incident VTE was diagnosed in 36 (9%) patients, largely comprised of DVT (n = 32; 89%). Infection overall was associated with increased risk of subsequent VTE (adjusted OR 4.5, 95% CI 1.6–12.6). Respiratory (adjusted OR 5.7, 95% CI 2.8–11.7) and BSI (adjusted OR 4.0, 95% CI 1.3–11.0) were associated with future VTE. Urinary and other infections were not associated with subsequent VTE. CONCLUSIONS: Infections are associated with subsequent risk of VTE among patients with ICH. Further investigation is required to elucidate mechanisms behind this association and to improve VTE prevention after ICH.


title: Ultrasound-guided supraclavicular cannulation of the brachiocephalic vein may reduce central line–associated bloodstream infection in preterm infants

text: The objective of this study was to assess the risk of central line–associated bloodstream infection (CLABSI) of ultrasound (US)-guided cannulation of the brachiocephalic vein (BCV) compared to standard epicutaneous cava catheters (ECCs) in preterm infants. This was a retrospective cohort study in preterm infants with a birth weight of less than 1500 g. Each BCV catheter was matched 1:3 with ECCs according to sex, birth weight, and year of insertion. The main outcome was the CLABSI density rate per 1000 days. Secondary outcomes included CLABSI episodes, CLABSI episodes per infant, and CLABSI/death. A multivariate Cox regression analysis was performed to assess whether the type of catheter (ECC vs. BCV) was associated with CLABSI risk. Ninety-six catheters (21 BCVs and 75 ECCs) in 79 infants were included (993 catheter days). BCV catheters were associated with a reduced CLABSI density rate compared to ECCs (3.05/1000 days vs 21.1/1000 days; p < 0.001). ECCs were associated with increased CLABSI risk compared to BCV catheters in multivariate analysis (hazard ratio 36; (95% CI, 2.5–511); p = 0.008). Conclusion: US-guided supraclavicular cannulation of the BCV was associated with a reduced risk of CLABSI compared to ECCs. This finding deserves further multicenter research.


title: Lens-induced uveitis: an update

text: Ocular inflammation resulting from a lens pathology is rare in the absence of a cataract or lens trauma because of the lens’ immune privilege. The lens can be a source of ocular inflammation when the capsule is broken or when lens proteins leak out through an intact capsule. These uveitides are termed lens-induced uveitis (LIU) and are often associated with advanced cataracts. Cataracts are part of the normal aging process, and in today’s world, cataract surgery is a safe and affordable means of vision restoration in the developed world. In patients with neglected cataracts and in the developing world where cataract surgery rates are lower, LIU rates are higher together with the associated complications. In this literature review, we intend to equip the armamentarium of the practicing ophthalmologist with an updated knowledge on the demographic features, clinical characteristics, treatment options, and outcomes of LIU. This is to highlight the need for timely management of cataracts before the development of advanced cataracts and LIU.


title: Resilience in palliative healthcare professionals: a systematic review

text: PURPOSE: Exposure to end-of-life and chronic illness on a daily basis may put palliative healthcare professionals’ well-being at risk. Resilience may represent a protective factor against stressful and demanding challenges. Therefore, the aim is to systematically review the quantitative studies on resilience in healthcare professionals providing palliative care to adult patients. METHODS: A literature search on PubMed, Scopus, Web of Science and PsycINFO databases was performed. The review process has followed the international PRISMA statement guidelines. RESULTS: At the initial search, a total of 381 records were identified. Twelve articles were assessed for eligibility and, finally, 6 studies met all the inclusion criteria. Of these, four researches were observational and two interventional pilot studies. From the systematic synthesis, palliative care providers’ resilience revealed to be related to other psychological constructs, including secondary traumatic stress, vicarious posttraumatic growth, death anxiety, burnout, compassion satisfaction, hope and perspective taking. CONCLUSIONS: The current systematic review reported informative data leading to consider resilience as a process modulator and facilitator among palliative care professionals. A model on palliative healthcare providers’ experience and the role of resilience was proposed. Further studies may lead to its validation and implementation in assessment and intervention contributing to foster palliative healthcare professionals’ well-being.


title: Transcranial Doppler ultrasound findings in children with moderate-to-severe traumatic brain injury following abusive head trauma

text: PURPOSE: Abusive head trauma (AHT) is the leading cause of fatal head injuries for children under 2 years. The objective was to evaluate, using transcranial Doppler ultrasound (TCD), whether children with AHT have a similar neurovascular response to injury compared with children without AHT. METHODS: Retrospective sub-analysis of previously prospectively acquired data in a pediatric intensive care unit in a level 1 trauma hospital. TCD was performed daily until hospital day 8, discharge, or death. Neurologic outcome was assessed using the Glasgow Outcome Scale Extended (GOS-E Peds) at 1 month from initial injury. RESULTS: Sixty-nine children aged 1 day to 17 years with moderate-to-severe traumatic brain injury were enrolled. Fifteen children suffered AHT and 54 had no suspicion for AHT. Fifteen children with AHT underwent 80 serial TCD examinations; 54 children without AHT underwent 308 exams. After standardization for age and gender normative values, there was no statistically significant difference in mean cerebral blood flow velocity of the middle cerebral artery (V(MCA)) between children with and without AHT. There was no difference in the incidence of extreme cerebral blood flow velocity (CBFV, greater or less than 2 standard deviations from normative value) between groups. Within the AHT group, there were no statistically significant differences in V(MCA) between children with a favorable (GOS-E Peds 1–4) versus unfavorable neurologic outcome (GOS-E Peds 5–8). CONCLUSION: Children with AHT have no significant differences in V(MCA) or percentage of extreme CBFV in the middle cerebral artery compared to with those without AHT.


title: An index to prioritize the preventive maintenance of medical equipment

text: We propose an index to prioritize preventive maintenance for medical equipment. Our index considers seven variables: type of equipment, equipment function, maintenance requirements, calibration, equipment age, equipment location, and equipment hazards. We developed a mathematical model using these variables, and its result is interpreted as an index of equipment maintenance priority. The numerical output of the index was classified into three categories: high, medium, and low priority. We proposed our index model to technical staff at the Department of Biomedical Engineering of the National Institute of Respiratory Diseases in Mexico as a protocol for scheduling appropriate preventive maintenance for medical equipment during the year. The index was tested in a sample of 16 different medical equipment. Our model provides a guide to define the priority and the number of preventive maintenance routines required for medical equipment per year.


title: Clinical characteristics and risk factors of tigecycline-associated hypofibrinogenaemia in critically ill patients

text: PURPOSE: To analyze the clinical features and risk factors of tigecycline-associated hypofibrinogenaemia and study whether cefoperazone/sulbactam combined with tigecycline aggravates coagulopathy or hypofibrinogenaemia. METHODS: A retrospective case–control study of patients with severe infection who were treated with tigecycline was conducted. Patients were assigned to the hypofibrinogenaemia group (< 2.0 g/L) and normal fibrinogen (normal) group (≥ 2.0 g/L) to assess the clinical features of patients with tigecycline-associated hypofibrinogenaemia. The traits of patients treated with cefoperazone/sulbactam in the hypofibrinogenaemia group were also analyzed. RESULTS: In total, 127 patients were enrolled in the study, including 71 patients with hypofibrinogenaemia and 56 patients with normal fibrinogen levels. Hypofibrinogenaemia developed at a median of 6 (4–8) days after tigecycline treatment, and the fibrinogen level returned to normal at a median of 3 (3–5) days after tigecycline discontinuation. In the multivariate analysis, intra-abdominal infection (p = 0.005), fibrinogen level at tigecycline initiation (p < 0.001), maintenance dose (p = 0.039), and treatment duration (p = 0.002) were found to be related to hypofibrinogenaemia. Treatment with cefoperazone/sulbactam was not associated with hypofibrinogenaemia (p = 0.681), but patients treated with cefoperazone/sulbactam had a higher incidence of coagulopathy (p = 0.009) and needed more blood products (p = 0.003) than those treated without cefoperazone/sulbactam. CONCLUSION: Tigecycline-associated hypofibrinogenaemia often developed on the 6th (4th–8th) day of tigecycline use and was associated with intra-abdominal infection, fibrinogen level at tigecycline initiation, maintenance dose, and treatment duration of tigecycline but not cefoperazone/sulbactam.


title: What Would the Screen-and-Treat Strategy for Helicobacter pylori Mean in Terms of Antibiotic Consumption?

text: Several guidelines recommend the screen-and-treat strategy, i.e. active search for the presence of Helicobacter pylori infection and its eradication to prevent the possibility of gastric cancer. It is thought that a relatively short duration antibiotic regimen given once in a lifetime would not significantly increase overall antibiotic consumption. However, this would mean offering antibiotic treatment to the majority of the population in countries with the biggest burden of gastric cancer who would, therefore, have the greatest benefit from such a strategy. So far, no country has implemented an eradication strategy. With an example based on the current situation in Latvia, we have estimated the increase in antibiotic consumption if the screen-and-treat strategy was applied. Depending on the scenario that might be chosen, clarithromycin consumption would increase up to sixfold, and amoxicillin consumption would double if the recommendations of the current guideline in the local circumstances was applied. It appears that an increase in commonly used antibiotic consumption cannot be justified from the viewpoint of antibiotic stewardship policies. Solutions to this problem could be the use of antibiotics that are not required for treating life-threatening diseases or more narrow selection of the target group, e.g. young people before family planning to avoid transmission to offspring. Additional costs related to the increase in resistome should be considered for future cost-effectiveness modelling of the screen-and-treat strategy.


title: Train-Associated Injuries Pose a Significant Burden on Trauma Care Systems of Emerging Economies

text: BACKGROUND: The Indian railway system is the fourth largest in the world and causes about 15 deaths every day, due to intentional or unintentional reasons. This study presents a 5-year retrospective analysis of patients injured due to train-associated events, managed at a level-1 trauma center in India. MATERIALS AND METHODS: Hospital-based trauma registry data of train-associated injuries presenting between 2012 and 2016 were analyzed. Data from 726 patients were analyzed for demographics, injury events, injury regions, their management and outcomes. ISS and NISS were used to quantify the injury severity. RESULTS: Mean age was 33 years, with male-to-female ratio 86 to 14%. The majority of patients (62%) were between 20–40 years. The median ISS was 9 (IQR 4–16), median hospital stays 11 days (IQR6-23), with in-hospital mortality of 17.4%. Presence of head injury; ISS > 9 and CPR in ED were independent risk factors of mortality. Trespassers on the rail track had significantly more severe injuries compared to passengers (Median ISS 13 vs. 9, p = 0.012; Median NISS 22 vs.17, p = 0.015); however, mortality and hospital length of stay were not significantly different. Location of injury event (on platform or tracks) showed no difference between the severity of injuries, mortality and hospital length of stay. CONCLUSIONS: Current study reports comprehensive injury patterns and outcomes of train-associated injuries from a low- and middle-income country (LMIC). Apart from the mortality, there is a high incidence of permanent disabilities from extremity amputations. No significant difference was noted in the severity and outcomes among patients injured on or off train platforms, emphasizing the need for comprehensive safety measures including enforcement and promoting safe behavior not only on locations like train tracks but equally at platforms.


title: The effects of oral feeding while on nasal continuous positive airway pressure (NCPAP) in preterm infants

text: OBJECTIVE: To determine whether delaying oral feeding until coming off NCPAP will alter feeding and respiratory-related morbidities in preterm infants. DESIGN: In this retrospective pre–post analysis, outcomes were compared in two preterm infant groups (≤32 weeks gestation). Infants in Group 1 were orally fed while on NCPAP, while infants in Group 2 were only allowed oral feedings after ceasing NCPAP. RESULTS: Although infants in Group 2 started feeds at a later postmenstrual age (PMA), they reached full oral feeding at a similar PMA compared with Group 1. Interestingly, there was a positive correlation between the duration of oral feeding while on NCPAP and the time spent on respiratory support in Group 1. CONCLUSIONS: Delayed oral feeding until ceasing NCPAP did not contribute to feeding-related morbidities. We recommend caution when initiating oral feedings in preterm infants on NCPAP without evaluating the safety of the infants and their readiness for oral feedings.


title: An endotracheal tube providing “pressurized sealing” prevents fluid leakage in mechanically ventilated critically ill patients: a pilot study

text: Microaspiration of bacteriologically contaminated oropharyngeal secretions alongside the cuff of an endotracheal tube (ETT) is a key mechanism for development of ventilator-associated pneumonia. We have constructed a prototype double-cuffed ETT equipped with a supplemental port in-between the cuffs through which continuous positive airway pressure (CPAP) is delivered. Pressure in the intercuff space propels secretions upwards and produces 100% tracheal sealing in an in vitro model. We conducted a 24 h study to investigate the sealing effect of this ETT in 12 critically ill mechanically ventilated patients. Methylene blue, instilled through a bronchoscope on top of the proximal cuff, was used as leakage tracer. Fiberoptic visualisation of the trachea was performed 1 h and 24 h thereafter. Leakage was confirmed if blue dye was detected on the tracheal mucosa beyond the tip of the ETT. In no patient, dye passed by the cuffs during the study period. Presence of the ETT did not interfere with ventilator settings, patient mobilization, physiotherapy, and technical acts. Overall, pressures in the intercuff space remained between 10 and 15 cmH(2)O. Excessive pressure swings were swiftly corrected by the CPAP system. A double-cuffed ETT, offering “pressurized sealing” of the trachea, safely and effectively prevented leakage during 24 h mechanical ventilation.


title: Pre-admission air pollution exposure prolongs the duration of ventilation in intensive care patients

text: PURPOSE: Air pollutant exposure constitutes a serious risk factor for the emergence or aggravation of (existing) pulmonary disease. The impact of pre-intensive care ambient air pollutant exposure on the duration of artificial ventilation was, however, not yet established. METHODS: The medical records of 2003 patients, admitted to the intensive care unit (ICU) of the Antwerp University Hospital (Flanders, Belgium), who were artificially ventilated on ICU admission or within 48 h after admission, for the duration of at least 48 h, were analyzed. For each patient’s home address, daily air pollutant exposure [particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM(2.5)) and ≤ 10 µm (PM(10)), nitrogen dioxide (NO(2)) and black carbon (BC)] up to 10 days prior to hospital admission was modeled using a high-resolution spatial–temporal model. The association between duration of artificial ventilation and air pollution exposure during the last 10 days before ICU admission was assessed using distributed lag models with a negative binomial regression fit. RESULTS: Controlling for pre-specified confounders, an IQR increment in BC (1.2 µg/m(3)) up to 10 days before admission was associated with an estimated cumulative increase of 12.4% in ventilation duration (95% CI 4.7–20.7). Significant associations were also observed for PM(2.5), PM(10) and NO(2), with cumulative estimates ranging from 7.8 to 8.0%. CONCLUSION: Short-term ambient air pollution exposure prior to ICU admission represents an unrecognized environmental risk factor for the duration of artificial ventilation in the ICU. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-05999-3) contains supplementary material, which is available to authorized users.


title: Refractory and Super-refractory Status Epilepticus

text: CONTEXT: Refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) are neurological emergencies with considerable mortality and morbidity. In this paper, we provide an overview of causes, evaluation, treatment, and consequences of RSE and SRSE, reflecting the lack of high-quality evidence to inform therapeutic approach. SOURCES: This is a narrative review based on personal practice and experience. Nevertheless, we searched MEDLINE (using PubMed and OvidSP vendors) and Cochrane central register of controlled trials, using appropriate keywords to incorporate recent evidence. RESULTS: Refractory status epilepticus is commonly defined as an acute convulsive seizure that fails to respond to two or more anti-seizure medications including at least one nonbenzodiazepine drug. Super-refractory status epilepticus is a status epilepticus that continues for ≥24 hours despite anesthetic treatment, or recurs on an attempted wean of the anesthetic regimen. Both can occur in patients known to have epilepsy or de novo, with increasing recognition of autoimmune and genetic causes. Electroencephalography monitoring is essential to monitor treatment response in refractory/super-refractory status epilepticus, and to diagnose non-convulsive status epilepticus. The mainstay of treatment for these disorders includes anesthetic infusions, primarily midazolam, ketamine, and pentobarbital. Dietary, immunological, and surgical treatments are viable in selected patients. Management is challenging due to multiple acute complications and long-term adverse consequences. CONCLUSIONS: We have provided a synopsis of best practices for diagnosis and management of refractory/superrefractory status epilepticus and highlighted the lack of sufficient high-quality evidence to drive decision making, ending with a brief foray into avenues for future research.


title: A physiology-based mathematical model for the selection of appropriate ventilator controls for lung and diaphragm protection

text: Mechanical ventilation is used to sustain respiratory function in patients with acute respiratory failure. To aid clinicians in consistently selecting lung- and diaphragm-protective ventilation settings, a physiology-based decision support system is needed. To form the foundation of such a system, a comprehensive physiological model which captures the dynamics of ventilation has been developed. The Lung and Diaphragm Protective Ventilation (LDPV) model centers around respiratory drive and incorporates respiratory system mechanics, ventilator mechanics, and blood acid–base balance. The model uses patient-specific parameters as inputs and outputs predictions of a patient’s transpulmonary and esophageal driving pressures (outputs most clinically relevant to lung and diaphragm safety), as well as their blood pH, under various ventilator and sedation conditions. Model simulations and global optimization techniques were used to evaluate and characterize the model. The LDPV model is demonstrated to describe a CO(2) respiratory response that is comparable to what is found in literature. Sensitivity analysis of the model indicate that the ventilator and sedation settings incorporated in the model have a significant impact on the target output parameters. Finally, the model is seen to be able to provide robust predictions of esophageal pressure, transpulmonary pressure and blood pH for patient parameters with realistic variability. The LDPV model is a robust physiological model which produces outputs which directly target and reflect the risk of ventilator-induced lung and diaphragm injury. Ventilation and sedation parameters are seen to modulate the model outputs in accordance with what is currently known in literature. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10877-020-00479-x) contains supplementary material, which is available to authorized users.


title: Trends in 3D Printing Processes for Biomedical Field: Opportunities and Challenges

text: [Image: see text]


title: Dendritic cells and Brucella spp. interaction: the sentinel host and the stealthy pathogen

text: As dendritic cells (DCs) are among the first cells to encounter antigens, these cells trigger both innate and T cell responses, and are the most potent antigen-presenting cells. Brucella spp., which is an intracellular facultative and stealthy pathogen, is able to evade the bactericidal activities of professional phagocytes. Several studies have demonstrated that Brucella can survive and replicate intracellularly, thereby provoking impaired maturation of DCs. Therefore, the interaction between DCs and Brucella becomes an interesting model to study the immune response. In this review, we first will describe the most common techniques for DCs differentiation in vitro as well as general features of brucellosis. Then, the interaction of DCs and Brucella, including pathogen recognition, molecular mechanisms of bacterial pathogenesis, and intracellular trafficking of Brucella to subvert innate response, will be reviewed. Finally, we will debate diversity in immunological DC response and the controversial role of DC activation against Brucella infection.


title: Epitope Prediction by Novel Immunoinformatics Approach: A State-of-the-art Review

text: Immunoinformatics is a science that helps to create significant immunological information using bioinformatics softwares and applications. One of the most important applications of immunoinformatics is the prediction of a variety of specific epitopes for B cell recognition and T cell through MHC class I and II molecules. This method reduces costs and time compared to laboratory tests. In this state-of-the-art review, we review about 50 papers to find the latest and most used immunoinformatic tools as well as their applications for predicting the viral, bacterial and tumoral structural and linear epitopes of B and T cells. In the clinic, the main application of prediction of epitopes is for designing peptide-based vaccines. Peptide-based vaccines are a considerably potential alternative to low-cost vaccines that may reduce the risks related to the production of common vaccines.


title: Integrating nanoparticle quantification and statistical design of experiments for efficient HIV-1 virus-like particle production in High Five cells

text: The nature of enveloped virus-like particles (VLPs) has triggered high interest in their application to different research fields, including vaccine development. The baculovirus expression vector system (BEVS) has been used as an efficient platform for obtaining large amounts of these complex nanoparticles. To date, most of the studies dealing with VLP production by recombinant baculovirus infection utilize indirect detection or quantification techniques that hinder the appropriate characterization of the process and product. Here, we propose the application of cutting-edge quantification methodologies in combination with advanced statistical designs to exploit the full potential of the High Five/BEVS as a platform to produce HIV-1 Gag VLPs. The synergies between CCI, MOI, and TOH were studied using a response surface methodology approach on four different response functions: baculovirus infection, VLP production, VLP assembly, and VLP productivity. TOH and MOI proved to be the major influencing factors in contrast with previous reported data. Interestingly, a remarkable competition between Gag VLP production and non-assembled Gag was detected. Also, the use of nanoparticle tracking analysis and flow virometry revealed the existence of remarkable quantities of extracellular vesicles. The different responses of the study were combined to determine two global optimum conditions, one aiming to maximize the VLP titer (quantity) and the second aiming to find a compromise between VLP yield and the ratio of assembled VLPs (quality). This study provides a valuable approach to optimize VLP production and demonstrates that the High Five/BEVS can support mass production of Gag VLPs and potentially other complex nanoparticles. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00253-019-10319-x) contains supplementary material, which is available to authorized users.