title: Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation

text: The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a ‘disarming’ strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.


Author Correction: A Engineered immunogen binding to alum adjuvant enhances humoral immunity


title: Severe blunt trauma in Finland and Estonia: comparison of two regional trauma repositories

text: PURPOSE: Evolving trauma system of Estonia has undergone several reforms; however, performance and outcome indicators have not been benchmarked previously. Thus, we initiated a baseline study to compare demographics, management and outcomes of severely injured patients between Southern Finland and Northern Estonia utilizing regional trauma repositories. METHODS: A comparison of data fields of the Helsinki University Hospital trauma registry (HTR) and trauma registry at the North Estonia Medical Centre in Tallinn (TTR) between 1/1/2015 and 31/12/2016 was performed. The inclusion criterion was Injury Severity Score > 15. Transferred patients, patients with penetrating injuries, and pediatric patients were excluded. The data for comparison included demographics, Trauma Score-Injury Severity Score (TRISS), mortality, and standardized mortality ratio (SMR). Primary outcome was mortality and SMR per TRISS methodology. RESULTS: During the 2-year study period, 324 patients from the HTR and 152 from the TTR were included. Demographic profile was similar between the repositories with the exception of severe abdominal injuries being more prevalent at the TTR (25.0% vs. 13.3%, p = 0.002). Predominant injury mechanism was non-ground level fall in both repositories. Mortality was similar at 14.5% and 13.6% at the TTR and HTR, respectively (adj. p = 0.762; OR 1.13, 95% CI 0.64–1.99). SMR was lower at the HTR compared to the TTR (0.65 vs. 0.77, p > 0.05), however, the difference did not reach statistical significance. CONCLUSION: Benchmarking trauma repositories at a national level provides opportunities for quality and performance improvements. We observed comparable demographic profile and outcome indicators in the compared regional trauma systems.


title: Canine parvovirus 2b in fecal samples of asymptomatic free-living South American coatis (Nasua nasua, Linnaeus, 1766)

text: Canine parvovirus type 2 (CPV-2) is classified into three subtypes (CPV-2a, CPV-2b, and CPV-2c) and is the main cause of enteritis and myocarditis in young domestic and wild animals. This study aimed to evaluate the presence of CPV-2 in the feces of asymptomatic free-living coatis from Garden Forest Reserve, Palmital city, SP, Brazil. Fecal samples from 21 coatis (both sexes, different ages, and different aspects of feces) were collected in August 2014 and March 2015. The nucleic acid extracted was submitted to a polymerase chain reaction (PCR) assay to amplify a fragment of the VP2 gene of CPV-2. Eight (38%) fecal samples were positive in the PCR assay and were confirmed by sequencing. The 7 nucleotide (nt) sequences analyzed showed 100% nt identity with the prototype strain of CPV-2b (CPV-39 strain). The analysis of the deduced amino acid (aa) sequence revealed the presence of the GAT codon (aa D-Asp) at position 426 of the VP2 viral protein (subtype 2b). This study describes for the first time the identification of CPV-2b in asymptomatic free-living coatis (Nasua nasua) and suggests that coatis are susceptible to Carnivore protoparvovirus 1 infection and are important as a reservoir and an asymptomatic carrier to other wild and domestic animal species.


title: Complex abdominal wall hernia repair with biologic mesh in elderly: a propensity matched analysis

text: BACKGROUND: Complex abdominal wall reconstruction (CAWR) has become a common surgical procedure both in non-elderly and elderly patients. OBJECTIVE: The aim of this study is to analyze the outcomes of the elderly compared to nonelderly undergoing CAWR using propensity score matching. METHODS: All patients who underwent CAWR using porcine-derived, non-crosslinked acellular dermal matrix (ADM) (Strattice™) between January 2014 and July 2017 were studied retrospectively. Propensity matched analysis was performed for risk adjustment in multivariable analysis and for one-to-one matching. The outcomes were analyzed for differences in postoperative complications, reoperations, mortality, hospital length of stay and adverse discharge disposition. RESULTS: One hundred-thirty-six patients were identified during the study period. Non-elderly (aged 18–64 years) constituted 70% (n = 95) and elderly (aged ≥ 65 years) comprised 30% of the overall patient population (n = 41). Seventy-three (56.7%) were females. After adjustment through the propensity score, which included 35 pairs, the surgical site infection (p = 1.000), wound necrosis (p = 1.000), the need for mechanical ventilation (p = 0.259), mortality (p = 0.083), reoperation rate (p = 0.141), hospital length of stay (p = 0.206), and discharge disposition (p = 0.795) were similar. CONCLUSION: Elderly patients undergoing CAWR with biological mesh have comparable outcomes with non-elderly patients when using propensity matching score.


title: Surfactant replacement therapy: from biological basis to current clinical practice

text: This review summarizes the current knowledge on the physiological action of endogenous and exogenous pulmonary surfactant, the role of different types of animal-derived and synthetic surfactants for RDS therapy, different modes of administration, potential risks and strategies of ventilation, and highlights the most promising aims for future development. Scientists have clarified the physicochemical properties and functions of the different components of surfactant, and part of this successful research is derived from the characterization of genetic diseases affecting surfactant composition or function. Knowledge from functional tests of surfactant action, its immunochemistry, kinetics and homeostasis are important also for improving therapy with animal-derived surfactant preparations and for the development of modified surfactants. In the past decade newly designed artificial surfactants and additives have gained much attention and have proven different advantages, but their particular role still has to be defined. For clinical practice, alternative administration techniques as well as postsurfactant ventilation modes, taking into account alterations in lung mechanics after surfactant placement, may be important in optimizing the potential of this most important drug in neonatology.


title: Longer term hemodialysis-dependent chronic renal failure increases the risk of post-cardiac surgery vasoplegic syndrome

text: PURPOSE: We evaluated whether longer term hemodialysis (HD) is associated with a higher incidence of vasoplegic syndrome (VS) after cardiac surgery. METHODS: This retrospective, single-center cohort study included 562 consecutive patients who underwent cardiac surgery in a tertiary hospital from January 2015 to December 2016. We assessed VS occurrence and its relationship with HD duration and other risk factors. To assess the effect of the HD duration on VS occurrence, we constructed ordinal variables: HD = 0 (non-HD), 0 < HD ≤ 5 (HD ≤ 5 years), 5 < HD ≤ 10, and 10 < HD. RESULTS: The overall mean (± standard deviation) age of patients was (73 ± 11) years, and there were 60.9% men. Forty-one patients (7.3%) were HD dependent. Cardiac surgeries included all coronary artery bypass graft procedures, all valvular procedures, and aortic surgery involving cardiopulmonary bypass (CPB). Sixty-six patients (10%) developed VS. Most preoperative patient characteristics were comparable between the VS and no-VS groups; a chronic HD status and a total CPB time of > 180 min were significantly more common in the VS group (P < 0.0001 and P = 0.02, respectively). Longer term HD significantly correlated with VS incidence (P < 0.0001). Ordinal variables for the HD duration and age and known risk factors for VS (preoperative use of angiotensin-converting enzyme inhibitors and beta-blockers, low left-ventricular ejection fraction, and CPB time > 180 min) were subjected to multivariate regression analysis. Long-term HD was identified as an independent predictor of VS (odds ratio, 2.29, 95% confidence interval, 1.66–3.18). CONCLUSIONS: Longer term HD may be associated with a higher VS incidence after cardiac surgery. VS should be given attention after cardiac surgery in chronic HD-dependent patients.


title: A multi-epitope plant-made chimeric protein (LTBentero) targeting common enteric pathogens is immunogenic in mice

text: KEY MESSAGE: A plant-based multiepitopic protein (LTBentero) containing epitopes from ETEC, S. typhimurium, and V. parahaemolyticus was produced in plants cells and triggered systemic and intestinal humoral responses in immunized mice. ABSTRACT: Around 200 million people suffer gastroenteritis daily and more than 2 million people die annually in developing countries due to such pathologies. Vaccination is an alternative to control this global health issue, however new low-cost vaccines are needed to ensure proper vaccine coverage. In this context, plants are attractive hosts for the synthesis and delivery of subunit vaccines. Therefore, in this study a plant-made multiepitopic protein named LTBentero containing epitopes from antigens of enterotoxigenic E. coli, S. typhimurium, and V. parahaemolyticus was produced and found immunogenic in mice. The LTBentero protein was expressed in tobacco plants at up to 5.29 µg g(−1) fresh leaf tissue and was deemed immunogenic when administered to BALB/c mice either orally or subcutaneously. The plant-made LTBentero antigen induced specific IgG (systemic) and IgA (mucosal) responses against LTB, ST, and LptD epitopes. In conclusion, multiepitopic LTBentero was functionally produced in plant cells, being capable to trigger systemic and intestinal humoral responses and thus it constitutes a promising oral immunogen candidate in the fight against enteric diseases.


title: Antibodies generated against dextransucrase exhibit potential anticariostatic properties in Streptococcus mutans

text: Streptococcus mutans is a common principal causative agent of dental caries. In this communication, we describe that the antibodies raised against purified dextransucrase effectively inhibited the growth of S. mutans. The purified enzyme showed 58-fold enrichment, 17.5% yield and a specific activity of 3.96 units/mg protein. Purified IgG fraction of the antibody showed significant affinity with the antigenic protein. Immunotritation of the enzyme with dextransucrase antibody showed a gradual increase in inhibition of dextransucrase activity. The growth of S. mutans was also inhibited by 85% in the presence of 28 μg of IgG fraction of the antibody. Antibodies also impaired glucosyltransferase activity (72.8%) and biofilm formation by 92.6% in S. mutans. Western blot analysis revealed no cross reactivity with the various tissues of mice, rat, rabbit and humans. Dot blot analysis showed little reactivity with Lactobacillus acidophilus and Staphylococcus aureus and there was no reactivity with other bacterial strains like Enterococcus faecalis, Escherichia coli and Salmonella typhimurium. These findings suggest that antibody raised against dextransucrase exhibit inhibitory effects on the growth of S. mutans and biofilm formation with no reactivity with various mammalian tissues, thus it could be an effective anticariogenic agent.


title: Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)

text: Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time propose and investigate local application of atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles (SLNs), as self-administrable eye drops. Insolubility, instability, and high molecular weight > 500 of ATS, and ensuring that SLNs reach posterior eye were the challenges to be met. ATS-SLNs, developed (2339/DEL/2014) using suitable components, quality-by-design (QBD) approach, and scalable hot high-pressure homogenization, were characterized and evaluated comprehensively for ocular suitability. ATS-SLNs were 8 and 12 times more bioavailable (AUC) in aqueous and vitreous humor, respectively, than free ATS. Three-tier (in vitro, ex vivo, and in vivo) ocular safety, higher corneal flux (2.5-fold), and improved stability (13.62 times) including photostability of ATS on incorporation in ATS-SLNs were established. Autoclavability and aqueous nature are the other highlights of ATS-SLNs. Presence of intact fluorescein-labeled SLNs (F-SLNs) in internal eye tissues post–in vivo application as eye drops provides direct evidence of successful delivery. Perinuclear fluorescence in ARPE-19 cells confirms the effective uptake of F-SLNs. Prolonged residence, up to 7 h, was attributed to the mucus-penetrating nature of ATS-SLNs. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13346-020-00733-4) contains supplementary material, which is available to authorized users.


title: Bacterial vaccines in poultry

text: BACKGROUND: Poultry bacterial pathogens are mainly controlled by using high-cost sanitary measures and medical treatment. However, the drug-resistant strains of pathogens continuously emerge, and medical treatments are often ineffective. Moreover, there is increasing public objections to drug residues in poultry products. The other important type of control is the vaccination which depends on immunity. This immunological control is the major practical alternative to chemotherapy. Success of vaccines in combating poultry diseases depends mainly on the choice of the proper type of vaccines, correct time of its usage, and method of administration. The types of vaccines include attenuated live vaccines, and these vaccines were shown to be effective in inducing protection. The second type is killed vaccine or whole bacteria extracts which is less successful in providing protection compared to live vaccines. The metabolic product vaccine (toxoids) is the third type of vaccine. The recombinant DNA technique was adopted to produce the protective antigens in a sufficient amount and in cost-effective ways. CONCLUSIONS: Protection studies against bacterial diseases were performed by using several trials: living vaccines (live attenuated vaccines; live, non-pathogenic microorganisms; live, low virulence microorganism), inactivated (killed) vaccines (heat-inactivated, chemical inactivates, radiation), metabolic product vaccines (toxoids), subunit vaccines (whole cell proteins, outer membrane proteins, purified flagellar proteins (flagellin), fimbrial proteins, pilus proteins, lipopolysaccharides), vaccines produced by recombinant deoxyribonucleic acid (DNA) technology, and DNA vaccines.


title: Nicorandil, a K(ATP) Channel Opener, Attenuates Ischemia–Reperfusion Injury in Isolated Rat Lungs

text: PURPOSE: Nicorandil is a hybrid between nitrates and K(ATP) channel opener activators. The aim of this study was to evaluate the nicorandil’s effects on ischemia–reperfusion (IR) lung injury and examine the mechanism of its effects. METHODS: Isolated rat lungs were divided into 6 groups. In the sham group, the lungs were perfused and ventilated for 150 min. In the IR group, after perfusion and ventilation for 30 min, they were interrupted (ischemia) for 60 min, and then resumed for 60 min. In the nicorandil (N) + IR group, nicorandil 6 mg was added before ischemia (nicorandil concentration was 75 µg ml(−1)). In the glibenclamide + N + IR group, the L-NAME (N(ω)-Nitro-l-arginine methyl ester) + N + IR group and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) + N + IR group, glibenclamide 3 µM, L-NAME 100 µM, and ODQ 30 µM were added 5 min before nicorandil administration, respectively. We measured the coefficient of filtration (Kfc) of the lungs, total pulmonary vascular resistance, and the wet-to-dry lung weight ratio (WW/DW ratio). RESULTS: Kfc was significantly increased after 60 min reperfusion compared with baseline in the IR group, but no change in the sham group. An increase in Kfc was inhibited in the N + IR group compared with the IR group (0.92 ± 0.28 vs. 2.82 ± 0.68 ml min(−1) mmHg(−1) 100 g(−1); P < 0.01). Also, nicorandil attenuated WW/DW ratio was compared with IR group (8.3 ± 0.41 vs. 10.9 ± 2.5; P < 0.05). Nicorandil’s inhibitory effect was blocked by glibenclamide and ODQ (P < 0.01), but not by L-NAME. CONCLUSIONS: Nicorandil attenuated IR injury in isolated rat lungs. This protective effect appears to involve its activation as K(ATP) channel opener as well as that of the sGC-cGMP pathway.


title: Is Protocolised Weaning that Includes Early Extubation Onto Non-Invasive Ventilation More Cost Effective Than Protocolised Weaning Without Non-Invasive Ventilation? Findings from the Breathe Study

text: BACKGROUND: Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. OBJECTIVES: Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. METHODS: We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. RESULTS: NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58% that NIV is cost effective. The probability that NIV is cost effective was higher for those with COPD (84%). NIV was cost effective over 5 years, with an estimated incremental cost-effectiveness ratio of £4618 ($US6594 per QALY gained). CONCLUSIONS: The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s41669-020-00210-1) contains supplementary material, which is available to authorized users.


title: Coinfection, Altered Vector Infectivity, and Antibody-Dependent Enhancement: The Dengue–Zika Interplay

text: Although dengue and Zika cocirculation has increased within the past 5 years, very little is known about its epidemiological consequences. To investigate the effect of dengue and Zika cocirculation on the spread of both pathogens, we create a deterministic dengue and Zika coinfection model, the first to incorporate altered infectivity of mosquitoes (due to coinfection). The model also addresses increased infectivity due to antibody-dependent enhancement (ADE) within the human population. Central to our analysis is the derivation and interpretation of the basic reproductive number and invasion reproductive number of both pathogens. In addition, we investigate how model parameters impact the persistence of each disease. Our results identify threshold conditions under which one disease facilitates the spread of the other and show that ADE has a greater impact on disease persistence than altered vector infectivity. This work highlights the importance of ADE and illustrates that while the endemic presence of dengue facilitates the spread of Zika, it is possible for high Zika prevalence to prevent the establishment of dengue.


title: Event-Driven ECG Sensor in Healthcare Devices for Data Transfer Optimization

text: The long-term monitoring of cardiovascular signs requires a wearable and connected electrocardiogram (ECG) healthcare device. It increases user’s comfort and diagnosis quality of chronic cardiac and/or high-risk patients. This paper covers the enormous data to be transmitted from the ECG device to the physician’s, namely the cardiologist’s, control unit. Existent ECG devices uniformly sample analog signals and convert them to digital samples which are compressed before data transmission. However, event-driven sampling simultaneously compresses and samples. Therefore, this paper quantitatively compares successive approximation register analog-to-digital converter (SAR ADC) with discrete wavelet transform (DWT) compression and level-crossing analog-to-digital converter (LC-ADC). Evaluation metrics are the percent root-mean-square difference ([Formula: see text] ), bit compression ratio ([Formula: see text] ) and data length in bits. When a 12-bit reconstruction is operated on the outputs of an 8-bit LC-ADC with 12-bit and 10-kHz reference counter, the [Formula: see text] is equal to 80% for 75% of test ECG signals. That is better than the 71.87% [Formula: see text] of the 12-bit 1-kHz SAR ADC with DWT compression. The modeled LC-ADC guarantees a signal quality in terms of [Formula: see text] comparable to the [Formula: see text] of the SAR ADC with DWT compression. The data length in bits of the LC-ADC is lower than the data length in bits of the SAR ADC with more than 14-bit resolution with DWT compression for 82% of the test ECG signals. However, for lower resolutions, to obtain lower power consumption for radiofrequency transmission, a better alternative remains the SAR ADC with DWT compression.


title: In silico prediction of toxicity and its applications for chemicals at work

text: OBJECTIVE AND METHODS: This study reviewed the concept of in silico prediction of chemical toxicity for prevention of occupational cancer and future prospects in workers’ health. In this review, a new approach to determine the credibility of in silico predictions with raw data is explored, and the method of determining the confidence level of evaluation based on the credibility of data is discussed. I searched various papers and books related to the in silico prediction of chemical toxicity and carcinogenicity. The intention was to utilize the most recent reports after 2015 regarding in silico prediction. RESULTS AND CONCLUSION: The application of in silico methods is increasing with the prediction of toxic risks to human and the environment. The various toxic effects of industrial chemicals have triggered the recognition of the importance of using a combination of in silico models in the risk assessments. In silico occupational exposure models, industrial accidents, and occupational cancers are effectively managed and chemicals evaluated. It is important to identify and manage hazardous substances proactively through the rigorous evaluation of chemicals.


title: Making Medical Decisions for Incapacitated Patients Without Proxies: Part II

text: In the United States, there is no consensus about who should make decisions in acute but non-emergent situations for incapacitated patients who lack surrogates. For more than a decade, our academic medical center has utilized community volunteers from the hospital ethics committee to engage in shared decision-making with the medical providers for these patients. In order to add a different point of view and minimize conflict of interest, the volunteers are non-clinicians who are not employed by the hospital. Using case examples and interviews with the community members, this paper describes how the protocol has translated into practice over the years since its inception. Members reported comfort with the role as well as satisfaction with the thoroughness of their discussions with the medical team. They acknowledged feelings of moral uncertainty, but expressed confidence in the process. Questions raised by the experience are discussed. Overall, the protocol has provided oversight, transparency, and protection from conflict of interest to the decision-making process for this vulnerable patient population.


The CSF Diversion via Lumbar Drainage to Treat Dialysis Disequilibrium Syndrome in the Critically Ill Neurological Patient


docid: lyvoajtd

title: Schistosomiasis—from immunopathology to vaccines

text: Schistosomiasis (bilharzia) is a neglected tropical disease caused by trematode worms of the genus Schistosoma. The transmission cycle involves human (or other mammalian) water contact with surface water contaminated by faeces or urine, as well as specific freshwater snails acting as intermediate hosts. The main disease-causing species are S. haematobium, S. mansoni and S. japonicum. According to the World Health Organisation, over 250 million people are infected worldwide, leading to considerable morbidity and the estimated loss of 1.9 million disability-adjusted life years (DALYs), a likely underestimated figure. Schistosomiasis is characterised by focal epidemiology and an over-dispersed population distribution, with higher infection rates in children. Complex immune mechanisms lead to the slow acquisition of immune resistance, but innate factors also play a part. Acute schistosomiasis, a feverish syndrome, is most evident in travellers following a primary infection. Chronic schistosomiasis affects mainly individuals with long-standing infections residing in poor rural areas. Immunopathological reactions against schistosome eggs trapped in host tissues lead to inflammatory and obstructive disease in the urinary system (S. haematobium) or intestinal disease, hepatosplenic inflammation and liver fibrosis (S. mansoni and S. japonicum). An effective drug—praziquantel—is available for treatment but, despite intensive efforts, no schistosomiasis vaccines have yet been accepted for public use. In this review, we briefly introduce the schistosome parasites and the immunopathogenic manifestations resulting from schistosomiasis. We then explore aspects of the immunology and host-parasite interplay in schistosome infections paying special attention to the current status of schistosomiasis vaccine development highlighting the advancement of a new controlled human challenge infection model for testing schistosomiasis vaccines.


Howard Grey 1932–2019


Accidental Burn in a Neonate in Neonatal Intensive Care Unit: What Could be the Cause?


title: Cognitive Function in Liver Transplantation

text: PURPOSE OF REVIEW: Liver transplantation (LT) remains the only way to cure patients with severe liver diseases. Important questions about neurological sequelae and quality of life after LT have emerged. In this review, we discuss the neurocognitive changes associated with LT and we conclude with recommendations in this regard for patients, caregivers, and physicians. RECENT FINDINGS: Compared with other solid organ recipients, LT patients tend to have a higher incidence (up to 30%) of neurological complications post-LT. Even in absence of previous episodes of hepatic encephalopathy (HE), some patients display new onset of neurological symptoms post-LT, raising the concern about the role of other factors that may have a direct impact on cognitive function. SUMMARY: Different mechanisms have been postulated to explain these postoperative neurological symptoms. They include sequelae of HE, persistent impairment of cognitive function due to cirrhosis, or postoperative decompensation of an unknown or undiagnosed neurodegenerative disorder.


title: Immunogenicity noninferiority study of 2 doses and 3 doses of an Escherichia coli-produced HPV bivalent vaccine in girls vs. 3 doses in young women

text: A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9–14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15–17 years (n=149) and women aged 18–26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9–17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9–14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1007/s11427-019-9547-7 and is accessible for authorized users.


title: Study of the Binding Pattern of HLA Class I Alleles of Indian Frequency and cTAP Binding Peptide for Chikungunya Vaccine Development

text: Chikungunya is a mosquito-borne disease, caused by the member of the Togaviridae family belongs to the genus alphavirus, making it a major threat in all developing countries as well as some developed countries. The mosquito acts as a vector for the disease and carries the CHIK-Virus. To date there is no direct treatment available and that demands the development of more effective vaccines. In this study author employed Immune Epitope Database and Analysis Resource, a machine learning-based algorithm principally working on the Artificial Neural Network (ANN) algorithm, also known as (IEDB-ANN) for the prediction and analysis of Epitopes. A total of 173 epitopes were identified on the basis of IC50 values, among them 40 epitopes were found, sharing part with the linear B-cell epitopes and exposed to the cTAP1protein, and out of 40, 6 epitopes were noticed to show interactions with the cTAP with their binding energy ranging from − 3.61 to − 1.22 kcal/mol. The six epitopes identified were exposed to the HLA class I alleles and from this all revealed interaction with the HLA alleles and minimum binding energy that ranges from − 4.12 to − 5.88 kcal/mol. Besides, two T cell epitopes i.e. (145)KVFTGVYPE(153) and (395)STVPVAPPR(403) were found most promiscuous candidates. These promiscuous epitopes-HLA complexes were further analyzed by the molecular dynamics simulation to check the stability of the complex. Results obtained from this study suggest that the identified epitopes i.e. and (395)STVPVAPPR(403), are likely to be capable of passing through the lumen of ER to bind withthe HLA class I allele and provide new insights and potential application in the designing and development of peptide-based vaccine candidate for the treatment of chikungunya.


docid: rhwnjnif

title: Xentry-Gap19 inhibits Connexin43 hemichannel opening especially during hypoxic injury

text: Hypoxic injury results in cell death, tissue damage and activation of inflammatory pathways. This is mediated by pathological Connexin43 (Cx43) hemichannel (HC) opening resulting in osmotic and ionic imbalances as well as cytokine production perpetuating the inflammatory environment. Gap19 is an intracellularly acting Cx43 mimetic peptide that blocks HC opening and thus promotes cell survival. However, native Gap19, which must enter the cell in order to function, exhibits low cell permeability. In this study, Gap19 was conjugated to the cell-penetrating peptide, Xentry, to investigate if cellular uptake could be improved while maintaining peptide function. Cellular uptake of Xentry-Gap19 (XG19) was much greater than that of native Gap19 even under normal cell culture conditions. Peptide function was maintained post uptake as shown by reduced ethidium homodimer influx and ATP release due to Cx43 HC block. While XG19 blocked pathologic HC opening though, normal gap junction communication required for cell repair and survival mechanisms was not affected as shown in a dye scrape-load assay. Under hypoxic conditions, increased expression of Syndecan-4, a plasma membrane proteoglycan targeted by Xentry, enabled even greater XG19 uptake leading to higher inhibition of ATP release and greater cell survival. This suggests that XG19, which is targeted specifically to hypoxic cells, can efficiently and safely block Cx43 HC and could therefore be a novel treatment for hypoxic and inflammatory diseases. [Figure: see text]


title: An unusual case of Aspergillus endocarditis of native aortic valve following ECMO

text: Fungal endocarditis following Extracorporeal membrane oxygenation (ECMO) is rare and very rarely reported. Though rare it has a high mortality rate. A 49-year-old male patient who had venovenous ECMO presented with aortic valve endocarditis after 40 days. He underwent sutureless bioprosthehtic valve placement and debridement of abscess. Abscess fluid grew aspergillus species and was started on dual antifungal intravenous amphotericin and variconazole. He was discharged after 1 month with oral variconazole. Incidence of aseptic endocarditis (AE) has been on rise due to increase in invasive procedures. Blood culture is mostly sterile, and fever may be absent. Abscess debridement and aggressive dual antifungal treatment helped our patient in his road to recovery. In current era with increasing use of ECMO, newer rarer complications should be kept in mind. High index of suspicion is required for diagnosing fungal endocarditis after ECMO.


title: Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

text: Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.


Intensivist coverage and patient outcomes


title: What drives change in neonatal intensive care units? A qualitative study with physicians and nurses in six European countries

text: BACKGROUND: Innovation is important to improve patient care, but few studies have explored the factors that initiate change in healthcare organizations. METHODS: As part of the European project EPICE on evidence-based perinatal care, we carried out semi-structured interviews (N = 44) with medical and nursing staff from 11 randomly selected neonatal intensive care units in 6 countries. The interviews focused on the most recent clinical or organizational change in the unit relevant to the care of very preterm infants. Thematic analysis was performed using verbatim transcripts of recorded interviews. RESULTS: Reported changes concerned ventilation, feeding and nutrition, neonatal sepsis, infant care, pain management and care of parents. Six categories of drivers to change were identified: availability of new knowledge or technology; guidelines or regulations from outside the unit; need to standardize practices; participation in research; occurrence of adverse events; and wish to improve care. Innovations originating within the unit, linked to the availability of new technology and seen to provide clear benefit for patients were more likely to achieve consensus and rapid implementation. CONCLUSIONS: Innovation can be initiated by several drivers that can impact on the success and sustainability of change.


title: Production and immunogenicity of Fubc subunit protein redesigned from DENV envelope protein

text: Dengue virus (DENV) is a vector-borne human pathogen that usually causes dengue fever; however, sometime it leads to deadly complications such as dengue with warning signs (DWS+) and severe dengue (SD). Several studies have shown that fusion (Fu) and bc loop of DENV envelope domain II are highly conserved and consist some of the most dominant antigenic epitopes. Therefore, in this study, Fu and bc loops were joined together to develop a short recombinant protein as an alternative of whole DENV envelope protein, and its immunogenic potential as fusion peptide was estimated. For de novo designing of the antigen, Fu and bc peptides were linked with an optimised linker so that the three dimensional conformation was maintained as it is in DENV envelope protein. The redesigned Fubc protein was expressed in E. coli and purified. Subsequently, structural integrity of the purified protein was verified by CD spectroscopy. To characterise immune responses against recombinant Fubc protein, BALB/c mice were subcutaneously injected with emulsified antigen preparation. It was observed by ELISA that Fubc fusion protein elicited higher serum IgG antibody response either in the presence or in absence of Freund’s adjuvant in comparison to the immune response of Fu and bc peptides separately. Furthermore, the binding of Fubc protein with mice antisera was validated by SPR analysis. These results suggest that Fu and bc epitope-based recombinant fusion protein could be a potential candidate towards the development of the effective subunit vaccine against DENV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00253-020-10541-y) contains supplementary material, which is available to authorized users.


title: Seasonal and pandemic influenza: 100 years of progress, still much to learn

text: Influenza viruses are highly transmissible, both within and between host species. The severity of the disease they cause is highly variable, from the mild and inapparent through to the devastating and fatal. The unpredictability of epidemic and pandemic outbreaks is accompanied but the predictability of seasonal disease in wide areas of the Globe, providing an inexorable toll on human health and survival. Although there have been great improvements in understanding influenza viruses and the disease that they cause, our knowledge of the effects they have on the host and the ways that the host immune system responds continues to develop. This review highlights the importance of the mucosa in defence against infection and in understanding the pathogenesis of disease. Although vaccines have been available for many decades, they remain suboptimal in needing constant redesign and in only providing short-term protection. There are real prospects for improvement in treatment and prevention of influenza soon, based on deeper knowledge of how the virus transmits, replicates and triggers immune defences at the mucosal surface.


title: Early Surgical Closure of Atrial Septal Defect Improves Clinical Status of Symptomatic Young Children with Underlying Pulmonary Abnormalities

text: Elective closure of atrial septal defect (ASD) is usually recommended during preschool ages. However, ASD may contribute to deteriorating health in the presence of significant comorbidity and, thus, may need earlier closure. There is a lack of clarity regarding the indications for and outcomes after ASD closure in infancy and early childhood. We investigated the benefits and safety of surgical ASD closure in symptomatic patients under 2 years of age. Retrospective chart review was conducted in patients who underwent surgical ASD closure within the first 2 years of life. Of 31 symptomatic ASD patients, 22 had persistent respiratory symptoms, 24 failure to thrive, and 9 pulmonary hypertension. Overall, 26 patients (84.0%) showed clinical improvement after ASD closure, including improved respiratory status (17/22; 77.3%), resumption of normal growth (15/24; 62.5%), and resolution of pulmonary hypertension (7/7; 100%, 2 patients unable to assess postoperatively). Two medically complicated patients died a few months after surgery unrelated to surgical complications. Four out of 8 ventilator-dependent patients were weaned from mechanical ventilation within 1 month after ASD closure. Closure of ASD did not improve those patients with highly advanced lung disease and/or medically complex conditions including underlying genetic abnormalities. Surgical complications were uncommon. Postoperative hospital stay was 4 to 298 days (median 8 days). The majority of our patients demonstrated significant clinical improvement after ASD closure. Early ASD closure is safe and beneficial for symptomatic infants and young children with associated underlying pulmonary abnormalities, especially bronchopulmonary dysplasia.


title: Higher virulence of swine H1N2 influenza viruses containing avian-origin HA and 2009 pandemic PA and NP in pigs and mice

text: Pigs are capable of harbouring influenza A viruses of human and avian origin in their respiratory tracts and thus act as an important intermediary host to generate novel influenza viruses with pandemic potential by genetic reassortment between the two viruses. Here, we show that two distinct H1N2 swine influenza viruses contain avian-like or classical swine-like hemagglutinins with polymerase acidic (PA) and nucleoprotein (NP) genes from 2009 pandemic H1N1 influenza viruses that were found to be circulating in Korean pigs in 2018. Swine H1N2 influenza virus containing an avian-like hemagglutinin gene had enhanced pathogenicity, causing severe interstitial pneumonia in infected pigs and mice. The mortality rate of mice infected with swine H1N2 influenza virus containing an avian-like hemagglutinin gene was higher by 100% when compared to that of mice infected with swine H1N2 influenza virus harbouring classical swine-like hemagglutinin. Further, chemokines attracting inflammatory cells were strongly induced in lung tissues of pigs and mice infected by swine H1N2 influenza virus containing an avian-like hemagglutinin gene. In conclusion, it is necessary for the well-being of humans and pigs to closely monitor swine influenza viruses containing avian-like hemagglutinin with PA and NP genes from 2009 pandemic H1N1 influenza viruses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-020-04572-z) contains supplementary material, which is available to authorized users.


title: Comparing MMPI-2-Restructured Form Scores by Service Era for Veterans Assessed Within the Veteran Affairs Healthcare System

text: This study compares profiles of Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) scale scores from 1492 VA test-takers who served during the Vietnam or Gulf War service eras. The sample includes all such cases collected at any VA posttraumatic stress disorder Clinical Teams across the United States between January 1, 2008 and May 31, 2015 using the MMPI-2 or MMPI-2-RF (via the VA Mental Health Assistant suite). Associations between gender and score differences were also examined. In contrast to past research using the MMPI-2, results of this study suggest that veterans are generally homogeneous in their MMPI-2-RF profiles across different periods of service. Specifically, the magnitudes of mean differences are small and not clinically significant. Thus, responses on the MMPI-2-RF do not appear influenced by service era. Implications for the clinical use of, and research with, the MMPI-2-RF are discussed within the VA healthcare system.


title: Efficient smooth muscle cell differentiation of iPS cells on curcumin-incorporated chitosan/collagen/polyvinyl-alcohol nanofibers

text: Bladder dysfunction is one of the most common diseases that occur for a number of reasons and the current treatment modalities do not improve much in its recovery process. Tissue engineering in the last two decades has given great hope for the treatment of these disorders. In this study, a composite nanofibrous scaffold was fabricated from chitosan, collagen, and polyvinyl-alcohol polymer blend while curcumin incorporated in scaffold fibers. The scaffold supportive functions from smooth muscle cell differentiation were studied when human-induced pluripotent stem cells were cultured on the scaffolds under differentiation medium. Biocompatibility of the fabricated scaffold increased significantly by incorporating curcumin in the scaffold fibers, where protein adsorption, cell attachment, and viability were increased in the nanofiber/curcumin group compared with the other groups. In addition, the expression level of smooth muscle cell-related genes, including alpha-smooth muscle actin (αSMA), smooth muscle 22 alpha (SM-22a), Caldesmon1, and Calponin1in the stem cells upregulated while cultured in the presence of curcumin, but this increase was significantly improved while cells cultured on the nanofibers/curcumin. In addition, αSMA protein in the cells cultured on the nanofibers/curcumin expressed significantly higher than those cells cultured on the nanofibers without curcumin. It can be concluded that smooth muscle cell differentiation of the induced pluripotent stem cells promoted by curcumin and this promotion was synergistically improved while curcumin incorporated in the nanofibers. [Figure: see text]


title: Engineering strategies to overcome the current roadblocks in CAR T cell therapy

text: T cells genetically engineered to express chimeric antigen receptors (CARs) have proven — and impressive — therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. Nevertheless, various barriers restrict the efficacy and/or prevent the widespread use of CAR T cell therapies in these patients as well as in those with other cancers, particularly solid tumours. Key challenges relating to CAR T cells include severe toxicities, restricted trafficking to, infiltration into and activation within tumours, suboptimal persistence in vivo, antigen escape and heterogeneity, and manufacturing issues. The evolution of CAR designs beyond the conventional structures will be necessary to address these limitations and to expand the use of CAR T cells to a wider range of malignancies. Investigators are addressing the current obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. In this Review, we discuss the innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with diverse cancers.


Early versus late tracheostomy in patients with traumatic brain injury


title: Pre-hospital trauma care in Switzerland and Germany: do they speak the same language?

text: PURPOSE: Swiss and German (pre-)hospital systems, distribution and organization of trauma centres differ from each other. It is unclear if outcome in trauma patients differs as well. Therefore, this study aims to determine differences in characteristics, therapy and outcome of trauma patients between both German-speaking countries. METHODS: The TraumaRegister DGU(®) (TR-DGU) was used. Patients with Injury Severity Score ≥ 9 admitted to a level 1 trauma centre between 01/2009 and 12/2017 were included if they required ICU care or died. Trauma pattern, pre-hospital procedures and outcome were compared between Swiss (CH, n = 4768) and German (DE, n = 66,908) groups. RESULTS: Swiss patients were older than German patients (53 vs. 50 years). ISS did not differ between groups (CH 23.8 vs. DE 23.0 points). There were more low falls < 3 m (34% vs. 21%) at the expense of less traffic accidents (37% vs. 52%) in the Swiss population. In Switzerland 30% of allocations were done without physician involvement, whereas this occurred in 4% of German cases. Despite a comparable number of patients with a GCS ≤ 8 (CH 29.6%; DE 26.4%), differences in pre-hospital intubation rates occurred (CH 31% vs. DE 40%). Severe traumatic brain injuries were diagnosed most frequently in Switzerland (CH 62% vs. DE 49%). Admission vital signs were similar, and standardized mortality ratios were close to one in both countries. CONCLUSION: This study demonstrates that patients’ age, trauma patterns and pre-hospital care differ between Germany and Switzerland. However, adjusted mortality was almost similar. Further benchmarking studies are indicated to optimize trauma care in both German-speaking countries.


title: Sequence analysis of the first B5 subgenogroup strain of enterovirus 71 isolated in Korea

text: Enterovirus A71 (EV71), the main etiological agent of handfoot- mouth disease (HFMD), circulates in many areas of the world and has caused large epidemics since 1997, especially in the Asia-Pacific region. In this study, we determined the full-genome sequence of CMC718, a newly isolated EV71 strain in Korea. The CMC718 genome was 7,415 nucleotides in length and was confirmed by whole-genome phylogenetic analysis to belong to the B5 genotype. In particular, CMC718 demonstrated maximum identity with strain M988 of the B5 genotype and numerous amino acid variants were detected in the 3D domain of the viral protein P3, which is consistent with the mutation pattern of a B5 strain isolated in 2012–2013. Comparison of the CMC718 sequence with other EV71 reference strains confirmed the relationship and genetic variation of CMC718. Our study was a full-genome sequence analysis of the first EV71 strain of the B5 genotype isolated in South Korea. This information will be a valuable reference for the development of methods for the detection of recombinant viruses, the tracking of infections, and the diagnosis of EV71.


title: HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development

text: Clinical progress in the field of HER2-positive breast cancer therapy has been dramatically improved by understanding of the immune regulatory mechanisms of tumor microenvironment. Passive immunotherapy utilizing recombinant monoclonal antibodies (mAbs), particularly trastuzumab and pertuzumab has proved to be an effective strategy in HER2-positive breast cancer treatment. However, resistance to mAb therapy and relapse of disease are still considered important challenges in clinical practice. There are increasing reports on the induction of cellular and humoral immune responses in HER2-positive breast cancer patients. More recently, increasing efforts are focused on using HER2-derived peptide vaccines for active immunotherapy. Here, we discuss the development of various HER2-derived vaccines tested in animal models and human clinical trials. Different formulations and strategies to improve immunogenicity of the antigens in animal studies are also discussed. Furthermore, other immunotherapeutic approaches to HER2 breast cancer including, CTLA-4 inhibitors, immune checkpoint inhibitors, anti PD-1/PD-L1 antibodies are presented.


title: The Conundrums of Counselling Women in Violent Intimate Partner Relationships in South Africa: Implications for Practice

text: Little research focuses on how counsellors experience counselling encounters concerning intimate partner violence. This study reports on narrative research conducted with eight South African non-governmental organisation counsellors. Participants spoke of creating productive and caring counselling dynamics, and providing non-directive counselling. However, they also indicated providing moral guidance, particularly in cases where pregnancy or children were involved. Success was viewed rather narrowly as the women leaving the relationship, setting up ‘all-or-nothing’ outcomes. Such ‘success’ led to counsellor happiness, whilst failure in this regard led to counsellors experiencing anger and burn-out. We conclude that the conundrums evident in these data are grounded in patriarchal systems, limiting the efficacy of counselling based on a bondage and deliverance narrative. Implications for practice and training are also outlined.


Bio-electrical impedance analysis in critically ill patients: are we ready for prime time?


title: Repair of ventricular septal defect through anterolateral thoracotomy with central cannulation: our experience

text: BACKGROUND: At present thoracotomy with femoro-femoral bypass is an established approach for minimally invasive open heart surgeries, but thoracotomy with conventional cannulation is yet to be established. We performed 54 cases of ventricular septal defect (VSD) closure via anterolateral thoracotomy approach with central cannulation. Here we are describing our results and experience of VSD closure via anterolateral thoracotomy approach. AIM AND OBJECTIVE: The aim of our study was to evaluate early outcomes of VSD repair via anterolateral thoracotomy with central cannulation. METHODS: This is a retrospective, observational, descriptive type of study. Fifty four patients (31 males, 23 females) underwent VSD repair from November 2016 to November 2018 via anterolateral thoracotomy with age ranges from 3 to 22 years (mean age 10.57 + 8.88 years). Mean body weight was 22.29 + 13.44 kg (range 10 to 48 kg). The VSD was perimembranous in 47 patients, subpulmonic in 2, muscular in 2, and inlet in 3 patients. RESULTS: There was no operative or late mortality. The mean incision length was 7.16 ± 02.08 cm (range, 5 cm to 9 cm). Average duration of cardiopulmonary bypass (CPB) was 61.72 ± 14.20 min (range, 48–78 min), and aortic cross-clamp time was 38.51 ± 13.08 min (range, 26–56 min). The average postoperative intensive care unit (ICU) stay was 1.83 ± 1.32 days (range, 1–3 days), and hospital stay was 4.92 ± 1.82 days (range, 4–7 days). CONCLUSION: Anterolateral thoracotomy with conventional central cannulation can be a safe alternative to median sternotomy with superior cosmetic results for the repair of VSDs.


title: Smp76, a Scorpine-Like Peptide Isolated from the Venom of the Scorpion Scorpio maurus palmatus, with a Potent Antiviral Activity Against Hepatitis C Virus and Dengue Virus

text: Growing global viral infections have been a serious public health problem in recent years. This current situation emphasizes the importance of developing more therapeutic antiviral compounds. Hepatitis C virus (HCV) and dengue virus (DENV) belong to the Flaviviridae family and are an increasing global health threat. Our previous study reported that the crude venom of Scorpio maurus palmatus possessed anti-HCV and anti-DENV activities in vitro. We report here the characterization of a natural antiviral peptide (scorpion-like peptide Smp76) that prevents HCV and DENV infection. Smp76 was purified from S. m. palmatus venom and contains 76 amino acids with six residues of cysteine. Smp76 antiviral activity was evaluated using a cell culture technique utilizing Huh7it-1, Vero/SLAM, HCV (JFH1, genotype 2a) and DENV (Trinidad 1751, type 2). A potential antiviral activity of Smp76 was detected in culture cells with an approximate IC(50) of 0.01 μg/ml. Moreover, Smp76 prevents HCV infection and suppresses secondary infection, by inactivating extra-cellular infectious particles without affecting viral replication. Interestingly, Smp76 is neither toxic nor hemolytic in vitro at a concentration 1000-fold higher than that required for antiviral activity. Conclusively, this report highlights novel anti-HCV and anti-DENV activities of Smp76, which may lay the foundation for developing a new therapeutic intervention against these flaviviruses.


title: Oxygen saturation histograms predict nasal continuous positive airway pressure-weaning success in preterm infants

text: BACKGROUND: Continuous positive airway pressure (CPAP) is widely used in preterm infants. Identification of readiness for weaning from CPAP can balance benefits with risks of CPAP exposure. We tested the hypothesis that preterm infants that successfully transition off CPAP have higher oxygen saturations prior to weaning compared with infants who fail weaning from CPAP. METHODS: This was a single-center-matched case–control study in infants ≤30 weeks’ gestation receiving ≤30% FiO(2) weaned off CPAP during the first postnatal week. Cases were infants placed back on CPAP within 7 days of being taken off CPAP, whereas control infants remained off CPAP for 7 consecutive days following CPAP discontinuation. Infants were matched on gestational age at birth (±10 days). Prospectively collected histograms detailing the distribution of oxygen saturations prior to CPAP discontinuation were compared between cases and controls. RESULTS: Over a 12-month monitoring period, 36 infants met inclusion criteria. Baseline characteristics, morbidities, and clinical variables did not differ between cases and controls. Controls achieved oxygen saturations of 95–97 and 97–100% for longer duration compared to cases (p < 0.05). CONCLUSIONS: In preterm infants with RDS receiving CPAP and ≤30% FiO(2), infants with higher oxygen saturations had greater success in transitioning off CPAP.


What is new in non-ventilated ICU-acquired pneumonia?


title: Improving the prognostic value of ∆PCO(2) following cardiac surgery: a prospective pilot study

text: Conflicting results have been published on prognostic significance of central venous to arterial PCO(2) difference (∆PCO(2)) after cardiac surgery. We compared the prognostic value of ∆PCO(2) on intensive care unit (ICU) admission to an original algorithm combining ∆PCO(2), ERO(2) and lactate to identify different risk profiles. Additionally, we described the evolution of ∆PCO(2) and its correlations with ERO(2) and lactate during the first postoperative day (POD1). In this monocentre, prospective, and pilot study, 25 patients undergoing conventional cardiac surgery were included. Central venous and arterial blood gases were collected on ICU admission and at 6, 12 and 24 h postoperatively. High ∆PCO(2) (≥ 6 mmHg) on ICU admission was found to be very frequent (64% of patients). Correlations between ∆PCO(2) and ERO(2) or lactate for POD1 values and variations were weak or non-existent. On ICU admission, a high ∆PCO(2) did not predict a prolonged ICU length of stay (LOS). Conversely, a significant increase in both ICU and hospital LOS was observed in high-risk patients identified by the algorithm: 3.5 (3.0–6.3) days versus 7.0 (6.0–8.0) days (p = 0.01) and 12.0 (8.0–15.0) versus 8.0 (8.0–9.0) days (p < 0.01), respectively. An algorithm incorporating ICU admission values of ∆PCO(2), ERO(2) and lactate defined a high-risk profile that predicted prolonged ICU and hospital stays better than ∆PCO(2) alone.


title: Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

text: PURPOSE OF REVIEW: CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection. RECENT FINDINGS: Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. SUMMARY: No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.


title: Interventions to improve wellbeing among obstetricians and midwives at Cork University Maternity Hospital

text: BACKGROUND: There is an increasing body of research demonstrating stress, burnout, and compassion fatigue among those working in obstetrics and gynaecology. The literature is lacking with respect to targeted interventions aimed at improving staff wellbeing. AIMS: To investigate whether an intervention which increases support for staff is feasible to implement and effective at improving staff wellbeing. METHODS: This study was conducted in a tertiary university teaching maternity hospital. All doctors in training (DITs) (N = 28) and midwives (N = 69) working in the delivery suite were invited to participate. Wellbeing was assessed by measuring burnout, compassion fatigue, and perceived stress using validated questionnaires. These were distributed pre-intervention and 6 months after implementation of the interventions. The support interventions consisted of posters promoting self-care, team bonding sessions, and end of shift meetings. RESULTS: Eighteen (64%) DITs and 22 (31%) midwives returned pre-intervention questionnaires. Thirteen (18%) midwives retuned post-intervention questionnaires, of which five midwives (7%) returned both the pre-intervention questionnaire and the post-intervention questionnaire. Eighty-seven percent of participants were experiencing emotional exhaustion pre-intervention. There was a statistically significant decrease in the Professional Quality of Life burnout score from pre-intervention (M = 25.8) to post-intervention (M = 21.4), p = 0.02. End of shift meetings were discontinued after 5 weeks due to low attendance. End of shift meetings provided an opportunity for support and debriefing; however, the timing of these sessions impaired their long-term feasibility. CONCLUSION: DITs and midwives of this sample are experiencing high levels of burnout and compassion fatigue. End of shift meetings for midwives and team bonding sessions for DITs may positively impact on wellbeing, but in current format, they are not feasible for long-term implementation. The low level of participation highlights a challenge in implementing institution-wide support interventions.


title: Pneumocystis jirovecii Pneumonia and Other Infections in Idiopathic Inflammatory Myositis

text: PURPOSE OF REVIEW: The management of patients with idiopathic inflammatory myositis (IIM) can be complex and challenging due to the myriad of complications they can experience. The continued use of corticosteroids, in addition to the rise of combination immunosuppressive therapy, has contributed to the ongoing concern for infection. Perhaps the most feared infection in IIM patients is Pneumocystis jirovecii pneumonia (PJP) given its infrequent occurrence yet high mortality. The field has been, and continues to be, without evidence-based guidelines to help clinicians determine which patients with IIM to prescribe prophylaxis. Herein, we review this literature to provide the clinician with an up-to-date view of infections in IIM. RECENT FINDINGS: In the past 5 years, a number of studies have been reported highlighting various infectious complications, which help us better understand their frequency and associated risk factors. In addition, data has been published on the potential harms of PJP prophylaxis, to better inform the risk/benefit of our decision-making. SUMMARY: Infection remains a major contributor to morbidity and mortality in IIM. A better understanding of which patient subgroups are at risk for particular infections will inform optimal management strategies.


title: Pretreatment with glucose–insulin–potassium improves ventricular performances after coronary artery bypass surgery: a randomized controlled trial

text: Heart failure is the main cause of poor outcome following open heart surgery and experimental studies have demonstrated that glucose–insulin–potassium (GIK) infusion exerts cardioprotective effects by reducing myocardial ischemia–reperfusion injuries. This randomized controlled trial was designed to assess the effects of GIK on left ventricular function in moderate-to-high risk patients undergoing on-pump isolated coronary artery bypass surgery (CABGS), or combined with aortic valve replacement. The primary outcomes were the effects of GIK on two- and three-dimensional left ventricular ejection fraction (2D and 3D-LVEF), and on transmitral flow propagation velocity (Vp), that occurred between the pre- and post-CPB periods. GIK administration was associated with favorable interaction effects (p < 0.001) on 2D-LVEF, 3D-LVEF and Vp changes over the study periods. In GIK pretreated patients (N = 54), 2-D and 3D-LVEF and Vp increased slightly during surgery (mean difference [MD] + 3.5%, 95% confidence interval [95% CI] − 0.2 to 7.1%, MD + 4.0%, 95% CI 0.6–7.4%, and MD + 22.2%, 95% CI 16.0–28.4%, respectively). In contrast, in the Placebo group (N = 46), 2D-and 3D-LVEF, as well as Vp all decreased after CPB (MD − 7.5% [− 11.6 to − 3.4%], MD − 12.0% [− 15.2 to − 8.8%] and MD − 21.3% [− 25.7 to − 16.9%], respectively). In conclusion, the administration of GIK resulted in better preservation of systolic and diastolic ventricular function in the early period following weaning from CPB.


title: Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

text: The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used (123/131)I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. (11)C-HED and (18)F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00702-020-02180-4) contains supplementary material, which is available to authorized users.


title: Factors associated with development of early and late pulmonary hypertension in preterm infants with bronchopulmonary dysplasia

text: OBJECTIVE: To investigate factors associated with development of early and late pulmonary hypertension (E/LPH) in preterm infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: A retrospective case-control observational study of preterm infants with BPD admitted to a level IV referral neonatal intensive care unit over 5 years. We compared pre- and postnatal characteristics between infants with or without BPD-associated EPH and LPH. RESULTS: Fifty-nine out of 220 infants (26.8%) had LPH, while 85 out of 193 neonates (44%) had EPH. On multiple logistic regression, novel factors associated with development of BPD–LPH included presence of maternal diabetes, EPH, tracheostomy, tracheitis, intraventricular hemorrhage (IVH, grade ≥3) and systemic steroid use. For EPH, these were maternal diabetes, IVH grade ≥3, high frequency ventilator use, and absence of maternal antibiotics use. CONCLUSION: We identified novel factors and confirmed previously established factors with development of LPH and EPH, which can help develop a screening strategy in BPD patients.


title: Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis

text: BACKGROUND: Studies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial. OBJECTIVES: To assess systematically the effectiveness and safety of high dose tigecycline in the treatment of severe infections. METHODS: Pubmed, Web of Science, Embase, MEDLINE, Cochrane Library and ClinicalTrials were searched up to February 20, 2019 for studies that compared the effectiveness and safety of high dose tigecycline with standard dose tigecycline or other non-tigecycline-containing regimens in the treatment of severe infections. Rates for all-cause mortality, clinical cure, microbiological eradication and adverse events were analysed. RESULTS: Ten studies with 593 patients were included. The results indicated that using high dose tigecycline resulted in better outcomes compared with controls with lower all-cause mortality (OR 0.44, 95% CI 0.30–0.66, p < 0.0001), higher clinical cure (OR 3.43, 95% CI 2.09–5.63, p < 0.00001), higher microbiological eradication (OR 2.25, 95% CI 1.44–3.50, p = 0.0003), and without increasing adverse events rates. Subgroup analysis showed that high dose tigecycline reduced all-cause mortality in nosocomial acquired pneumonia (OR 0.39, 95% CI 0.22–0.70, p = 0.002), bloodstream infections (OR 0.19, 95% CI 0.06–0.58, p = 0.004) and mixed infections (OR 0.20, 95% CI 0.07–0.59, p = 0.003), with no statistical differences in complicated intra-abdominal infections (OR 2.04, 95% CI 0.80–5.23, p = 0.14). In carbapenem-resistant pathogens, the microbiological eradication rate in those given high dose tigecycline did not differ from controls (OR 1.07, 95% CI 0.44–2.60, p = 0.87), although mortality was reduced (OR 0.20, 95% CI 0.09–0.45, p = 0.0001). The main limitation of the review is that most of the included studies are observational studies with small sample sizes and high risks of bias. CONCLUSIONS: High dose tigecycline treatment is effective and safe for severe infections owing to its lower all-cause mortality, higher clinical cure, microbiological eradication and comparable adverse events. However, as a result of the high risks of bias of the included studies, well-designed randomised clinical trials are warranted to establish the effectiveness and safety of high dose tigecycline compared with standard dose tigecycline and other commonly used antibiotics.


title: Clinical Profile of Critical Pertussis in Children at a Pediatric Intensive Care Unit in Northern India

text: OBJECTIVE: To delineate the clinical profile, complications, intensive care needs, and predictors of mortality in children with critical pertussis. METHODS: Retrospective analysis of case records of children in the pediatric intensive care unit of a tertiary-care hospital, with a diagnosis of critical pertussis over 3 years. Diagnostic criteria included CDC case definition and confirmation by polymerase chain reaction (PCR), when available. Survivors and nonsurvivors were compared to identify predictors of mortality. RESULTS: 36 records were analysed, most cases were infants (31, 86.1%). 10 (27.7%) were (below 6 weeks of age). In the rest, 16 (61.5%) were partially immunized or unimmunized against pertussis. Rapid breathing (88.9%), paroxysmal cough (86.1%) and apnea (41.7%) were common presenting complaints. Hypoxemia (97.2%), hyperleukocytosis (61.1%) and encephalopathy (52.8%) were common complications. Intensive care needs were mechanical ventilation in 11 (30.6%), vasoactive support in 7 (19.4%) and exchange transfusion in 3 (8.3%). Female gender, apnea, hyperleukocytosis, encephalopathy, need for vasoactive support, and mechanical ventilation predicted mortality. CONCLUSION: Pertussis demands attention due to its varied presentation, increased complications and higher mortality.


title: Synthesis, Type II diabetes inhibitory activity, antimicrobial evaluation and docking studies of indeno[1,2-c]pyrazol-4(1H)-ones

text: We report a convenient and efficient synthesis of indeno[1,2-c]pyrazol-4(1H)-ones (4a‒o) by the reaction of a variety of 2-acyl-(1H)-indene-1,3(2H)-diones (1) and 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles (2) in the presence of glacial acetic acid in good yields. The structure of the compounds thus prepared were confirmed by analytical and spectral (FT-IR, (1)H NMR, (13)C NMR, and HRMS) techniques. All the synthesized indeno[1,2-c]pyrazol-4(1H)-ones (4a‒o) were assayed for their in vitro Type II diabetes inhibitory activity by using Acarbose as standard drug and in vitro antimicrobial activity utilizing Streptomycin and Fluconazole as reference drugs. Among the synthesized derivatives, 4e (IC(50) = 6.71 μg/mL) was found to be more potent against α-glucosidase enzyme as compared with the standard Acarbose (IC(50) = 9.35 μg/mL) and 4i (IC(50) = 11.90 μg/mL) exhibited good inhibitory activity against α-amylase enzyme as compared with the standard Acarbose (IC(50) = 22.87 μg/mL). Also, all the titled compounds showed good antimicrobial activity. In addition, in vitro α-glucosidase and α-amylase inhibition were supported by docking studies performed on the derivatives 4e and 4o, respectively. [Image: see text]


title: Strongyloides stercoralis Hyper infection Syndrome

text: Strongyloides stercoralis is a helminth, widely distributed in tropical and subtropical countries. Its infestation in humans usually does not produce symptoms. However, in some patients, severe and life-threatening forms of this infection can occur, especially in immunocompromised individuals. Severe parasitic infection is triggered by any imbalance in the host’s immunity favouring the auto-infective cycle. This results in an increase in the intraluminal parasitic burden. In addition, tissue infestation is also very common. Clinical presentation is variable, and it is very difficult to diagnose clinically. Diagnosis requires a high index of suspicion. In some cases, the diagnosis is established only on histopathological examination of the excised tissue by the pathologist. Here, the authors report a case of an elderly male diabetic patient, who presented to the emergency department with the features of acute abdomen. On exploratory laparotomy, he was found to have the features suggestive of gangrene of small bowel. Resection of the gangrenous bowel was done, and end-to-end anastomosis was done as the rest of the bowel appeared to be normal. However, the patient died of multi-organ failure and septicaemia on the second postoperative day. The resected intestine showed tissue infestation of Strongyloides stercoralis on histopathological examination. In this review article, the authors summarize a case of hyper infection syndrome of strongyloidiasis and discuss the various aspects of Strongyloides stercoralis infection with emphasis on life cycle of the parasite and different clinical features of the disease.


title: Self-compassion as a Stress Moderator: A Cross-sectional Study of 1700 Doctors, Nurses, and Medical Students

text: OBJECTIVES: Work stress is common in healthcare and reliably predicts negative outcomes, including burnout and lower quality of life (QOL). However, few studies have investigated factors that might attenuate the impact of stress on these negative outcomes. We investigated whether the tendency to be kind to the self during times of difficulty—self-compassion—might buffer the effect of work stress on outcomes. METHODS: Registered nurses (n = 801), physicians (n = 516), and medical students (n = 383) were recruited using convenience sampling in New Zealand. Following consent, participants (N = 1700) completed a survey including the Copenhagen Burnout Inventory, Satisfaction with Life Scale, and Self-Compassion Scale–Short Form. RESULTS: Across groups, greater work stress consistently predicted greater burnout and lower QOL, while greater self-compassion predicted lower burnout and better QOL. Self-compassion moderated the relationship between stress and burnout in nurses (albeit in the opposite direction to what had been predicted), but not in doctors or medical students. CONCLUSIONS: While self-compassion predicted better outcomes (and may thus represent a target to enhance wellbeing), it strengthened the association between stress and burnout in nurses. How self-compassion impacts the experience of stress and its correlates and why it does so differently in different groups of professionals remains unclear.


title: Measuring the Quality of Palliative Care for Patients with End-Stage Liver Disease

text: BACKGROUND/AIMS: We examined the quality of palliative care received by patients with decompensated cirrhosis using an explicit set of palliative care quality indicators (QIs) for patients with end-stage liver disease (PC-ESLD). METHODS: We identified patients newly diagnosed with decompensated cirrhosis at a single veterans health center and followed up them for 2 years or until death. We piloted measurement of PC-ESLD QIs in all patients confirmed to have ESLD using a chart abstraction tool. RESULTS: Out of 167 patients identified using at least one sampling strategy, 62 were confirmed to meet ESLD criteria with chart abstraction. Ninety-eight percent of veterans in the cohort were male, mean age at diagnosis was 61 years, and 74% were White. The overall QI pass rate was 68% (64% for information care planning QIs and 76% for supportive care QIs). Patients receiving specialty palliative care consultation were more likely to receive information care planning QIs (67% vs. 37%, p = 0.02). The best performing sampling strategy had a sensitivity of 62% and specificity of 60%. CONCLUSION: Measuring the quality of palliative care for patients with ESLD is feasible in the veteran population. Our single-center data suggest that the quality of palliative care is inadequate in the veteran population with ESLD, though patients offered specialty palliative care consultation and those affected by homelessness, drug, and alcohol abuse may receive better care. Our combination of ICD-9 codes can be used to identify a cohort of patients with ESLD, though better sensitivity and specificity may be needed.


title: Left ventricular overloading identified by critical care echocardiography is key in weaning-induced pulmonary edema

text: PURPOSE: To assess the role of left ventricular overload and cumulated fluid balance in the development weaning-induced pulmonary edema (WIPO). METHODS: Ventilated patients in sinus rhythm with COPD and/or heart failure (ejection fraction ≤ 40%) were studied. Echocardiography was performed immediately before and during a 30-min spontaneous breathing trial (SBT) using a T-tube. Patients who failed were treated according to echocardiography results before undergoing a second SBT. RESULTS: Twelve of 59 patients failed SBT, all of them developing WIPO. Patients who succeeded SBT had lower body weight (− 2.5 kg [− 4.8; − 1] vs. + 0.75 kg [− 2.95; + 5.57]: p = 0.02) and cumulative fluid balance (− 2326 ml [− 3715; + 863] vs. + 143 ml [− 2654; + 4434]: p = 0.007) than those who developed WIPO. SBT-induced central hemodynamic changes were more pronounced in patients who developed WIPO, with higher E wave velocity (122 cm/s [92; 159] vs. 93 cm/s [74; 109]: p = 0.017) and E/A ratio (2.1 [1.2; 3.6] vs. 0.9 [0.8; 1.4]: p = 0.001), and shorter E wave deceleration time (85 ms [72; 125] vs. 147 ms [103; 175]: p = 0.004). After echocardiography-guided treatment, all patients who failed the first SBT were successfully extubated. Fluid balance was then negative (− 2224 ml [− 7056; + 100] vs. + 146 ml [− 2654; + 4434]: p = 0.005). Left ventricular filling pressures were lower (E/E′: 7.3 [5; 10.4] vs. 8.9 [5.9; 13.1]: p = 0.028); SBT-induced increase in E wave velocity (+ 10.6% [− 2.7/ + 18] vs. + 25.6% [+ 12.7/ + 49]: p = 0.037) and of mitral regurgitation area were significantly smaller. CONCLUSION: In high-risk patients, WIPO appears related to overloaded left ventricle associated with excessive fluid balance. SBT-induced central hemodynamic changes monitored by CCE help in guiding therapy for successful weaning. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-06061-y) contains supplementary material, which is available to authorized users.


title: Effects of Mindfulness-Based Interventions on Self-compassion in Health Care Professionals: a Meta-analysis

text: OBJECTIVES: Health care professionals have elevated rates of burnout and compassion fatigue which are correlated with poorer quality of life and patient care, and inversely correlated with self-compassion. Primary studies have evaluated the extent to which mindfulness-based interventions increase self-compassion with contradictory findings. A meta-analytic review of the literature was conducted to quantitatively synthesize the effects of mindfulness-based interventions on self-compassion among health care professionals. METHODS: Twenty-eight treatment outcome studies were identified eligible for inclusion. Five cumulative effect sizes were calculated using random-effects models to evaluate differences of changes in self-compassion for treatment and control groups. Within and between group comparisons were evaluated. Sub-group and moderator analyses were conducted to explore potential moderating variables. RESULTS: Twenty-seven articles (k = 29, N = 1020) were utilized in the pre-post-treatment meta-analysis. Fifteen samples (52%) included health care professionals and fourteen (48%) professional health care students. Results showed a moderate effect size between pre-post-treatment comparisons (g = .61, 95% CI = .47 to .76) for self-compassion and a strong effect size for pre-treatment to follow-up (g = .76, 95% CI = .41 to 1.12). The effect size comparing post-treatment versus post-control was moderate. One exploratory moderator analysis was significant, with stronger effects for interventions with a retreat component. CONCLUSIONS: Findings suggest mindfulness-based interventions improve self-compassion in health care professionals. Additionally, a variety of mindfulness-based programs may be useful for employees and trainees. Future studies with rigorous methodology evaluating effects on self-compassion and patient care from mindfulness-based interventions are warranted to extend findings and explore moderators. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12671-020-01342-5) contains supplementary material, which is available to authorized users.


title: Generating Survival Times Using Cox Proportional Hazards Models with Cyclic and Piecewise Time-Varying Covariates

text: Time-to-event outcomes with cyclic time-varying covariates are frequently encountered in biomedical studies that involve multiple or repeated administrations of an intervention. In this paper, we propose approaches to generating event times for Cox proportional hazards models with both time-invariant covariates and a continuous cyclic and piecewise time-varying covariate. Values of the latter covariate change over time through cycles of interventions and its relationship with hazard differs before and after a threshold within each cycle. The simulations of data are based on inverting the cumulative hazard function and a log link function for relating the hazard function to the covariates. We consider closed-form derivations with the baseline hazard following the exponential, Weibull, or Gompertz distribution. We propose two simulation approaches: one based on simulating survival data under a single-dose regimen first before data are aggregated over multiple-dosing cycles and another based on simulating survival data directly under a multiple-dose regimen. We consider both fixed intervals and varying intervals of the drug administration schedule. The method’s validity is assessed in simulation experiments. The results indicate that the proposed procedures perform well in generating data that conform to their cyclic nature and assumptions of the Cox proportional hazards model. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12561-020-09266-3) contains supplementary material, which is available to authorized users.


title: Designing intervention scheme for vaccine market: a bilevel programming approach

text: Public-interest goods benefit consumers and also generate external benefits boosting societal welfare. Despite this characteristic of these goods, their level of consumption or production are generally well below the socially desirable levels without intervention. Motivated by influenza vaccine market, this paper examines the intervention design problem for a public-interest good facing yield uncertainty in production as well as inefficiencies in distribution and allocation. The proposed mechanism considers two intervention tools with the aim of resolving the inefficiencies in the system and allowing the actors to take socially desirable decisions. The first tool is to intervene so that demand level for the good is increased; we call it demand increasing strategy. The second tool aims to support the production, allocation, and distribution by investing in research and development and better planning and enhances the availability; we call this as availability increasing strategy. The intervention design problem is based on stylized demand and availability models that take into account investments made to improve them. The model suggested is experimented by a numerical study to analyze the impact of applying proposed joint mechanism in US influenza vaccine market. The results show that proposed strategy is very effectual in terms of vaccination percentages achieved and budget savings realized beyond the current practices, and the improvement in vaccination percentages is even greater when uncertainty in the system is higher. Besides, the results suggest that as long as the parameter calibration and decision problems are solved consistently, availability can be approximated by its average value when necessary.


docid: yccdlahn

title: Secondary Trauma: Emotional Safety in Sensitive Research


title: Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine

text: OBJECTIVE: To develop evidence-based clinical practice recommendations regarding transfusion practices in non-bleeding, critically ill adults. DESIGN: A task force involving 13 international experts and three methodologists used the GRADE approach for guideline development. METHODS: The task force identified four main topics: red blood cell transfusion thresholds, red blood cell transfusion avoidance strategies, platelet transfusion, and plasma transfusion. The panel developed structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. RESULTS: The task force generated 16 clinical practice recommendations (3 strong recommendations, 13 conditional recommendations), and identified five PICOs with insufficient evidence to make any recommendation. CONCLUSIONS: This clinical practice guideline provides evidence-based recommendations and identifies areas where further research is needed regarding transfusion practices and transfusion avoidance in non-bleeding, critically ill adults. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05884-8) contains supplementary material, which is available to authorized users.


Immunity check should be performed for all patients with septic shock? Yes


title: An intervention to decrease time to parents’ first hold of infants in the Neonatal Intensive Care Unit requiring respiratory support

text: BACKGROUND: There are many barriers to parental skin-to-skin contact for critically ill neonates. Our aims were to decrease median time to first parental hold of neonates requiring respiratory support from 6.4 to 3 days, and to increase the percentage of neonates held within the first 24 h after birth from 6 to 75%. METHODS: Lean Six Sigma methodology was used to identify barriers to holding and opportunities for improvement. INTERVENTION: A multifactorial improvement bundle was implemented to reduce the time to first parental hold of critically ill neonates. RESULTS: Median time to first parental hold was reduced from 6.4 to 1.2 days (p < 0.01). Infants held within the first 24 h after birth increased from 6 to 35%. There was no increase in adverse events associated with parental holding. CONCLUSIONS: Implementation of an improvement bundle resulted in a significant reduction in time to first parental hold of infants requiring respiratory support.


title: The Role of Social Support in the Link Between Economic Abuse and Economic Hardship

text: More data is needed about the pathways through which intimate partner violence (IPV) impacts the economic well-being of survivors. The current study assesses the moderating influence of social support on the association between economic abuse (EA) and economic hardship. Female participants (n = 435) were recruited to participate in a web-based survey which included standardized measures of EA, other forms of IPV, domains of social support, and economic hardship. Analysis included bivariate and multivariate regression with an investigation into interaction effects.Experiencing EA was significantly correlated with economic hardship, even with extent of physical and emotional IPV controlled. Both tangible and appraisal support had significant negative association with extent of material hardship. Significant interactions between forms of social support and economic abuse were observed. For those at high levels of economic abuse, support had less influence on economic hardship. A mix of direct economic aid, advocacy, education and support could provide a blueprint for addressing the economic hardship experiences of community-dwelling survivors of economic abuse. A comprehensive response to EA requires interventions aimed directly at economically controlling and exploitative tactics, including credit building, individual economic advocacy, and education. Interventions that seek to enhance survivors’ access to social support may be necessary but not sufficient to buffer the impacts of violence on survivors’ economic outcomes.


title: External validation of a prognostic model for intensive care unit mortality: a retrospective study using the Ontario Critical Care Information System

text: PURPOSE: To externally validate an intensive care unit (ICU) mortality prediction model that was created using the Ontario Critical Care Information System (CCIS), which includes the Multiple Organ Dysfunction Score (MODS). METHODS: We applied the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) recommendations to a prospective longitudinal cohort of patients discharged between 1 July 2015 and 31 December 31 2016 from 90 adult level-3 critical care units in Ontario. We used multivariable logistic regression with measures of discrimination, calibration-in-the-large, calibration slope, and flexible calibration plots to compare prediction model performance of the entire data set and for each ICU subtype. RESULTS: Among 121,201 CCIS records with ICU mortality of 11.3%, the C-statistic for the validation data set was 0.805. The C-statistic ranged from 0.775 to 0.846 among the ICU subtypes. After intercept recalibration to adjust the baseline risk, the mean predicted risk of death matched actual ICU mortality. The calibration slope was close to 1 with all CCIS data and ICU subtypes of cardiovascular and community hospitals with low ventilation rates. Calibration slopes significantly less than 1 were found for ICUs in teaching hospitals and community hospitals with high ventilation rates whereas coronary care units had a calibration slope significantly higher than 1. Calibration plots revealed over-prediction in high risk groups to a varying degree across all cohorts. CONCLUSIONS: A risk prediction model primarily based on the MODS shows reproducibility and transportability after intercept recalibration. Risk adjusting models that use existing and feasible data collection can support performance measurement at the individual ICU level. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12630-020-01686-5) contains supplementary material, which is available to authorized users.


title: Inducing Brain Cooling Without Core Temperature Reduction in Pigs Using a Novel Nasopharyngeal Method: An Effectiveness and Safety Study

text: BACKGROUND: Acute brain lesions constitute an alarming public health concern. Neuroprotective therapies have been implemented to stabilize, prevent, or reduce brain lesions, thus improving neurological outcomes and survival rates. Hypothermia is the most effective approach, mainly attributed to the reduction in cellular metabolic activity. Whole-body cooling is currently implemented by healthcare professionals; however, adverse events are frequent, limiting the potential benefits of therapeutic hypothermia. Therefore, selective methods have been developed to reduce adverse events while delivering neuroprotection. Nasopharyngeal approaches are the safest and most effective methods currently considered. Our primary objective was to determine the effects of a novel nasopharyngeal catheter on the brain temperature of pigs. METHODS: In this prospective, non-randomized, interventional experimental trial, 10 crossbred pigs underwent nasopharyngeal cooling for 60 min followed by 15 min of rewarming. Nasopharyngeal catheters were inserted into the left nostril and properly positioned at the nasopharyngeal cavity. RESULTS: Nasopharyngeal cooling was associated with a decrease in brain temperature, which was more significant in the left cerebral hemisphere (p = 0.01). There was a reduction of 1.47 ± 0.86 °C in the first 5 min (p < 0.001), 2.45 ± 1.03 °C within 10 min (p < 0.001), and 4.45 ± 1.36 °C after 1 h (p < 0.001). The brain-core gradient was 4.57 ± 0.87 °C (p < 0.001). Rectal, esophageal, and pulmonary artery temperatures and brain and systemic hemodynamic parameters, remained stable during the procedure. Following brain cooling, values of oxygen partial pressure in brain tissue significantly decreased. No mucosal lesions were detected during nasal, pharyngeal, or oral inspection after nasopharyngeal catheter removal. CONCLUSIONS: In this study, a novel nasopharyngeal cooling catheter effectively induced and maintained exclusive brain cooling when combined with effective counter-warming methods. Exclusive brain cooling was safe with no device-related local or systemic complications and may be desired in selected patient populations.


title: The Mycobiome in Health and Disease: Emerging Concepts, Methodologies and Challenges

text: Fungal disease is an increasingly recognised global clinical challenge associated with high mortality. Early diagnosis of fungal infection remains problematic due to the poor sensitivity and specificity of current diagnostic modalities. Advances in sequencing technologies hold promise in addressing these shortcomings and for improved fungal detection and identification. To translate such emerging approaches into mainstream clinical care will require refinement of current sequencing and analytical platforms, ensuring standardisation and consistency through robust clinical benchmarking and its validation across a range of patient populations. In this state-of-the-art review, we discuss current diagnostic and therapeutic challenges associated with fungal disease and provide key examples where the application of sequencing technologies has potential diagnostic application in assessing the human ‘mycobiome’. We assess how ready access to fungal sequencing may be exploited in broadening our insight into host–fungal interaction, providing scope for clinical diagnostics and the translation of emerging mycobiome research into clinical practice.