title: Intranasal vaccination with Listeria ivanovii as vector of Mycobacterium tuberculosis antigens promotes specific lung-localized cellular and humoral immune responses

text: We have previously demonstrated that a recombinant Listeria ivanovii (LI) strain expressing the ESAT-6 or Ag85C protein of Mycobacterium tuberculosis (Mtb) as a tuberculosis (TB) vaccine candidates induced antigen-specific cellular immune responses after intravenous immunization of mice. However, whether such recombinant strains could induce desired immune responses in the lung, where TB infection occurs, is not clear. In this paper, C57BL/6 J mice were intranasally vaccinated with attenuated LIΔactAplcB-Rv3875 (Δ refers to gene deletion in the bacterial genome) or LIΔactAplcB-Rv0129c, the two vaccine candidates that utilize LI as an antigen delivery vector. Bacterial load in the target organs, histological changes in the infected organs, the percentage of specific cytokine-secreting T cells in the lung and spleen, IgG levels in the serum and secretory IgA (SIgA) levles in bronchoalveolar lavage (BAL) fluid were determined at specific days post inoculation (dpi). The results showed that both strains were mainly confined to the lung and were eliminated at 10 dpi. The histological damage caused by the infection in the lung was slight and recovered by day 5. Intranasal vaccination of the mice twice at an interval of 4 weeks notably elicited TB antigen-specific CD4(+) and CD8(+) T cell responses in the lung and SIgA secretion in the pulmonary mucosa, and significantly enhanced the percentage of double-functional CD8(+) T cells (IFN-γ(+) TNF-α(+) CD8(+)). To our knowledge, this is the first report regarding the used of LI vector vaccines to induce promising lung-localized cellular and humoral immune responses by intranasal vaccination. These data suggest that LI could be a novel and promising live vector to construct an intranasal vaccine against respiratory diseases.


title: A C-terminal Pfs48/45 malaria transmission-blocking vaccine candidate produced in the baculovirus expression system

text: The Plasmodium falciparum gametocyte surface protein, Pfs48/45, is a potential target for malaria transmission-blocking vaccines. However, due to its size and complexity, expression of the full-length protein has been difficult, leading to focus on the C-terminal six cysteine domain (6C) with the use of fusion proteins to facilitate expression and folding. In this study, we utilized the baculovirus system to evaluate the expression of three Pfs48/45 proteins including the full-length protein, the 6C domain fragment and the 6C domain mutant to prevent glycosylation. Expression of the recombinant Pfs48/45 proteins was conducted in super Sf9 cells combined with the use of tunicamycin to prevent N-glycosylation. The proteins were then evaluated as immunogens in mice to demonstrate the induction of functionally active polyclonal antibody responses as measured in the standard membrane feeding assay (SMFA). Only the 6C protein was found to exhibit significant transmission-reducing activity. Further characterization of the biologically active 6C protein demonstrated it was homogeneous in terms of size, charge, conformation, absence of glycosylation, and containing proper disulfide bond pairings. This study presents an alternative expression system, without the need of a fusion protein partner, for the Pfs48/45 6C protein fragment including further evaluation as a potential transmission-blocking vaccine candidate.


title: Estimating epidemic exponential growth rate and basic reproduction number

text: The initial exponential growth rate of an epidemic is an important measure of the severeness of the epidemic, and is also closely related to the basic reproduction number. Estimating the growth rate from the epidemic curve can be a challenge, because of its decays with time. For fast epidemics, the estimation is subject to over-fitting due to the limited number of data points available, which also limits our choice of models for the epidemic curve. We discuss the estimation of the growth rate using maximum likelihood method and simple models.


title: Continuous Vital Sign Analysis for Predicting and Preventing Neonatal Diseases in the 21(st) Century - Big Data to the Forefront

text: In the neonatal intensive care unit (NICU), heart rate, respiratory rate, and oxygen saturation are vital signs (VS) that are continuously monitored in infants, while blood pressure is often monitored continuously immediately after birth, or during critical illness. Although changes in VS can reflect infant physiology or circadian rhythms, persistent deviations in absolute values or complex changes in variability, can indicate acute or chronic pathology. Recent studies demonstrate that analysis of continuous VS trends can predict sepsis, necrotizing enterocolitis, brain injury, bronchopulmonary dysplasia, cardiorespiratory decompensation, and mortality. Subtle changes in continuous VS patterns may not be discerned even by experienced clinicians reviewing spot VS data or VS trends captured in the monitor. In contrast, objective analysis of continuous VS data can improve neonatal outcomes by allowing heightened vigilance or preemptive interventions. In this review, we provide an overview of the studies that have used continuous analysis of single or multiple VS, their interactions, and combined VS and clinical analytic tools, to predict or detect neonatal pathophysiology. We make the case that big-data analytics are promising, and with continued improvements, can become a powerful tool to mitigate neonatal diseases in the 21(st) century.


title: Antiviral immunity is impaired in COPD patients with frequent exacerbations

text: Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.


title: A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease

text: The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored vaccines (ChAdOx1) that induce swift and robust anti-CHIKV immune responses with a single dose, without the need for adjuvants or booster vaccines. Here, we report the vaccines’ protective efficacies against CHIKV infection in a lethal A129 mouse model. Our results indicate that a single, un-adjuvanted ChAdOx1 Chik or ChAdOx1 Chik ΔCap dose provided complete protection against a lethal virus challenge and prevented CHIKV-associated severe inflammation. These candidate vaccines supported survival equal to the attenuated 181/25 CHIKV reference vaccine but without the vaccine-related side effects, such as weight loss. Vaccination with either ChAdOx1 Chik or ChAdOx1 Chik ΔCap resulted in high titers of neutralizing antibodies that are associated with protection, indicating that the presence of the capsid within the vaccine construct may not be essential to afford protection under the conditions tested. We conclude that both replication-deficient ChAdOx1 Chik vaccines are safe even when used in A129 mice and afford complete protection from a lethal challenge.


title: Recombinant Lactobacillus casei Expressing Capsid Protein VP60 can Serve as Vaccine Against Rabbit Hemorrhagic Disease Virus in Rabbits

text: Rabbit hemorrhagic disease virus (RHDV) is the causative agent of rabbit hemorrhagic disease (RHD). RHD, characterized by hemorrhaging, liver necrosis, and high morbidity and mortality in rabbits and hares, causes severe economic losses in the rabbit industry worldwide. Due to the lack of an efficient in-vitro propagation system for RHDV, the current vaccine is produced via chemical inactivation of crude RHDV preparation derived from the livers of infected rabbits. Inactivated vaccines are effective for controlling RHD, but the potential problems of biosafety and animal welfare have negative effects on the application of inactivated vaccines. In this study, an oral Lactobacillus casei (L. casei) vaccine was used as an antigen delivery system to express RHDV capsid protein VP60(VP1)-eGFP fusion protein. The expression of the recombinant protein was confirmed via western blotting and immunofluorescence (IFA). Our results indicate that oral administration of this probiotic vaccine can stimulate secretory immunoglobulin A (SIgA)-based mucosal and IgG-based humoral immune responses in rabbits. The immunized rabbits were completely protected against challenge with RHDV. Our findings indicate that the L. casei expression system is a new strategy for the development of a safe and efficient vaccine against RHDV.


title: Antiviral Activity of Germacrone against Pseudorabies Virus in Vitro

text: Pseudorabies virus (PRV), a member of the Herpesviridae, is the causative agent of an acute infectious disease in a variety of animals. The emergence of a novel variant strain brought huge economic losses to the pig industry since classical vaccine strains were not completely effective against variant strains. Therefore, the development of new anti-pseudorabies virus drugs and vaccines is of great significance for the treatment and prevention of pseudorabies. In this study, we found that germacrone, one of the major components of the essential oils extracted from Rhizoma Curcuma, was able to effectively inhibit PRV replication in a dose-dependent manner in vitro. Germacrone showed antiviral activity against PRV in the early phase of the viral replication cycle. Moreover, we found that germacrone does not directly kill the virus, nor does it affect the expression of the PRV receptor protein nectin-1, nectin-2, and CD155. Our results suggest germacrone could be used as an efficient microbicide or immunomodulatory agent in the control of the emerging variant PRV.


title: Vaccination against Paediatric Respiratory Pathogens

text: Acute respiratory infections (ARIs) are extremely common in children, especially those under 5 years old. They can lead to complications, super-infection, respiratory failure, and even compromised respiratory function in adulthood. For some of the responsible pathogens, vaccines are available. This review reports current issues about vaccines against the main respiratory pathogens to highlight the available strategies to reduce the burden of paediatric respiratory disease. The optimal use of influenza, pneumococcal, pertussis and measles vaccines is required in order to reduce ARI burden. Vaccination coverage rates must be improved to achieve the full benefits of these vaccines. Recently, advances in the knowledge of respiratory syncytial virus structural biology and immunology as well as the development of new techniques to generate vaccine candidates have increased the number of promising vaccines even against this harmful pathogen.


title: Antimicrobial Stewardship Programs in Community Health Systems Perceived by Physicians and Pharmacists: A Qualitative Study with Gap Analysis

text: Antimicrobial stewardship program (ASP) is one of the most important strategies for managing infectious disease treatment and preventing antimicrobial resistance. The successful implementation of ASP in the community health system (CHS) has been challenging. We evaluated perceptions of current ASP, potential setbacks of ASP implementation, and future demands on ASP services among physicians and pharmacists in the CHS. The qualitative research was conducted through in-depth individual interviews and focus group discussions with 11 physicians and 11 pharmacists. In addition, a quantitative gap analysis was conducted to assess the different awareness and demands on services of ASP and preferred antimicrobial-related problems (ARP). In overall, perceptions of ASP varied by profession. The identified setbacks were unorganized institutional leadership, the undefined roles of healthcare professionals, a lack of reimbursement, the hierarchical structure of the health system, and the labor-intensive working environment of pharmacy services. Although demands for ASP improvement were similar among professionals, they had different preferences in prioritizing each service item of ASP/ARP development and the profession responsible for each service. Continuous administrative and financial investments, understanding ASP contents, ASP-specific information technology, and interdisciplinary collaboration with good communication among healthcare professions are needed to continue the progression of ASP.


title: Assessment of Immunogenicity and Efficacy of a Zika Vaccine Using Modified Vaccinia Ankara Virus as Carriers

text: Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has spread to more than 70 countries worldwide since 2015. Despite active research, there are currently no licensed vaccines or therapeutics. We have previously reported the development of various adenoviral vectored vaccine candidates (ChAdOx1 ZIKV) with the ability to stimulate effective immunity in mice and provide protection upon a ZIKV challenge model, using a non-adjuvanted single vaccination approach. In this study, we constructed various modified vaccinia Ankara (MVA) viruses to express the ZIKV Envelope (E) with modifications on the precursor membrane (prM) or on the C-terminus envelope transmembrane domain (TM), similar to our ChAdOx1 vaccine candidates. MVA-ZIKV vaccine candidates were evaluated as a non-adjuvanted single vaccination regimen against a ZIKV Brazilian isolate, using viraemia as the correlate of protection. Here, we report the induction of a modest level of anti-ZIKV E antibodies by all MVA vectored vaccines and sub-optimal efficacy in a ZIKV challenge model. Our results indicate the requirement of additional strategies when using MVA-ZIKV vaccines to afford sterile protection upon a non-adjuvanted and single vaccination regime.


title: Molecular epidemiology and antimicrobial resistance features of Acinetobacter baumannii clinical isolates from Pakistan

text: BACKGROUND: Acinetobacter baumannii is a Gram-negative opportunistic pathogen with a notorious reputation of being resistant to antimicrobial agents. The capability of A. baumannii to persist and disseminate between healthcare settings has raised a major concern worldwide. METHODS: Our study investigated the antibiotic resistance features and molecular epidemiology of 52 clinical isolates of A. baumannii collected in Pakistan between 2013 and 2015. Antimicrobial susceptibility patterns were determined by the agar disc diffusion method. Comparative sequence analyses of the ampC and bla(OXA-51-like) alleles were used to assign the isolates into clusters. The whole genomes of 25 representative isolates were sequenced using the MiSeq Desktop Sequencer. Free online applications were used to determine the phylogeny of genomic sequences, retrieve the multilocus sequence types (ST), and detect acquired antimicrobial resistance genes. RESULTS: Overall, the isolates were grouped into 7 clusters and 3 sporadic isolates. The largest cluster, Ab-Pak-cluster-1 (bla(OXA-66) and ISAba1-ampC-19) included 24 isolates, belonged to ST2 and International clone (IC) II, and was distributed between two geographical far-off cities, Lahore and Peshawar. Ab-Pak-clusters-2 (bla(OXA-66), ISAba1-ampC-2), and -3 (bla(OXA-66), ISAba1-ampC-20) and the individual isolate Ab-Pak-Lah-01 (ISAba1-bla(OXA-66), ISAba1-ampC-2) were also assigned to ST2 and IC II. On the other hand, Ab-Pak-clusters-4 (bla(OXA-69), ampC-1), -5 (bla(OXA-69), ISAba1-ampC-78), and -6A (bla(OXA-371), ISAba1-ampC-3) belonged to ST1, while Ab-Pak-cluster-6B (bla(OXA-371), ISAba1-ampC-8) belonged to ST1106, with both ST1 and ST1106 being members of IC I. Five isolates belonged to Ab-Pak-cluster-7 (bla(OXA-65), ampC-43). This cluster corresponded to ST158, showed a well-delineated position on the genomic phylogenetic tree, and was equipped with several antimicrobial resistance genes including bla(OXA-23) and bla(GES-11). CONCLUSIONS: Our study detected the occurrence of 7 clusters of A. baumannii in Pakistan. Altogether, 6/7 of the clusters and 45/52 (86.5%) of the isolates belonged to IC I (n = 9) or II (n = 36), making Pakistan no exception to the global domination of these two clones. The onset of ST158 in Pakistan marked a geographical dispersal of this clone beyond the Middle East and brought up the need for a detailed characterization.


title: Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

text: BACKGROUND: In endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. In subsequent pregnancies, women develop protective immunity to pregnancy-associated malaria and this has been hypothesized to be due to the acquisition of antibodies to the parasite variant surface antigen VAR2CSA. In this systematic review we provide the first synthesis of the association between antibodies to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes. METHODS: We conducted a systematic review and meta-analysis of population-based studies (published up to 07 June 2019) of pregnant women living in P. falciparum endemic areas that examined antibody responses to pregnancy-specific P. falciparum antigens and outcomes including placental malaria, low birthweight, preterm birth, peripheral parasitaemia, maternal anaemia, and severe malaria. RESULTS: We searched 6 databases and identified 33 studies (30 from Africa) that met predetermined inclusion and quality criteria: 16 studies contributed estimates in a format enabling inclusion in meta-analysis and 17 were included in narrative form only. Estimates were mostly from cross-sectional data (10 studies) and were heterogeneous in terms of magnitude and direction of effect. Included studies varied in terms of antigens tested, methodology used to measure antibody responses, and epidemiological setting. Antibody responses to pregnancy-specific pRBC and VAR2CSA antigens, measured at delivery, were associated with placental malaria (9 studies) and may therefore represent markers of infection, rather than correlates of protection. Antibody responses to pregnancy-specific pRBC, but not recombinant VAR2CSA antigens, were associated with trends towards protection from low birthweight (5 studies). CONCLUSIONS: Whilst antibody responses to several antigens were positively associated with the presence of placental and peripheral infections, this review did not identify evidence that any specific antibody response is associated with protection from pregnancy-associated malaria across multiple populations. Further prospective cohort studies using standardized laboratory methods to examine responses to a broad range of antigens in different epidemiological settings and throughout the gestational period, will be necessary to identify and prioritize pregnancy-specific P. falciparum antigens to advance the development of vaccines and serosurveillance tools targeting pregnant women.


title: A pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards

text: BACKGROUND: The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. METHODS: We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. RESULTS: A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1–4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients. CONCLUSION: It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02917551. Registered on September 28, 2016.


title: Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis

text: Standard inactivated influenza vaccines are poorly immunogenic in immunologically naive healthy young children, who are particularly vulnerable to complications from influenza. For them, there is an unmet need for better influenza vaccines. Oil-in-water emulsion-adjuvanted influenza vaccines are promising candidates, but clinical trials yielded inconsistent results. Here, we meta-analyze randomized controlled trials with efficacy data (3 trials, n = 15,310) and immunogenicity data (17 trials, n = 9062). Compared with non-adjuvanted counterparts, adjuvanted influenza vaccines provide a significantly better protection (weighted estimate for risk ratio of RT-PCR-confirmed influenza: 0.26) and are significantly more immunogenic (weighted estimates for seroprotection rate ratio: 4.6 to 7.9) in healthy immunologically naive young children. Nevertheless, in immunologically non-naive children, adjuvanted and non-adjuvanted vaccines provide similar protection and are similarly immunogenic. These results indicate that oil-in-water emulsion adjuvant improves the efficacy of inactivated influenza vaccines in healthy young children at the first-time seasonal influenza vaccination.


title: Leukocyte-derived extracellular DNA contributes to abnormal pressure elevation in the extracorporeal circulation circuit

text: An abnormal elevation in pressure is a serious complication involving the extracorporeal circulation circuit. Clot formation might be associated with this complication, but the precise mechanism of an abnormal elevation in pressure has not been identified. We investigated sufficient conditions for in-circuit elevation in pressure using an ex vivo re-circulation circuit with porcine blood. Specifically, we investigated the effect of blood conditions, the type of anticoagulation, and pro-inflammatory stimulation on in-circuit pressure. We also examined the cause of an abnormal elevation of in-circuit pressure by specifically degrading DNA, RNA, or protein components of an obstructed filter and by using immunofluorescent techniques. Neither a change in temperature nor change in pH in the blood increased in-circuit pressure. In contrast, long-term storage of blood, pro-inflammatory stimulation by phorbol myristate acetate, and heparin administration significantly increased in-circuit pressure. Abnormal in-circuit elevation in pressure was associated with deposition of extracellular DNA on the outlet surface of the filter. Administration of DNase resulted in a rapid decline of in-circuit pressure. In an ex vivo re-circulation circuit system, extracellular DNA deposition on the filter is responsible for an abnormal in-circuit elevation in pressure. Senescent leukocytes, stimulated leukocytes, and heparin exposure are associated with extracellular DNA deposition.


title: Description of the Risk Management of Medication Errors for Centrally Authorised Products in the European Union

text: INTRODUCTION: Medication errors can have serious consequences for patients. To prevent the occurrence of medication errors in clinical practice, safety concerns may be included in the risk management plan and subsequently be addressed with routine and/or additional risk minimisation measures. OBJECTIVE: This study aims to describe safety concerns around medication errors and the risk minimisation measures for centrally authorised products in the European Union. METHODS: All safety concerns included in the risk management plans of originator centrally authorised products, authorised between 1 January, 2010 and 31 December, 2017, were collected from the European Public Assessment Report registry. Medication error safety concerns were categorised by Anatomical Therapeutic Classification code, year of authorisation, type of medication error and type of risk minimisation measure. RESULTS: During the study period, 311 centrally authorised products were approved, of which 84 had at least one medication error safety concern. The proportion of centrally authorised products with medication error safety concerns showed variation between 2010 and 2017 ranging from 15.2% to 36.4%. In total, 95 medication error safety concerns were identified. The type of medication error was highly variable, drug administration error was listed most frequently (n = 17). For 27 out of 95 medication error safety concerns, corresponding to 23 centrally authorised products, additional risk minimisation measures were required. All additional risk minimisation measures consisted of educational material targeted at healthcare professionals (85.2%) and/or patients (51.9%). For 78.3% of centrally authorised products with additional risk minimisation measures for medication errors, studies to evaluate the effectiveness of the additional risk minimisation measures were agreed upon. CONCLUSIONS: Medication error safety concerns were listed for almost a quarter of centrally authorised products approved during the study period. Further research is needed to evaluate the effectiveness and continued need for additional risk minimisation measures for medication errors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40264-019-00874-7) contains supplementary material, which is available to authorized users.


title: Evolution and Determinants of Lung Function until Late Infancy among Infants Born Preterm

text: To investigate the evolution of lung function in preterm infants with and without bronchopulmonary dysplasia (BPD) and to determine the perinatal characteristics associated with indexes of lung function in later infancy. Longitudinal lung function assessments were performed at approximately 6, 12, 18, and 24 months of corrected age in preterm infants. Perinatal characteristics were further analyzed to ascertain the determinants of lung function indexes. Although all preterm infants (n = 121; 61 without BPD and 60 with BPD) exhibited decreased lung function in early infancy (6 months of age), after body length was adjusted for, only infants with BPD exhibited poor performance. Furthermore, the lung function of infants with mild to moderate BPD caught up gradually, but the generally poor lung function performance of infants with severe BPD, especially in forced expiratory flow, persisted until later age (24 months). Regarding perinatal characteristics, the z-score of body length at the time of examination and total number of days on positive-pressure ventilation are the major determinants of lung function in later infancy.


title: In vivo rescue of recombinant Zika virus from an infectious cDNA clone and its implications in vaccine development

text: Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family that has been known to circulate for decades causing mild febrile illness. The more recent ZIKV outbreaks in the Americas and the Caribbean associated with congenital malformations and Guillain-Barré syndrome in adults have placed public health officials in high alert and highlight the significant impact of ZIKV on human health. New technologies to study the biology of ZIKV and to develop more effective prevention options are highly desired. In this study we demonstrate that direct delivery in mice of an infectious ZIKV cDNA clone allows the rescue of recombinant (r)ZIKV in vivo. A bacterial artificial chromosome containing the sequence of ZIKV strain Paraiba/2015 under the control of the cytomegalovirus promoter was complexed with a commercial transfection reagent and administrated using different routes in type-I interferon receptor deficient A129 mice. Clinical signs and death associated with ZIKV viremia were observed in mice. The rZIKV recovered from these mice remained fully virulent in a second passage in mice. Interestingly, infectious rZIKV was also recovered after intraperitoneal inoculation of the rZIKV cDNA in the absence of transfection reagent. Further expanding these studies, we demonstrate that a single intraperitoneal inoculation of a cDNA clone encoding an attenuated rZIKV was safe, highly immunogenic, and provided full protection against lethal ZIKV challenge. This novel in vivo reverse genetics method is a potentially suitable delivery platform for the study of wild-type and live-attenuated ZIKV devoid of confounding factors typical associated with in vitro systems. Moreover, our results open the possibility of employing similar in vivo reverse genetic approaches for the generation of other viruses and, therefore, change the way we will use reverse genetics in the future.


title: Quantitative and Fast Sterility Assurance Testing of Surfaces by Enumeration of Germinable Endospores

text: A fast Endospore Germinability Assay (EGA) was validated with traditional plate counts to enumerate single endospore germination events for monitoring surface sterilization. The assay is based on a time-gated luminescence microscopy technique enabling visualization and enumeration of individual germinating endospores. Germinating endospores release calcium dipicolinate to form highly luminescent terbium dipicolinate complexes surrounding each germinating endospore. EGA and heterotrophic plate counting (HPC) were used to evaluate the swab/rinse recovery efficiency of endospores from stainless steel surfaces. EGA and HPC results were highly correlated for endospore recovery from stainless steel coupons inoculated with range of 1,000 endospores per coupon down to sterility. Dosage-dependent decrease of surface endospore germinability were observed in dry heat, UV irradiation, oxygen plasma and vaporized hydrogen peroxide treatments, measured with EGA and HPC. EGA is a fast and complementary method to traditional HPC for quantitative sterility assurance testing of surfaces. This work introduces and validates a 15-minute or faster assay for germinable endospores to complement the conventional lengthy, culture-based surface sterility validation, which is critical in hospitals, food and pharmaceutical industries to help minimize nosocomial infection, food spoilage, and pharmaceutical contamination.


title: Dissecting the Contemporary Clerkship: Theory‐based Educational Trial of Videos Versus Lectures in Medical Student Education

text: BACKGROUND: Despite increasing use of the flipped classroom (FC) technique in undergraduate medical education, the benefit in learning outcomes over lectures is inconsistent. Best practices in preclass video design principles are rarely used, and it is unclear if videos can replace lectures in contemporary medical education. METHODS: We conducted a prospective quasi‐experimental controlled educational study comparing theory‐based videos to traditional lectures in a medical student curriculum. Medical students enrolled in an emergency medicine clerkship were randomly assigned to either a lecture group (LG) or a video group (VG). The slide content was identical, and the videos aligned with cognitive load theory‐based multimedia design principles. Students underwent baseline (pretest), week 1 (posttest), and end‐of‐rotation (retention) written knowledge tests and an observed structured clinical examination (OSCE) assessment. We compared scores between both groups and surveyed student attitudes and satisfaction with respect to the two learning methods. RESULTS: There were 104 students who participated in OSCE assessments (49 LG, 55 VG) and 101 students who participated in knowledge tests (48 LG, 53 VG). The difference in OSCE scores was statistically significant 1.29 (95% confidence interval = 0.23 to 2.35, t(102) = 2.43, p = 0.017), but the actual score difference was small from an educational standpoint (12.61 for LG, 11.32 for VG). All three knowledge test scores for both groups were not significantly different. CONCLUSIONS: Videos based on cognitive load theory produced similar results and could replace traditional lectures for medical students. Educators contemplating a FC approach should devote their valuable classroom time to active learning methods.


title: Strategies to Target Specific Components of the Ubiquitin Conjugation/Deconjugation Machinery

text: The regulation of ubiquitination status in the cell is controlled by ubiquitin ligases acting in tandem with deubiquitinating enzymes. Ubiquitination controls many key processes in the cell from division to death making its tight regulation key to optimal cell function. Activity based protein profiling has emerged as a powerful technique to study these important enzymes. With around 100 deubiquitinating enzymes and 600 ubiquitin ligases in the human genome targeting a subclass of these enzymes or even a single enzyme is a compelling strategy to unpick this complex system. In this review we will discuss different approaches adopted, including activity-based probes centered around ubiquitin-protein, ubiquitin-peptide and mutated ubiquitin scaffolds. We examine challenges faced and opportunities presented to increase specificity in activity-based protein profiling of the ubiquitin conjugation/deconjugation machinery.


title: Evaluating DREAMS HIV prevention interventions targeting adolescent girls and young women in high HIV prevalence districts in South Africa: protocol for a cross-sectional study

text: BACKGROUND: Young women in sub-Saharan Africa remain at the epicentre of the HIV epidemic, with surveillance data indicating persistent high levels of HIV incidence. In South Africa, adolescent girls and young women (AGYW) account for a quarter of all new HIV infections. Determined, Resilient, Empowered, AIDS-free, Mentored and Safe (DREAMS) is a strategy introduced by the United States President’s Emergency Plan for AIDS Relief (PEPFAR) aimed at reducing HIV incidence among AGYW in 10 countries in sub-Saharan Africa by 25% in the programme’s first year, and by 40% in the second year. This study will assess the change in HIV incidence and reduction in risk associated behaviours that can be attributed to the DREAMS initiative in South Africa, using a population-based cross-sectional survey. METHODS: Data will be collected from a household-based representative sample of AGYW (between the ages 12–24 years) in four high prevalence districts (more than 10% of the population have HIV in these districts) in South Africa in which DREAMS has been implemented. A stratified cluster-based sampling approach will be used to select eligible participants for a cross-sectional survey with 18,500, to be conducted over 2017/2018. A questionnaire will be administered containing questions on sexual risk behaviour, selected academic and developmental milestones, prevalence of gender based violence, whilst examining exposure to DREAMS programmes. Biological samples, including two micro-containers of blood and self-collected vulvovaginal swab samples, are collected in each survey to test for HIV infection, HIV incidence, sexually transmitted infections (STIs) and pregnancy. This study will measure trends in population level HIV incidence using the Limiting antigen (LAg) Avidity Enzyme Immuno-Assay (EIA) and monitor changes in HIV incidence. DISCUSSION: Ending the HIV/AIDS pandemic by 2030 requires the continual monitoring and evaluation of prevention programmes, with the aim of optimising efforts and ensuring the achievement of epidemic control. This study will determine the impact DREAMS interventions have had on HIV incidence among AGYW in a ‘real world, non-trial setting’.


title: Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia

text: BACKGROUND: Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for which new treatment and prevention strategies are urgently required, due to severely limited therapeutic options. South and Southeast Asia are major hubs for antimicrobial-resistant (AMR) K. pneumoniae and also for the characteristically antimicrobial-sensitive, community-acquired “hypervirulent” strains. The emergence of hypervirulent AMR strains and lack of data on exopolysaccharide diversity pose a challenge for K. pneumoniae BSI control strategies worldwide. METHODS: We conducted a retrospective genomic epidemiology study of 365 BSI K. pneumoniae from seven major healthcare facilities across South and Southeast Asia, extracting clinically relevant information (AMR, virulence, K and O antigen loci) using Kleborate, a K. pneumoniae-specific genomic typing tool. RESULTS: K. pneumoniae BSI isolates were highly diverse, comprising 120 multi-locus sequence types (STs) and 63 K-loci. ESBL and carbapenemase gene frequencies were 47% and 17%, respectively. The aerobactin synthesis locus (iuc), associated with hypervirulence, was detected in 28% of isolates. Importantly, 7% of isolates harboured iuc plus ESBL and/or carbapenemase genes. The latter represent genotypic AMR-virulence convergence, which is generally considered a rare phenomenon but was particularly common among South Asian BSI (17%). Of greatest concern, we identified seven novel plasmids carrying both iuc and AMR genes, raising the prospect of co-transfer of these phenotypes among K. pneumoniae. CONCLUSIONS: K. pneumoniae BSI in South and Southeast Asia are caused by different STs from those predominating in other regions, and with higher frequency of acquired virulence determinants. K. pneumoniae carrying both iuc and AMR genes were also detected at higher rates than have been reported elsewhere. The study demonstrates how genomics-based surveillance—reporting full molecular profiles including STs, AMR, virulence and serotype locus information—can help standardise comparisons between sites and identify regional differences in pathogen populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0706-y) contains supplementary material, which is available to authorized users.


title: Implementation of human factors engineering approach to improve environmental cleaning and disinfection in a medical center

text: BACKGROUND: Inadequate hospital cleaning may contribute to cross-transmission of pathogens. It is important to implement effective cleaning for the safe hospital environment. We conducted a three-phase study using human factors engineering (HFE) approach to enhance environmental cleanliness. METHODS: This study was conducted using a prospective interventional trial, and 28 (33.3%) of 84 wards in a medical center were sampled. The three-phases included pre-intervention analysis (Phase 1), implementing interventions by HFE principles (Phase 2), and programmatic analysis (Phase 3). The evaluations of terminal cleaning and disinfection were performed using the fluorescent marker, the adenosine triphosphate bioluminescence assay, and the aerobic colony count method simultaneously in all phases. Effective terminal cleaning and disinfection was qualified with the aggregate outcome of the same 10 high-touch surfaces per room. A score for each high-touch surface was recorded, with 0 denoting a fail and 10 denoting a pass by the benchmark of the evaluation method, and the total terminal cleaning and disinfection score (TCD score) was a score out of 100. RESULTS: In each phase, 840 high-touch surfaces were collected from 84 rooms after terminal cleaning and disinfection. After the interventions, the TCD score by the three evaluation methods all showed significant improved. The carriage incidence of multidrug-resistant organism (MDRO) decreased significantly from 4.1 per 1000 patient-days to 3.6 per 1000 patient-days (P = .03). CONCLUSION: The HFE approach can improve the thoroughness and the effectiveness of terminal cleaning and disinfection, and resulted in a reduction of patient carriage of MDRO at hospitals. Larger studies are necessary to establish whether such efforts of cleanliness can reduce the incidence of healthcare-associated infection.


title: Human antibodies neutralizing diphtheria toxin in vitro and in vivo

text: Diphtheria is an infectious disease caused by Corynebacterium diphtheriae. The bacterium primarily infects the throat and upper airways and the produced diphtheria toxin (DT), which binds to the elongation factor 2 and blocks protein synthesis, can spread through the bloodstream and affect organs, such as the heart and kidneys. For more than 125 years, the therapy against diphtheria has been based on polyclonal horse sera directed against DT (diphtheria antitoxin; DAT). Animal sera have many disadvantages including serum sickness, batch-to-batch variation in quality and the use of animals for production. In this work, 400 human recombinant antibodies were generated against DT from two different phage display panning strategies using a human immune library. A panning in microtiter plates resulted in 22 unique in vitro neutralizing antibodies and a panning in solution combined with a functional neutralization screening resulted in 268 in vitro neutralizing antibodies. 61 unique antibodies were further characterized as scFv-Fc with 35 produced as fully human IgG1. The best in vitro neutralizing antibody showed an estimated relative potency of 454 IU/mg and minimal effective dose 50% (MED50%) of 3.0 pM at a constant amount of DT (4x minimal cytopathic dose) in the IgG format. The targeted domains of the 35 antibodies were analyzed by immunoblot and by epitope mapping using phage display. All three DT domains (enzymatic domain, translocation domain and receptor binding domain) are targets for neutralizing antibodies. When toxin neutralization assays were performed at higher toxin dose levels, the neutralizing capacity of individual antibodies was markedly reduced but this was largely compensated for by using two or more antibodies in combination, resulting in a potency of 79.4 IU/mg in the in vivo intradermal challenge assay. These recombinant antibody combinations are candidates for further clinical and regulatory development to replace equine DAT.


title: Novel Chimeric Multiepitope Vaccine for Streptococcosis Disease in Nile Tilapia (Oreochromis niloticus Linn.)

text: Streptococcus agalactiae is a causative agent of streptococcosis disease in various fish species, including Nile tilapia (Oreochromis niloticus Linn.). Vaccination is an effective disease prevention and control method, but limitations remain for protecting against catastrophic mortality of fish infected with different strains of streptococci. Immunoproteomics analysis of S. agalactiae was used to identify antigenic proteins and construct a chimeric multiepitope vaccine. Epitopes from five antigenic proteins were shuffled in five helices of a flavodoxin backbone, and in silico analysis predicted a suitable RNA and protein structure for protein expression. 45F2 and 42E2 were identified as the best candidates for a chimeric multiepitope vaccine. Recombinant plasmids were constructed to produce a recombinant protein vaccine and DNA vaccine system. Overexpressed proteins were determined to be 30 kDa and 25 kDa in the E. coli and TK1 systems, respectively. The efficacy of the chimeric multiepitope construct as a recombinant protein vaccine and DNA vaccine was evaluated in Nile tilapia, followed by S. agalactiae challenge at 1 × 10(7) CFU/mL. Relative percentage survival (RPS) and cumulative mortality were recorded at approximately 57–76% and 17–30%, respectively. These chimeric multiepitope vaccines should be applied in streptococcosis disease control and developed into a multivalent vaccine to control multiple diseases.


title: An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

text: Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two- and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.


title: The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

text: BACKGROUND: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. METHODS: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. DISCUSSION: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? TRIAL REGISTRATION: EudraCT number: 2017–004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.


title: A self-aggregating peptide: implications for the development of thermostable vaccine candidates

text: BACKGROUND: The use of biomaterials has been expanded to improve the characteristics of vaccines. Recently we have identified that the peptide PH((1–110)) from polyhedrin self-aggregates and incorporates foreign proteins to form particles. We have proposed that this peptide can be used as an antigen carrying system for vaccines. However, the immune response generated by the antigen fused to the peptide has not been fully characterized. In addition, the adjuvant effect and thermostability of the particles has not been evaluated. RESULTS: In the present study we demonstrate the use of a system developed to generate nano and microparticles carrying as a fusion protein peptides or proteins of interest to be used as vaccines. These particles are purified easily by centrifugation. Immunization of animals with the particles in the absence of adjuvant result in a robust and long-lasting immune response. Proteins contained inside the particles are maintained for over 1 year at ambient temperature, preserving their immunological properties. CONCLUSION: The rapid and efficient production of the particles in addition to the robust immune response they generate position this system as an excellent method for the rapid response against emerging diseases. The thermostability conferred by the particle system facilitates the distribution of the vaccines in developing countries or areas with no electricity.


title: Is countries’ transparency associated with gaps between countries’ self and external evaluations for IHR core capacity?

text: BACKGROUND: This study aims to evaluate the gap between countries’ self-evaluation and external evaluation regarding core capacity of infectious disease control required by International Health Regulations and the influence factors of the gap. METHODS: We collected countries’ self-evaluated scores (International Health Regulations Monitoring tool, IHRMT) of 2016 and 2017, and external evaluation scores (Joint External Evaluation, JEE) from WHO website on 4rd and 27rd November, 2018. There were 127 and 163 countries with IHRMT scores in 2016 and in 2017, and 74 countries with JEE scores included in the analysis. The gap between countries’ self-evaluation and external evaluation was represented by the difference between condensed IHR scores and JEE. Civil liberties (CL) scores were collected as indicators of the transparency of each country. The Human Development Index (HDI) and data indicating the density of physicians and nurses (HWD) were collected to reflect countries’ development and health workforce statuses. Then, chi-square test and logistic regression were performed to determine the correlation between the gap of IHRMT and JEE, and civil liberties, human development, and health workforce status. RESULTS: Countries’ self-evaluation scores significantly decreased from 2016 to 2017. Countries’ external evaluation scores are consistently 1 to 1.5 lower than self-evaluation scores. There were significantly more countries with high HDI status, high CL status and high HWD status in groups with bigger gap between IHRMT and JEE. And countries with higher HDI status presented a higher risk of having bigger gap between countries’ self and external scores (OR = 3.181). CONCLUSION: Our study result indicated that countries’ transparency represented by CL status do play a role in the gap between IHR and JEE scores. But HDI status is the key factor which significantly associated with the gap. The main reason for the gap in the current world is the different interpretation of evaluation of high HDI countries, though low CL countries tended to over-scored their capacity.


title: Anesthetic management of a patient with a continuous-flow left ventricular assist device for video-assisted thoracoscopic surgery: a case report

text: BACKGROUND: As patients with left ventricular assist device (LVAD) have long expected survival, the incidence of noncardiac surgery in this patient population is increasing. Here, we present the anesthetic management of a patient with a continuous-flow LVAD who underwent video-assisted thoracic surgery (VATS). CASE PRESENTATION: A 37-year-old man with LVAD was scheduled to undergo VATS because of repeated spontaneous pneumothorax. Generally, patients with these devices have marginal right heart function; therefore, it is important to avoid factors that worsen pulmonary vascular resistance (PVR). However, VATS requires one-lung ventilation (OLV) and it tends to cause increase in PVR, leading to right heart failure. In the present case, when the patient was set in a lateral decubitus position and progressive hypoxia was observed during OLV, transesophageal echocardiography demonstrated a dilated right ventricle and a temporally flattened interventricular septum, and the central venous pressure increased to approximately 20 mmHg. Because we anticipated deterioration of right heart function, dobutamine and milrinone were administered and/or respirator settings were changed to decrease PVR for maintaining LVAD performance. Finally, resection of a bulla was completed, and the patient was discharged in stable condition on postoperative day 37. CONCLUSIONS: The anesthetic management of a patient with LVAD during VATS is challenging because the possible hemodynamic changes induced by hypoxia associated with OLV affect LVAD performance and right heart function. In our experience, VATS that requires OLV will be well tolerated in a patient with LVAD with preserved right heart function, and a multidisciplinary approach to maintain right heart function will be needed.


title: Comparing “insider” and “outsider” news coverage of the 2014 Ebola outbreak

text: OBJECTIVES: Information provided by news media during an infectious disease outbreak can affect the actions taken to safeguard public health. There has been little evaluation of how the content of news published during an outbreak varies by location of the news outlet. This study analyzes coverage of the 2014 Ebola outbreak by one news outlet operating within a country affected by the outbreak and one country not directly affected. METHODS: A qualitative content analysis was conducted of articles published in two national news outlets, The Globe and Mail (Canada) and the Vanguard (Nigeria), between January 1 and December 31, 2014. Articles available through LexisNexis Academic were sorted by date and sampled using a stratified sampling method (The Globe and Mail n = 100; Vanguard n = 105). A coding scheme was developed and modified to incorporate emerging themes until saturation was achieved. RESULTS: There were substantial differences in outbreak coverage in terms of the topic and content of the articles, as well as the sources consulted. The Globe and Mail framed the outbreak in terms of national security and national interests, as well as presenting it as an international humanitarian crisis. In contrast, the Vanguard framed the outbreak almost exclusively in terms of public health. CONCLUSION: Our findings highlight how different geographic contexts can shape reporting on the same event. Further research is required to investigate how the political, social or economic situations of a country shape its news media, potentially influencing actions taken to control disease outbreaks.


title: Pioneering Experience of Uniportal Video-Assisted Thoracoscopic Surgery for Anterior Release of Severe Thoracic Scoliosis

text: The optimal way to treat severe thoracic scoliosis remains controversial. Compared with conventional procedures, the uniportal video-assisted thoracoscopic surgery (UniVATS) rises in popularity in thoracic surgery because of less pain and faster recovery. This retrospective study aimed to apply UniVATS to treat severe thoracic scoliosis. Between October 2013 and March 2018, eight scoliotic patients with extremely large Cobb angle and profoundly limited flexibility underwent UniVATS for anterior release, followed by posterior instrumentation and fusion. The mean age at the time of surgery was 14.8 ± 2.4 years and the mean follow-up was 2.2 ± 1.3 years. The average levels of anterior thoracic discectomy and posterior fusion were 3.6 ± 0.7 and 11.5 ± 1.2, respectively. The mean coronal and sagittal correction rates were 70 ± 19% and 71 ± 23%, respectively. UniVATS contributed to minor access trauma (3-cm incision) with minimal blood loss, shorter operation time (75 ± 13 mins), less requirement of stay in the intensive care unit (0.3 ± 0.5 day) or chest tube placement (0.3 ± 0.7 day), speedier and narcotic-free recovery, and earlier ambulation within one day. This is the first study to assess the safety and efficacy of UniVATS in the treatment of severely stiff thoracic scoliosis, providing comparable surgical outcomes, less pain, faster recovery and superior cosmetic results without significant complications.


title: Antibodies to watch in 2020

text: This 2020 installment of the annual ‘Antibodies to Watch’ series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry’s clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future. *Note on key updates through December 18, 2019: 1) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 6; 2) the European Commission approved romosozumab on December 9, 2019; 3) the European Medicines Agency issued a positive opinion for brolucizumab; 4) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 5) GlaxoSmithKline submitted a BLA for belantamab mafodotin; and 6) the status of the Phase 3 study (NCT04128696) of GSK3359609, a humanized IgG4 anti-ICOS antibody, in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting.


title: Canadian Newspaper Coverage of the A/H1N1 Vaccine Program

text: OBJECTIVES: The A/H1N1 mass vaccination program in Canada garnered considerable attention from the media, including extensive newspaper coverage. Media reports have been shown to influence the public’s health care decisions, including vaccination choices. We analyzed Canadian newspapers’ portrayal of the A/H1N1 vaccine including mention of risks and benefits of the vaccine and whether the article supported, questioned or was neutral about the vaccine. METHODS: We compiled a data set of Canadian newspaper articles (N=234) and conducted a frequency content analysis to examine discussion and/or mention of evidence concerning vaccination, risks of the A/H1N1 virus and the vaccine, and tone of article in regards to the vaccination program in Canada. RESULTS: Reasons for getting vaccinated appeared in 71.8% of the articles, whereas only 18.4% provided reasons against getting vaccinated. Discussion of evidence to support claims for or against getting vaccinated appeared in only 27.8% and 6.8% of the articles, respectively. Risks associated with contracting the A/H1N1 virus were discussed in 49.6% of the articles and risks of the A/H1N1 vaccine were discussed in 12.4% of the articles. CONCLUSION: Newspaper coverage in Canada was largely supportive of the A/H1N1 mass vaccination program. However, serious risks associated with contracting the A/H1N1 virus were also frequently discussed in the print media. The news articles rarely presented direct evidence to support statements that the vaccine was safe, effective and properly tested. Known risks (such as potential allergic reactions and flu-like side effects) of the vaccine were rarely reported. The relationship between media portrayals and vaccine uptake warrants further research.


Infectious Disease Prevention and Control: Remembering 1908 and Imagining 2108


title: A Comparison of Methods for Forecasting Emergency Department Visits for Respiratory Illness Using Telehealth Ontario Calls

text: Objectives: Anticipating increases in hospital emergency department (ED) visits for respiratory illness could help time interventions such as opening flu clinics to reduce surges in ED visits. Five different methods for estimating ED visits for respiratory illness from Telehealth Ontario calls are compared, including two non-linear modeling methods. Daily visit estimates up to 14 days in advance were made at the health unit level for all 36 Ontario health units. Methods: Telehealth calls from June 1, 2004 to March 14, 2006 were included. Estimates generated by regression, Exponentially Weighted Moving Average (EWMA), Numerical Methods for Subspace State Space Identification (N4SID), Fast Orthogonal Search (FOS), and Parallel Cascade Identification (PCI) were compared to the actual number of ED visits for respiratory illness identified from the National Ambulatory Care Reporting System (NACRS) database. Model predictor variables included Telehealth Ontario calls and upcoming holidays/weekends. Models were fit using the first 304 days of data and prediction accuracy was measured over the remaining 348 days. Results: Forecast accuracy was significantly better (p<0.0001) for the 12 Ontario health units with a population over 400,000 (75% of the Ontario population) than for smaller health units. Compared to regression, FOS produced better estimates (p=0.03) while there was no significant improvement for PCI-based estimates. FOS, PCI, EWMA and N4SID performed worse than regression over the remaining smaller health units. Conclusion: Telehealth can be used to estimate ED visits for respiratory illness at the health unit level. Non-linear modeling methods produced better estimates than regression in larger health units.


Response to Huang et al. “Herpesviridae reactivation for poor outcome in ARDS patients with ECMO: criminal or witness?”


title: Pandemic Influenza (H1N1): Our Canadian Response

text: The emergence of pandemic influenza (H1N1) 2009 in spring 2009 has provided a real test to the pandemic preparations that Canada, other countries and the World Health Organization have undertaken. Although formidable challenges remain, Canada is as well prepared as any country to address the second wave of the pandemic expected in the fall.


title: Restrictive Measures in an Influenza Pandemic: A Qualitative Study of Public Perspectives

text: OBJECTIVES: Recent experiences have demonstrated that restrictive measures remain a useful public health tool during infectious disease outbreaks. However, the use of restrictive measures is not without controversy, as there is no agreed-upon threshold for when and how to invoke restrictive measures. The objectives of this study are to solicit perspectives from Canadians on the ethical considerations of using restrictive measures in response to influenza pandemics, and in turn, to use public views to contribute to a better understanding of what is considered to be the justifiable use of restrictive measures. METHODS: A series of town hall focus groups with Canadian residents from June 2008 to May 2009, in three Canadian regions, in order to achieve broad public engagement (n=3 focus groups with a total of 17 participants). RESULTS: Two key themes emerged from all town hall focus groups: 1) create an environment for compliance through communication rather than enforcement, and 2) establish the delineation between individual rights, community values, and the greater good. CONCLUSION: While there is a need for a decision-making authority and even a mechanism for enforcement, our data suggest that a more tractable approach to restrictive measures is one that enables individuals to voluntarily comply by creating an environment to compel compliance based on communication. This approach requires restrictive measures to be a) proportional to the threat, b) implemented along with reciprocal arrangements provided to those affected, and c) accompanied by open and transparent communication throughout all stages so that citizens can both understand and participate in decision-making.


Public Health Nursing in Early 20(th) Century Canada


title: Risk factors of nosocomial infection after cardiac surgery in children with congenital heart disease

text: BACKGROUND: The aim of our study was to analyze the risk factors of nosocomial infection after cardiac surgery in children with congenital heart disease (CHD). METHODS: We performed a retrospective cohort study, and children with CHD who underwent open-heart surgeries at Shanghai Children’s Medical Center from January 1, 2012 to December 31, 2018 were included. The baseline characteristics of these patients of different ages, including neonates (0–1 months old), infants (1–12 months old) and children (1–10 years old), were analyzed, and the association of risk factors with postoperative nosocomial infection were assessed. RESULTS: A total of 11,651 subjects were included in the study. The overall nosocomial infection rate was 10.8%. Nosocomial infection rates in neonates, infants, and children with congenital heart disease were 32.9, 15.4, and 5.2%, respectively. Multivariate logistic regression analysis found age (OR 0798, 95%CI: 0.769–0.829; P < 0.001), STS risk grade (OR 1.267, 95%CI: 1.159–1.385; P < 0.001), body mass index (BMI) <5th percentile (OR 1.295, 95%CI: 1.023–1.639; P = 0.032), BMI >95th percentile (OR 0.792, 95%CI: 0.647–0.969; P = 0.023), cardiopulmonary bypass (CPB) time (OR 1.008, 95%CI: 1.003–1.012; P < 0.001) and aortic clamping time (OR 1.009, 1.002–1.015; P = 0.008) were significantly associated with nosocomial infection in CHD infants. After adjusted for confounding factors, we found STS risk grade (OR 1.38, 95%CI: 1.167–1.633; P < 0.001), BMI < 5th percentile (OR 1.934, 95%CI: 1.377–2.715; P < 0.001), CPB time (OR 1.018, 95%CI: 1.015–1.022; P < 0.001), lymphocyte/WBC ratio<cut off value (OR 3.818, 95%CI: 1.529–9.533; P = 0.004) and AST>cut off value (OR 1.546, 95%CI: 1.119–2.136; P = 0.008) were significantly associated with nosocomial infection in CHD children. CONCLUSION: Our study suggested STS risk grade, BMI, CPB duration, low lymphocyte/WBC or high neutrophil/WBC ratio were independently associated with nosocomial infection in CHD infant and children after cardiac surgery.


title: HIV testing, test results and factors influencing among infants born to HIV positive mothers in public hospitals of Mekelle City, North Ethiopia: a cross-sectional study

text: BACKGROUND: Timely infant testing for HIV is critical to ensure optimal treatment outcomes among exposed infants. While world health organization recommends HIV exposed infants to be tested between 4 to 6 weeks of age, in developing countries like Ethiopia, access to timely infant testing is still very limited. The study is intended to assess timely infant testing, testing for HIV at the 18th month, test results and factors influencing HIV positivity among infants born to HIV positive mothers in public hospitals of Mekelle, Ethiopia. METHODS: A cross-sectional study design was employed on 558 HIV exposed infants, using consecutive sampling technique. A checklist was used to extract 4 years (January 2014–December 2017) secondary data, collected from January–April 2018. Data were analyzed using SPSS version 20, and binary logistic regression model was used to examine the association of independent variables with the outcome variables. RESULTS: Timely infant testing for HIV accounted for 346(62.0%). Mothers who attended antenatal care (AOR: 2.77; 95% CI: 1.17, 6.55) and who were counselled on feeding options (AOR: 2.01; 95% CI: 1.11, 3.65) were strongly associated with timely infant testing. Poor maternal adherence status was associated with infants’ HIV positivity at the 18th month of antibody test (AOR: 15.93; 95% CI: 2.21, 94.66). Being rural resident (AOR: 4.0; 95% CI: 1.23, 13.04), being low birth weight (AOR: 5.64; 95% CI: 2.00, 16.71) and not receiving ARV prophylaxis (AOR: 4.70; 95% CI: 1.15, 19.11) were positively associated with the overall HIV positivity. CONCLUSIONS: A considerable proportion of exposed infants did not undergo timely testing for HIV. Antenatal care follow-up and counselling on feeding options were associated with timely infant testing. Mother’s poor adherence status was associated with infant’s HIV positivity at the 18th month of antibody testing. Being rural resident, being low birth weight, and not receiving ARV prophylaxis were the factors that enhance the overall HIV positivity. Timely infant testing, counselling on feeding options and adherence should be intensified, and prevention of mother-to-child transmission program in rural settings need to be strengthened.


title: Vasopressin and its analogues in shock states: a review

text: Activation of arginine–vasopressin is one of the hormonal responses to face vasodilation-related hypotension. Released from the post-pituitary gland, vasopressin induces vasoconstriction through the activation of V1a receptors located on vascular smooth muscle cells. Due to its non-selective receptor affinity arginine–vasopressin also activates V2 (located on renal tubular cells of collecting ducts) and V1b (located in the anterior pituitary and in the pancreas) receptors, thereby potentially promoting undesired side effects such as anti-diuresis, procoagulant properties due to release of the von Willebrand’s factor and platelet activation. Finally, it also cross-activates oxytocin receptors. During septic shock, vasopressin plasma levels were reported to be lower than expected, and a hypersensitivity to its vasopressor effect is reported in such situation. Terlipressin and selepressin are synthetic vasopressin analogues with a higher affinity for the V1 receptor, and, hence, potentially less side effects. In this narrative review, we present the current knowledge of the rationale, benefits and risks of vasopressin use in the setting of septic shock and vasoplegic shock following cardiac surgery. Clearly, vasopressin administration allows reducing norepinephrine requirements, but so far, no improvement of survival was reported and side effects are frequent, particularly ischaemic events. Finally, we will discuss the current indications for vasopressin and its agonists in the setting of septic shock, and the remaining unresolved questions.


“Think Tank on the Future of Public Health in Canada”: Calgary, May 10, 2003


title: Fortune Favours the Prepared Mind: A National Perspective on Pandemic Preparedness

text: The rapid spread of avian influenza H5N1 in Asia in late 2003 has moved the world to a new state of pandemic alert. The risk of further human cases will persist, as will opportunities for a pandemic virus to emerge. Therefore, Canada has taken a number of steps to strengthen national pandemic preparedness. Coordination has been fostered through the development of a national pandemic preparedness plan and ongoing development of systems and processes for national health emergency management. Specific areas of advancement include: enhancement of rapid surveillance and communication capacity, the pandemic vaccine strategy, acquisition of an antiviral stockpile, research prioritization, international collaboration, and an international meeting of Ministers of Health (October 2005) to enhance global cooperation and coordination in advance of a possible influenza pandemic. Key next steps include: publication of the 2005 edition of the Canadian Pandemic Influenza Plan; conducting emergency exercises to help strengthen planning at all levels and across health care, emergency management and NGO sectors; developing H5N1 vaccine and clinical trials; evaluating the need to supplement national antiviral stockpile; and undertaking public and key stakeholder consultations to provide further input into planning strategies and activities.


title: Rural Youth Violence: It Is a Public Health Concern!

text: Youth violence is a significant issue for public health because of the potential for longterm impacts on individuals, families and communities. Limited exposure to violence is seen as a component of healthy living. However, there is limited understanding of violence from a public health perspective within rural communities. Rural refers to those communities with a population less than 10,000 outside the main commuting zone of a large urban area. Population health approaches, including the social determinants of health, are well supported by public health officials. Generating information about rural youth violence from a Canadian perspective would add to our understanding of these social determinants while providing guidance for policy and program development. Current understandings of youth violence are limited to an urban, and oftentimes, American perspective. An ongoing two-phase Canadian study on rural youth violence included qualitative interviews with 52 youth and the completion of a questionnaire that had been developed from the qualitative responses. The questionnaire has been completed by a larger sample of rural youth. The findings generated from this ongoing study will be useful in linking violence with social factors that impact health and thereby guide population health programs and policies. In this way, the role of public health to develop policies and implement programs will be directly influenced by evidence while addressing an ongoing public health concern.


title: What’s Public? What’s Private?: Policy Trade-offs and the Debate Over Mandatory Annual Influenza Vaccination for Health Care Workers

text: Policy decisions about public health services differ from those for personal health services. Both require trade-offs between such policy goals as liberty, security, efficiency, and equity. In public health, however, decisions about who will approve, pay for, and deliver services are often accompanied by decisions on when and how to compel individual behaviour. Policy becomes complex because different stakeholders interpret evidence differently: stakeholders may assign different weights to policy goals and may even define the same goals differently. In the debate over mandatory annual influenza vaccination for health care workers, for example, proponents as well as opponents of mandatory vaccination may convey arguments in security terms. Those in favour of mandatory vaccination emphasize subclinical infections and duty of care (public security) while those opposed emphasize risk of adverse events (personal security). Proponents assert less worker absenteeism (efficiency) while opponents stress coercion and alternate personal infection control measures (liberty and individual rights/responsibilities). Consequently, stakeholders talk past each other. Determining the place of mandatory influenza vaccination for health care workers thus demands reconciling policy trade-offs and clarifying the underlying disputes hidden in the language of the policy debate.


SARS: Lessons Learned from a Provincial Perspective


title: Long-term feeding issue and its impact on the daily life of congenital diaphragmatic hernia survivors: results of the first patient-led survey

text: BACKGROUND: CDH UK is a registered charity governed by a volunteer committee and providing informal support to patients, families and healthcare workers affected directly or indirectly with congenital diaphragmatic hernia (CDH) internationally. This is the first patient-led survey undertaken by CDH UK aiming for highlighting the feeding problems and their impact on the daily life of CDH survivors. METHODS: Answers from CDH survivors were collected through an online questionnaire (SurveyMonkey(®)) undertaken by CDH UK. The questionnaire contained questions about their feeding problems and support they were receiving for it. MAIN RESULTS: Overall, 151 patients answered some parts of the survey and 102 patients completed the questionnaire. Overall, 116 (76.8%) responders reported suffering from any type of feeding issue. Gastric acid reflux (GER) and growth retardation were the commonest symptoms experienced by 97 (91.5%) and 72 (62.2%) responders, respectively. Only 18 (17.0%) responders have received any written information on feeding or details of patient/parent support. Eighty (75.5%) responders are satisfied with the level of support they are receiving, but 78 (76.4%) answered that the whole experience associated with the disease has been very or extremely stressful. CONCLUSIONS: CDH survivors frequently have various issues with feeding, which may not be adequately supported or discussed clinically. It is desirable to assist the patients to reliable resources of long-term support, including multidisciplinary team (MDT) approach.


title: Pre-extubation functional residual capacity and risk of extubation failure among patients with hypoxemic respiratory failure

text: Hypoxemic respiratory failure is usually accompanied with a certain extent of consolidation and alveolar derecruitment, which may still be present even after the patients have achieved the status of readiness to extubate. Functional residual capacity (FRC) is an indicator of lung aeration. This study aimed to evaluate whether pre-extubation FRC is associated with the risk of extubation failure in patients with hypoxemic respiratory failure. We prospectively included 92 patients intubated for hypoxemic respiratory failure. We used a technique based on a nitrogen multiple breath washout method to measure FRC before the planned extubation. The median FRC before extubation was 25 mL/kg (Interquartile range, 20–32 mL/Kg) per predicted body weight (pBW). After extubation, 20 patients (21.7%) were reintubated within 48 hours. The median FRC was higher in the extubation success group than in the extubation failure group (27 versus 21 mL/Kg, p < 0.001). Reduced FRC was associated with higher risk of extubation failure (odds ratio, 1.14 per each decreased of 1 mL/Kg of FRC/pBW, 95% CI, 1.05–1.23, p = 0.002). In conclusion, pre-extubation FRC is associated with the risk of extubation failure. Reduced FRC may be incorporated into the traditional risk factors to identify patients at high risk for extubation failure.


title: Reproductive performance of pandemic influenza A virus infected sow herds before and after implementation of a vaccine against the influenza A (H1N1)pdm09 virus

text: BACKGROUND: Reproductive failure in sow herds due to infection with influenza A viruses has been described in the literature, but only a few studies have focused on the pathogenesis and the clinical signs of the infection. Case reports indicate an association between infections with influenza A viruses and reduced reproductive performance, although it has been difficult to experimentally reproduce the clinical outcome of poor reproductive performance. The aim of the present longitudinal field study was to compare the reproductive performance parameters before and after the implementation of vaccination against the influenza A (H1N1)pdm09 virus in sow herds infected with pandemic influenza A virus. Therefore, farm-specific data of 137 sow herds in Germany, including 60,153 sows, as well as the clinical presentation of the infection were surveyed via questionnaire. Furthermore, average performance parameters (return to oestrus rate, abortion rate, stillbirth rate, number of piglets born alive per litter, preweaning mortality rate and number of piglets weaned per sow per year) were recorded for 6 months before vaccination and 6 months after completion of primary vaccination. RESULTS: In 79.8% of the farms, the clinical presentation of the infection was characterised by a reduced reproductive performance. These findings were confirmed by analysis of the performance parameters, which revealed a significant decline in the return to oestrus rate (p < 0.001), abortion rate (p < 0.001) and preweaning mortality rate (p = 0.023) and a significant increase of the number in piglets born alive (p = 0.001) and piglets weaned per sow per year (p < 0.001) after immunisation. The stillbirth rate did not change significantly. CONCLUSION: The present study represents the first attempt to demonstrate the association of influenza A virus infection, vaccination and the alteration in reproductive performance parameters, investigating a large number of cases. The results show that by vaccinating against the influenza A (H1N1)pdm09 virus, an improvement in reproductive performance can be achieved in sow herds infected with pandemic influenza A virus. Additionally, the large number of herds that were affected by poor reproductive performance after infection with the aforementioned virus confirms the assumption of an association between pandemic influenza A virus and reproductive losses.


Mechanical ventilation and neurocritical patients: is there a role for anti-neuroinflammatory therapies?


title: Immunological effects of adjuvants in subsets of antigen presenting cells of cancer patients undergoing chemotherapy

text: BACKGROUND: We have previously shown that HCC patients and healthy subjects are equally responsive to a RNAdjuvant(®), a novel TLR-7/8/RIG-I agonist based on noncoding RNA developed by CureVac, by an ex vivo evaluation. However, the immunological effect of adjuvants on immune cells from cancer patients undergoing chemotherapy remains to be demonstrated. Different adjuvants currently used in cancer vaccine clinical trials were evaluated in the present study on immune cells from cancer patients before and after chemotherapy in an ex vivo setting. METHODS: PBMCs were obtained from 4 healthy volunteers and 23 patients affected by either colon (OMA) or lung cancer (OT). The effect of CpG, Poly I:C, Imiquimod and RNA-based adjuvant (RNAdjuvant(®)) was assessed using a multiparametric approach to analyze network dynamics of early immune responses. Evaluation of CD80, CD86 and HLA-DR expression as well as the downstream effect on CD4(+) T cell phenotyping was performed by flow cytometry; cytokine and chemokine production was evaluated by Bio-Plex ProTM. RESULTS: Treatment with RNAdjuvant(®) induced the strongest response in cancer patients in terms of activation of innate and adoptive immunity. Indeed, CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4(+) T cell differentiation towards an effector phenotype. RNAdjuvant(®) was the only one to induce most of the cytokines/chemokines tested with a pronounced Th1 cytokine pattern. According to the different parameters evaluated in the study, no clear cut difference in immune response to adjuvants was observed between healthy subjects and cancer patients. Moreover, in the latter group, the chemotherapy treatment did not consistently correlate to a significant altered response in the different parameters. CONCLUSIONS: The present study is the first analysis of immunological effects induced by adjuvants in cancer patients who undergo chemotherapy, who are enrolled in the currently ongoing cancer vaccine clinical trials. The results show that the RNAdjuvant(®) is a potent and Th1 driving adjuvant, compared to those tested in the present study. Most importantly, it is demonstrated that chemotherapy does not significantly impair the immune system, implying that cancer patients are likely to respond to a cancer vaccine even after a chemotherapy treatment.


title: Schistosomiasis vaccine development: update on human clinical trials

text: Schistosomiasis causes significant levels of morbidity and mortality in many geographical regions of the world. The disease is caused by infections with parasitic blood flukes known as schistosomes. The control of schistosomiasis over the last several decades has been centered on the mass drug administration (MDA) of praziquantel (PZQ), which is the only drug currently available for treatment. Despite the concerted efforts of MDA programs, the prevalence and transmission of schistosomiasis has remained largely unchecked due to the fact that PZQ is ineffective against juvenile schistosomes, does not prevent re-infection and the emergence of PZQ-resistant parasites. In addition, other measures such as the water, sanitation and hygiene programs and snail intermediate hosts control have had little to no impact. These drawbacks indicate that the current control strategies are severely inadequate at interrupting transmission and therefore, implementation of other control strategies are required. Ideally, an efficient vaccine is what is needed for long term protection thereby eliminating the current efforts of repeated mass drug administration. However, the general consensus in the field is that the integration of a viable vaccine with MDA and other control measures offer the best chance of achieving the goal of schistosomiasis elimination. This review focuses on the present status of schistosomiasis vaccine candidates in different phases of human clinical trials and provide some insight into future vaccine discovery and design.


title: The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal

text: Rift Valley Fever (RVF) is an emerging zoonotic arbovirus with a complex cycle of transmission that makes difficult the prediction of its expansion. Recent outbreaks outside Africa have led to rediscover the human disease but it remains poorly known. The wide spectrum of acute and delayed manifestations with potential unfavorable outcome much complicate the management of suspected cases and prediction of morbidity and mortality during an outbreak. We reviewed literature data on bio-clinical characteristics and treatments of RVF human illness. We identified gaps in the field and provided a practical algorithm to assist clinicians in the cases assessment, determination of setting of care and prolonged follow-up.


title: Effects of inhaled nitric oxide for postoperative hypoxemia in acute type A aortic dissection: a retrospective observational study

text: BACKGROUND: Postoperative hypoxemia in acute type A aortic dissection (AADA) is a common complication and is associated with negative outcomes. This study aimed to analyze the efficacy of low-dose (5–10 ppm) inhaled nitric oxide (iNO) in the management of hypoxemia after AADA surgery. METHODS: In this retrospective observational study, Medical records of patients who underwent AADA surgery at two institutions between January 2015 and January 2018 were collected. Patients with postoperative hypoxemia were classified as iNO and control groups. Clinical characteristics and outcomes were compared using a propensity score-matched (PSM) analysis. RESULTS: Among 436 patients who underwent surgical repair, 187 (42.9%) had hypoxemia and 43 were treated with low-dose iNO. After PSM, patients were included in the iNO treatment (n = 40) and PSM control (n = 94) groups in a 1:3 ratio. iNO ameliorated hypoxemia at 6, 24, 48, and 72 h after initiation, and shortened the durations of ventilator support (39.0 h (31.3–47.8) vs. 69.0 h (47.8–110.3), p < 0.001) and ICU stay (122.0 h (80.8–155.0) vs 179.5 h (114.0–258.0), p < 0.001). There were no significant between-group differences in mortality, complications, or length of hospital stay. CONCLUSIONS: In this study, we found that low-dose iNO improved oxygenation in patients with hypoxemia after AADA surgery and shortened the durations of mechanical ventilation and ICU stay. No significant side effects or increase in postoperative mortality or morbidities were observed with iNO treatment. These findings warrant a randomized multicenter controlled trial to assess the exact efficiency of iNO for hypoxemia after AADA.


title: Flagellin adjuvanted F1/V subunit plague vaccine induces T cell and functional antibody responses with unique gene signatures

text: Yersinia pestis, the cause of plague, could be weaponized. Unfortunately, development of new vaccines is limited by lack of correlates of protection. We used pre- and post-vaccination sera and peripheral blood mononuclear cells from a flagellin adjuvanted F1/V vaccine trial to evaluate for protective markers. Here, we report for the first time in humans that inverse caspase-3 levels, which are measures of protective antibody, significantly increased by 29% and 75% on days 14 and 28 post-second vaccination, respectively. In addition, there were significant increases in T-cell responses on day 28 post-second vaccination. The strongest positive and negative correlations between protective antibody levels and gene expression signatures were identified for IFNG and ENSG00000225107 genes, respectively. Flagellin/F1/V subunit vaccine induced macrophage-protective antibody and significant CD4(+) T-cell responses. Several genes associated with these responses were identified that could serve as potential correlates of protection.


title: What Do We Have to Lose? Offloading Through Moral Technologies: Moral Struggle and Progress

text: Moral bioenhancement, nudge-designed environments, and ambient persuasive technologies may help people behave more consistently with their deeply held moral convictions. Alternatively, they may aid people in overcoming cognitive and affective limitations that prevent them from appreciating a situation’s moral dimensions. Or they may simply make it easier for them to make the morally right choice by helping them to overcome sources of weakness of will. This paper makes two assumptions. First, technologies to improve people’s moral capacities are realizable. Second, such technologies will actually help people get morality right and behave more consistently with whatever the ‘real’ right thing to do turns out to be. The paper then considers whether or not humanity loses anything valuable, particularly opportunities for moral progress, when being moral is made much easier by eliminating difficult moral deliberation and internal moral struggle. Ultimately, the worry that moral struggle has value as a catalyst for moral progress is rejected. Moral progress is understood here as the discovery and application of new values or sensitization to new sources of harm.


title: In silico Design of a Multivalent Vaccine Against Candida albicans

text: Invasive candidiasis (IC) is the most common nosocomial infection and a leading cause of mycoses-related deaths. High-systemic toxicity and emergence of antifungal-resistant species warrant the development of newer preventive approaches against IC. Here, we have adopted an immunotherapeutic peptide vaccine-based approach, to enhance the body’s immune response against invasive candida infections. Using computational tools, we screened the entire candida proteome (6030 proteins) and identified the most immunodominant HLA class I, HLA class II and B- cell epitopes. By further immunoinformatic analyses for enhanced vaccine efficacy, we selected the 18- most promising epitopes, which were joined together using molecular linkers to create a multivalent recombinant protein against Candida albicans (mvPC). To increase mvPC’s immunogenicity, we added a synthetic adjuvant (RS09) to the mvPC design. The selected mvPC epitopes are homologous against all currently available annotated reference sequences of 22 C. albicans strains, thus offering a higher coverage and greater protective response. A major advantage of the current vaccine approach is mvPC’s multivalent nature (recognizing multiple-epitopes), which is likely to provide enhanced protection against complex candida antigens. Here, we describe the computational analyses leading to mvPC design.


title: HopPER: an adaptive model for probability estimation of influenza reassortment through host prediction

text: BACKGROUND: Influenza reassortment, a mechanism where influenza viruses exchange their RNA segments by co-infecting a single cell, has been implicated in several major pandemics since 19th century. Owing to the significant impact on public health and social stability, great attention has been received on the identification of influenza reassortment. METHODS: We proposed a novel computational method named HopPER (Host-prediction-based Probability Estimation of Reassortment), that sturdily estimates reassortment probabilities through host tropism prediction using 147 new features generated from seven physicochemical properties of amino acids. We conducted the experiments on a range of real and synthetic datasets and compared HopPER with several state-of-the-art methods. RESULTS: It is shown that 280 out of 318 candidate reassortants have been successfully identified. Additionally, not only can HopPER be applied to complete genomes but its effectiveness on incomplete genomes is also demonstrated. The analysis of evolutionary success of avian, human and swine viruses generated through reassortment across different years using HopPER further revealed the reassortment history of the influenza viruses. CONCLUSIONS: Our study presents a novel method for the prediction of influenza reassortment. We hope this method could facilitate rapid reassortment detection and provide novel insights into the evolutionary patterns of influenza viruses.


Proceedings 31st Symposium ESVN‐ECVN


docid: ouafdyyc

title: Research Communications of the 29th ECVIM‐CA Congress


docid: ceorbnfz

title: Complete Genome Sequence of Bordetella bronchiseptica Strain KM22

text: Bordetella bronchiseptica isolate KM22 has been used in experimental infections of swine as a model of clinical B. bronchiseptica infection and to study host-to-host transmission. The draft genome sequence of KM22 was reported in 2014. Here, we report the complete genome sequence of KM22.