We describe the intra-operative surgical management of tracheal bronchus encountered in a lung transplant recipient.

Biopharmaceutical protein production using transgenic plant cell bioreactor processes offers advantages over microbial and mammalian cell culture platforms due to the ability to produce complex biologics, use of simple chemically-defined, animal component-free media, robustness of host cells, and biosafety. A disadvantage of plant cells from a traditional batch bioprocessing perspective is their slow growth rate which has motivated us to develop semicontinuous and/or perfusion processes. Although the economic benefits of plant cell culture bioprocesses are often mentioned in the literature, to our knowledge no rigorous techno-economic models or analyses have been published. Here we present techno-economic models in SuperPro Designer® for the large-scale production of recombinant butyrylcholinesterase (BChE), a prophylactic/therapeutic bioscavenger against organophosphate nerve agent poisoning, in inducible transgenic rice cell suspension cultures. The base facility designed to produce 25 kg BChE per year utilizing two-stage semicontinuous bioreactor operation manufactures a single 400 mg dose of BChE for $263. Semicontinuous operation scenarios result in 4-11% reduction over traditional two-stage batch operation scenarios. In addition to providing a simulation tool that will be useful to the plant-made pharmaceutical community, the model also provides a computational framework that can be used for other semicontinuous or batch bioreactor-based processes.

The current drug safety landscape inadequately serves the millions of children prescribed medications every year. Randomized clinical trials are limited in detecting pediatric adverse drug effects due to low participant enrollment, complicated study design, and short trial duration. While the biology of human development and the pathology of childhood diseases are well studied research topics, current pharmacoepidemiology approaches do not use this knowledge when investigating drug safety in children. Here, we describe how adverse drug effects manifest as children develop from birth through the teenage years. We discuss the benefits of an empirical approach for evaluating clinical relevance and biological causality of identified adverse drug effects in children. We argue that a data-driven strategy that leverages observational data and biomedical knowledge is an ethical and effective methodology to improve pediatric drug safety.

Event-based surveillance (EBS) systems monitor a broad range of information sources to detect early signals of disease emergence, including new and unknown diseases. Following the emergence of a newly identified coronavirus –so-called COVID-19, in humans in December 2019 in Wuhan, China, we conducted a retrospective analysis of the capacity of three Event-Based Systems (EBS) systems (ProMED, HealthMap and PADI-web) to detect early signals of this emergence. We evaluated the changes in the online news vocabulary coinciding with the period before / after the identification of COVID-19, as well as the assessment of its contagiousness and pandemic potential. ProMED was the timeliest EBS, detecting signals one day before the official notification. At this early stage, the specific vocabulary was related to “pneumonia symptoms” and “mystery illness”. Once COVID-19 was identified, the vocabulary changed to virus family and specific COVID-19 acronyms. Our results suggest the three EBS systems are complementary regarding data sources, and all need improvements regarding timeliness. EBS methods should be adapted to the different stages of disease emergence to improve the early detection of future emergence of unknown pathogens.

The coronavirus disease 2019 (COVID-19) pandemic has touched almost every continent. Personal protective equipment (PPE) is the final line of protection of healthcare workers (HCW). There is variation as well as controversy of infection control recommendation with regards to the use of PPE for HCW between institutions. The aim of this narrative review is to of examine and summarise the available evidence to guide recommendation for the safety of HCW. A literature search was conducted on the PubMed, MedLine, and Embase databases with the keywords “personal protective equipment”, “COVID 19”, “n95”, “health care worker”, and “mortality”. SARS-nCoV-2 is highly contagious. 3.5-20% of HCW has been reported to be infected. The mortality ranges from 0.53-1.94%. PPE is part of the measure within a package of prevention and control of pandemic, rather than a replacement of. Respirators are more effective than masks in preventing aerosol transmission to HCWs. Extended use may be considered if guidelines are adhered. PAPRs if available should be used in high risk procedures. Transmission of viruses is multimodal, and in the setting of a novel pathogen with high case fatality with no proven effective interventions, PPE that affords the best protection should be available to HCWs.

Background The WHO recommends testing any suspected person with Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2), in order to limit the spread of the epidemic. In Italy, some Regions opted for extensive testing, whereas others limited tests to selected subjects. To assess the influence of different strategies, we examined the incidence of death and severe cases in Italy. Methods Data on new cases of SARS-CoV-2, number of tests, deaths, and admissions to Intensive Care Units (ICU) were retrieved in each Italian Region, from February 24th to March 18th, 2020. As an index of different screening strategies, the number of tests/positive test results (T/P) ratio as of March 7th, 2020, was considered. The cumulative number of deaths and of new severe cases, between March 23thand 25th was recorded. The association of those two outcomes with the number of T/P ratio was assessed using linear regression models. Results In the interval between March 23th-25th, recorded deaths (*million inhabitants) were 14(3-54), whereas severe cases were 31(10-112). Both the number of deaths and that of severe cases showed a significant correlation (R2 .38 and .37, with p<.01) with the T/P ratio. Deaths and severe cases were associated with higher mean personal income and lower density of General Practioners (GPs). The association of T/P with severe cases and deaths retained statistical significance after adjusting for mean personal income (R2 .20 and .21, respectively; both p=.04) and GPs density (R2.22 and .21, respectively; both p=.03). Conclusions A more aggressive screening strategy for SARS-Cov-2, was associated with lower rates of death and severe disease in Regions of Italy.

Synthetic biology is the engineering approach to edit or write the genome aiming to design the biological devices (promoters, transcription factors, TFBS, terminators etc.) of an organism to achieve the improved properties, while, metabolic engineering aiming to engineer the microbes to produce metabolites on industrial scale through recombinant DNA technologies. Recently, both synthetic biology and metabolic engineering fields are growing quickly and are used to produce metabolites of interest. The main theme of Synthetic Biology – Metabolic Engineering book is to review the tools and techniques used in synthetic biology and metabolic engineering to design and engineer the microbes to produce value-added metabolites and its application in industrial biotechnology. The book is written by the world-renowned metabolic engineers and synthetic biologists in series of Advances in Biochemical Engineering/Biotechnology and primarily elaborates the synergy between metabolic engineering and synthetic biology.

Mini-commentary on BJOG-20-0076.R1: Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study

The world is confronting a dire situation due to the recent pandemic of the novel coronavirus disease (2019-nCoV) with so far mortality cases of 100,000 all over the world. Currently, there are no effective enough treatment options for this previously unknown virus. The current drugs in pipline and some plausible drug are overviewed in this paper. The potential molecular targets of each steps of the 2019-nCoV drug life cycle is discussed and highlights here. Although different types of anti-viral targets are applicable for 2019-nCoV drug screenings, the more promising targets can be considered as protease and RNA polymerase. Based on the results from antiviral agents repurposing and clinical studies, the remdesivir could be an encouraging drug in the frontline to be administrated for 2019-nCoV. Much progress in understanding the 2019-nCoV the molecular details of its life cycle followed by the identification of therapeutic targets seems to be an efficient approach in discovering potential drugs.

Recent research in island biogeography has highlighted the important role of late Quaternary sea-level fluctuations in shaping biogeographical patterns in insular systems, but largely focused on volcanic oceanic systems. Through this study we aim to extend this work by investigating the role of late Quaternary sea-level fluctuations in shaping species richness patterns in continental shelf island systems. Focusing on the Aegean archipelago, we first reconstructed the area’s geography using published data, under three sea-level stands: 1) current; 2) median over the last nine Glacial-Interglacial cycles; 3) Late Glacial Maximum (LGM). We compiled taxon-island occupancy for angiosperms (70 islands) and centipedes (56 islands). We investigated the impact of present-day and past geographical settings on chorological groups by analysing Island Species-Area Relationships (ISARs) and using Generalized Linear Mixed Models selection based on multiple metrics of goodness-of-fit. Our results confirm that the Aegean’s geography has changed dramatically since the LGM, while the median sea-level scenario only modestly differs from the present configuration. Paleogeographical changes largely shaped Aegean plant diversity patterns, and to a lesser degree centipede species richness patterns. The LGM geographic configuration affected both native and endemic species diversity through establishing connections between land-bridge islands and the mainland. Particularly on land-bridge islands we detected supersaturation of native species and stronger underrepresentation of endemics on those same islands. Unlike oceanic islands, where the longer lasting median configuration has ample effect on the current species diversity, the shorter lasting LGM configurations promoted increased connectivity with the mainland counteracting processes promoting endemism. Our study shows that in terms of processes affecting species richness patterns, continental archipelagos differ fundamentally from oceanic systems, highlighting the importance of distinguishing between them while studying biota from the perspective of historical biogeography.

Inappropriate use of telemetry frequently occurs in the inpatient, non-intensive care unit setting. Recent telemetry practice standards have attempted to guide appropriate use and limit the overuse of this important resource, with limited success. Clinical-effectiveness studies of these practice standards have thus far not included care settings in which resident-physicians are the primary caregivers. Furthermore, studies of the role of nurses in appropriate telemetry use are lacking. In this report, we describe two interventions implemented on general internal medicine units of a large academic hospital over three years. The first intervention, or nurse-discontinuation protocol, allowed nurses to trigger the discontinuation of telemetry once the appropriate duration had passed according to practice standards. The second intervention, or physician-discontinuation protocol, instituted a Best Practice Advisory that notified the resident-physician via the electronic medical record when the appropriate telemetry duration for each patient had elapsed and suggested termination of telemetry. Results showed that the nurse-discontinuation protocol reduced mean patient time on telemetry and the physician-discontinuation protocol reduced mean telemetry orders per patient. These findings validate a prior study and expand on our understanding of telemetry use in the academic care setting in which trainees serve as the primary caregivers.

Two papers in this issue, on births to Covid-19 infected mothers, are important additions to this rapidly evolving literature. They are both broadly reassuring.The paper from Lombardy, the epicentre of the pandemic in Italy, is the first detailed report of pregnancies from this large region (Ferrazzi et al. BJOG 2020 xxxx). Among 42 affected women, 19 developed pneumonia, of whom seven required oxygen and four critical care. Eighteen babies were delivered by Caesarean, although in eight the indication was unrelated to Covid-19. Three babies tested positive for SARS-COV-2. Two to women who had developed Covid-19 postnatally and had breast-fed without a mask; the presumed source was the mother. One baby who delivered vaginally and did not breast-feed, developed respiratory symptoms requiring one day’s ventilation and tested positive. No mothers or babies died.The paper from China reports SARS-COV-2 viral tests in a range of body fluids from mothers and babies with COVID-19, cared for at Renmin Hospital of Wuhan University (RHWU) (Yanting Wu et al. BJOG 2020 xxxx). This hospital appears on the Global Research Identifier Database (GRID) here https://grid.ac/institutes/grid.412632.0. Readers should know that the GRID database reports that RHWU has the following English aliases “People’s Hospital of Wuhan University”, “Hubei Provincial People’s Hospital”, “First Affiliated Hospital of Wuhan University”, “Wuhan University Renmin Hospital” and “Hubei General Hospital”. This raises the possibility that some or all of the cases may have been reported previously.With this proviso, the detailed information that 1/9 stool samples, 0/13 vaginal samples, and 1/3 breast milk samples were positive is important. Of the five babies who have delivered, none tested positive for Covid-19, although two, both preterm, had pneumonia diagnosed on chest x ray. Apart from one biochemical pregnancy in the first trimester in which a serum human chorionic gonadotrophin of 25.9 IU/L reverted to negative, no mothers or babies died.Taken together with other accumulating data, it is already clear that Covid-19 is less severe in pregnancy than the two previous coronavirus infections, Severe Acute Respiratory Syndrome-related coronavirus (SARS) and Middle East Respiratory Syndrome-related coronavirus (MERS). Nevertheless, four of the mothers from Lombardy required critical care, and there have been other reports of both mother and baby deaths in association with Covid-19. It remains an important disease in pregnancy, which should be taken seriously.No disclosures. A completed disclosure of interest form is available to view online as supporting information.

Background. Anti-citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA). ACPA-positive (ACPA+) and ACPA-negative (ACPA-) RA were suggested to be different disease subsets with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA+ and ACPA- RA and identify novel candidate gene signatures that might serve as therapeutic targets. Methods. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA+ and ACPA- RA patients, and healthy controls was performed via RNA sequencing. A validation cohort was used to further investigate differentially expressed genes via PCR and ELISA. Spearman’s correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Results. Expression of C-X-C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA+ RA than in ACPA- RA, which was validated in PBMCs and serum. CXCL2 promoted the migration of CD14+ monocytes and increased osteoclastogenesis in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via ERK MAPK and NFκB pathways. Conclusion. CXCL2 was highly expressed in ACPA+ RA than in ACPA- RA. CXCL2 promoted osteoclastogenesis and was related to bone erosion in RA, which suggest that the blockade of CXCL2 might be a novel strategy for the treatment of RA.

Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. In 2018, 1.5 million people died from TB worldwide and 440,000 of those were from India. The WHO End-TB strategy aims to reduce TB deaths by 95% and new TB cases by 90% by 2035, with a call for more basic research on TB pathogenesis and immunity. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune-correlates of protection. In this context, the role of regulatory T cells (Treg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of Treg function in TB. The review also provides a comprehensive critical analysis of the key features of Treg cells in TB; highlights the importance of a balanced immune response as being important in TB and discusses the importance of probing not just Treg frequency but also qualitative aspects of Treg function as part of a comprehensive search for novel TB treatments.

SARS-CoV-2 has infected millions of people around the world, with most cases recorded among adults. The cases reported among children have been acknowledged to be minimal in comparison to adults. Nevertheless, COVID-19 has been reported to affect children at all ages, including newborns. The symptoms among children have also been identified to be similar to those observed among adults, although pediatric patients have been noted to display spectrum of clinical features ranging from asymptomatic through mild to moderate symptoms. Despite ample publications on the ongoing pandemic, the literature is only replete with guidelines on treating SARS-CoV-2 infection among older people. In this narrative review, comprehensive updates on the infection in children have been discussed. The latest information on the spread of the disease among children around the world, the clinical features observed among the pediatric population, as well as recommended pharmaceutical treatments of COVID-19 among this special group of patients have been covered. Further, expert consensus statements regarding the management of this highly contagious disease among pregnant women and neonates have been discussed. It is believed that this comprehensive review will provide updated information on the epidemiology and clinical features of the ongoing pandemic among pediatric patients. Additionally, the guidelines for handling SARS-CoV-2 among pregnant women and children, as reviewed in this article, are anticipated to be useful to frontline clinicians battling this fatal disease around the globe.

Background : Critically ill patients with coronavirus disease 2019（COVID-19）was surging and far outnumbered existing beds. Aims :  To describe how to rapidly convert general wards to intensive care units for critically ill patients with COVID-19. Materials & Methods :  Comprehensive assessment and analysis of available resources and standard requirements. Results : The ICUs were successfully assembled in four days. The conversion included environment reconstruction, configuration and management of equipment, information system construction and human resource allocation. A total of 172 critically ill patients had been admitted to the contemporary ICUs and none medical staff was infected. Discussion :  The epidemic situation of COVID-19 poses a great challenge to various management departments of the hospital, especially for critically ill patients with high mortality rate. To save more critically ill patients, the conversion of a general ward to a quarantine ICU ward must be completed in a short time, and the optimal allocation of resources must be appropriate to ensure that the medical team works effectively and is of high quality. In face of the overloaded medical system, the ideal non-negative pressure ward is hard to achieve. However, we have demonstrated with evidence that our conversions are effective in both providing care to the critical patients and protecting the safety of our staff. Conclusion:  The conversion is successful and the running experience would be a reference for hospitals in other areas nationally or globally.

AIM: to determine if patients with heart failure and preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) have a higher comorbidity burden than those without T2DM, if other comorbidities are preferentially associated with T2DM, and if these conditions confer a worse patient prognosis. METHODS AND RESULTS: Cohort study based on the RICA Spanish Heart Failure Registry, a multicenter, prospective registry that enrolls patients admitted for decompensated HF and follows them for 1 year. We selected only patients with HFpEF, classified as having or not having T2DM, and performed an agglomerative hierarchical clustering based on variables such as the presence of arrhythmia, chronic obstructive pulmonary disease, dyslipidemia, liver disease, stroke, dementia, body mass index (BMI), hemoglobin levels, estimated glomerular filtration rate, and systolic blood pressure. 1,934 patients were analyzed: 907 had T2DM (mean age 78.4+/-7.6 years) and 1,027 did not (mean age 81.4+/- 7.6 years). The analysis resulted in 4 clusters in patients with T2DM, and 3 in the reminder. All clusters of patients with T2DM showed higher BMI, and more kidney disease and anemia than those without T2DM. Clusters of patients without T2DM had neither significantly better nor worse outcomes. However, among the T2DM patients, clusters 2, 3 and 4 all had significantly poorer outcomes, the worst being cluster 3 (HR 2.0, 95% CI 1.36-2.93, p=0.001). CONCLUSIONS: Grouping our patients with HFpEF and T2DM into clusters based on comorbidities revealed a greater disease burden and prognostic implications associated with the T2DM phenotype, compared to those without T2DM.

Acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in Coronavirus disease 19 (Covid-19) for which as of now there is no effective treatment. ARDS is caused and sustained by an uncontrolled inflammatory activation characterized by a massive release of cytokines (cytokine storm), diffuse lung edema, inflammatory cell infiltraton and disseminated coagulation. Macrophage and T lymphocyte dysfunction plays a central role in this syndrome. In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor. We hypothesize that this receptor might be an ideal candidate to target in Covid-19-associated ARDS.