bluuebunny/crossref_metadata_2025 huggingface dataset:
Protoporphyrin IX and verteporfin prevent SARS-CoV-2 infectionin vitroand in a mouse model expressing human ACE2
Authors: Gu Chenjian , Wu Yang , Guo Huimin , Zhu Yuanfei , Xu Wei , Wang Yuyan , Zhou Yu , Sun Zhiping , Cai Xia , Li Yutang , Liu Jing , Huang Zhong , Yuan Zhenghong , Zhang Rong , Deng Qiang , Qu Di , Xie Youhua
Published: May 2020

The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two FDA-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 μM and 0.31 μM respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human ACE2. The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.
Heat inactivation of the Severe Acute Respiratory Syndrome Coronavirus 2
Authors: Batéjat Christophe , Grassin Quentin , Manuguerra Jean-Claude , Leclercq India
Published: May 2020

Supernatants of cells infected with SARS-CoV-2, nasopharyngeal and sera samples containing SARS-CoV-2 were submitted to heat inactivation for various periods of time, ranging from 30 seconds to 60 minutes. Our results showed that SARS-CoV-2 could be inactivated in less than 30 minutes, 15 minutes and 3 minutes at 56°C, 65°C and 95°C respectively. These data could help laboratory workers to improve their protocols with handling of the virus in biosafety conditions.
The transmembrane proteins M6 and Anakonda cooperate to initiate tricellular junction assembly in epithelia ofDrosophila
Authors: Wittek Anna , Hollmann Manuel , Schleutker Raphael , Luschnig Stefan
Published: May 2020

Cell vertices in epithelia comprise specialized tricellular junctions (TCJs) that seal the paracellular space between three adjoining cells [1, 2]. Although TCJs play fundamental roles in tissue homeostasis, pathogen defense, and in sensing tension and cell shape [3-5], how they are assembled, maintained and remodeled is poorly understood. InDrosophilathe transmembrane proteins Anakonda (Aka [6]) and Gliotactin (Gli [7]) are TCJ components essential for epithelial barrier formation. Additionally, the conserved four-transmembrane-domain protein M6, the only myelin proteolipid protein (PLP) family member inDrosophila, localizes to TCJs [8, 9]. PLPs associate with cholesterol-rich membrane domains and induce filopodia formation [10, 11] and membrane curvature [12], andDrosophila M6acts as a tumor suppressor [8], but its role in TCJ formation remained unknown. Here we show that M6 is essential for the assembly of tricellular, but not bicellular occluding junctions, and for barrier function in embryonic epithelia. M6 and Aka localize to TCJs in a mutually dependent manner and are jointly required for TCJ localization of Gli, whereas Aka and M6 localize to TCJs independently of Gli. Aka acts instructively and is sufficient to direct M6 to cell vertices in the absence of septate junctions, while M6 is required permissively to maintain Aka at TCJs. Furthermore, M6 and Aka are mutually dependent for their accumulation in a low-mobility pool at TCJs. These findings suggest a hierarchical model for TCJ assembly, where Aka and M6 promote TCJ formation through synergistic interactions that demarcate a distinct plasma membrane microdomain at cell vertices.
Impaired hand dexterity function in a non-human primate model with chronic Parkinson’s disease
Authors: Seo Jincheol , Won Jinyoung , Kim Keonwoo , Park Junghyung , Yeo Hyeon-Gu , Kim Yu Gyeong , Baek Seung Ho , Lee Hoonwon , Jeon Chang-Yeop , Choi Won Seok , Lee Sangil , Kim Ki Jin , Park Sung-Hyun , Son Yeonghoon , Jeong Kang Jin , Lim Kyung Seob , Kang Philyong , Lee Hwal-Yong , Son Hee-Chang , Huh Jae-Won , Kim Young-Hyun , Jin Yeung Bae , Lee Dong-Seok , Lee Sang-Rae , Choi Ji-Woong , Lee Youngjeon
Published: May 2020

Symptoms of Parkinson’s disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed an alteration in Parkinsonian tremor symptoms, loss of dopaminergic neuron, and positron emission tomography (PET) imaging of dopamine transporters (DAT) in these models. HDT latency significantly increased in NHP-PD models. In addition, a significant inverse correlation between HDT and DAT was identified, but no local bias was found. The correlation with intention tremor symptoms was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.
Landscape structure and climate seasonality affect the amount, richness and diversity of pollen collected by honeybees in a Neotropical region of Colombia
Authors: Montoya-Pfeiffer Paula María , Nates-Parra Guiomar
Published: May 2020

Pollen is the main food for honeybee broods and young workers and so colony development and reproduction rely heavily on pollen availability, both spatially and temporally, in the environment. Intensification of agriculture and climate seasonality are known to alter honeybee foraging patterns and pollen intake through changes in resource availability in temperate regions; however, little is known about how honeybees respond to such environmental factors in tropical regions.

Pollen species collected by honeybees in a Neotropical agricultural region of Colombia were identified. The effects of landscape structure (landscape Shannon Diversity Index, forest area in 1000 m around the apiary) and climate seasonality (mean monthly precipitation) on the amount, richness and diversity of pollen collected by the honeybees were evaluated for all pollen species together and pollen species segregated according to forest and anthropic areas (croplands, grasslands, woodlands, urban areas).

Honeybees were found to be much more associated with anthropic than forest pollen species regardless of landscape structure or precipitation. However, the amount, richness and diversity of pollen from all species and forest species responded positively to landscape diversity and forest area, suggesting an advantage for honeybees in obtaining small quantities of pollen from forest species, in spite of being well-adapted to forage in anthropic areas. Precipitation was found not to be related to the overall amount and overall richness of pollen collected by honeybees, suggesting that climate seasonality was not an important factor for pollen foraging. Nonetheless, overall pollen diversity was negatively affected by precipitation in less diverse landscapes, while anthropic pollen diversity was negatively affected in more forested landscapes. These findings are compared with those from temperate regions, and the implications for honeybee productivity and survival, and their interactions with Neotropical native species, are discussed.
Peroxisome counteracts oxidative stresses by suppressing catalase import via Pex14 phosphorylation
Authors: Okumoto Kanji , El Shermely Mahmoud , Natsui Masanao , Kosako Hidetaka , Natsuyama Ryuichi , Marutani Toshihiro , Fujiki Yukio
Published: May 2020

Most of peroxisomal matrix proteins including a hydrogen peroxide (H2O2)-decomposing enzyme, catalase, are imported in a peroxisome-targeting signal type-1 (PTS1)-dependent manner. However, little is known about regulation of the membrane-bound protein import machinery. Here, we report that Pex14, a central component of the protein translocation complex in peroxisomal membrane, is phosphorylated in response to oxidative stresses such as H2O2in mammalian cells. H2O2-induced phosphorylation of Pex14 at Ser232 suppresses peroxisomal import of catalasein vivoand selectively decreases formation of PTS1 receptor Pex5-mediated ternary complex of Pex14 with catalasein vitro. Phosphomimetic Pex14-S232D mutant elevates the level of cytosolic catalase, but not canonical PTS1-proteins, conferring higher cell resistance to H2O2. We thus suggest that H2O2-induced phosphorylation of Pex14 spatiotemporally regulates peroxisomal import of catalase, functioning in counteracting action against oxidative stress by the increase of cytosolic catalase.
Whole Genome Comparison of Pakistani Corona Virus with Chinese and US Strains along with its Predictive Severity of COVID-19
Authors: Saif Rashid , Mahmood Tania , Ejaz Aniqa , Zia Saeeda , Qureshi Abdul Rasheed
Published: May 2020

Recently submitted 784 SARS-nCoV2 whole genome sequences from NCBI Virus database were taken for constructing phylogenetic tree to look into their similarities. Pakistani strain MT240479 (Gilgit1-Pak) was found in close proximity to MT184913 (CruiseA-USA), while the second Pakistani strain MT262993 (Manga-Pak) was neighboring to MT039887 (WI-USA) strain in the constructed cladogram in this article. Afterward, four whole genome SARS-nCoV2 strain sequences were taken for variant calling analysis, those who appeared nearest relative in the earlier cladogram constructed a week time ago. Among those two Pakistani strains each of 29,836 bases were compared against MT263429 from (WI-USA) of 29,889 bases and MT259229 (Wuhan-China) of 29,864 bases. We identified 31 variants in both Pakistani strains, (Manga-Pak vs USA=2del+7SNPs, Manga-Pak vs Chinese=2del+2SNPs, Gilgit1-Pak vs USA=10SNPs, Gilgit1-Pak vs Chinese=8SNPs), which caused alteration inORF1ab, ORF1aandNgenes with having functions of viral replication and translation, host innate immunity and viral capsid formation respectively. These novel variants are assumed to be liable for low mortality rate in Pakistan with 385 as compared to USA with 63,871 and China with 4,633 deaths by May 01, 2020. However functional effects of these variants need further confirmatory studies. Moreover, mutated N & ORF1a proteins in Pakistani strains were also analyzed by 3D structure modelling, which give another dimension of comparing these alterations at amino acid level. In a nutshell, these novel variants are assumed to be linked with reduced mortality of COVID-19 in Pakistan along with other influencing factors, these novel variants would also be useful to understand the virulence of this virus and to develop indigenous vaccines and therapeutics.
Actinobacillusutilizes a binding-protein dependent ABC transporter to acquire Vitamin B6
Authors: Pan Chuxi , Zimmer Alexandra , Shah Megha , Huynh Minhsang , Lai Christine C.L. , Sit Brandon , Hooda Yogesh , Curran David , Moraes Trevor F.
Published: May 2020

Bacteria require high efficiency uptake systems to survive and proliferate in nutrient limiting environments, such as those found in the host. The ABC transporters at the bacterial plasma membrane provide a mechanism for transport of many substrates. We recently demonstrated that an AfuABC operon, previously annotated as encoding a ferrous iron uptake system, is in fact a cyclic hexose/heptose-phosphate transporter with high selectivity and specificity for these metabolites. In this study, we examine a second operon containing a periplasmic binding protein discovered inActinobacillusfor its potential role in nutrient acquisition. Using electron density obtained from the crystal structure of the periplasmic binding protein we modeled a pyridoxal-5’-phosphate (P5P/PLP/Vitamin B6) ligand into the atomic resolution electron density map. The identity of the Vitamin B6bound to this periplasmic binding protein was verified by isothermal titration calorimetry, microscale thermophoresis, and mass spectrometry, leading us to name the protein P5PA and the operon P5PAB. To illustrate the functional utility of this uptake system, we introduced the P5PAB operon fromA. pleuropneumoniaeinto anE. coliK-12 strain that was devoid of a key enzyme required for Vitamin B6synthesis. The growth of this strain at low levels of Vitamin B6supports the role of this newly identify operon in Vitamin B6uptake.
Does quitting social networks change feelings of loneliness among freshmen? An experimental study
Authors: Agadullina Elena R. , Lovakov Andrey , Kiselnikova Natalia V.
Published: May 2020

Purpose

The first year of college is a stressful life period connected with the experience of loneliness, isolation and depression since the majority of freshmen can no longer maintain an equally close relationship with school friends and family. Social networks have become a significant part of students' daily lives and might be an effective tool for maintaining relationship and reducing loneliness. There are contradictory results concerning the relationship between social networks sites (SNS) use and feelings of loneliness.

Design/methodology/approach

A four-week experiment was conducted to study the effect of SNS on feelings of social and emotional loneliness across freshmen. The treatment group (n = 40) took a break from SNS, while the control group (n = 37) used SNS as usual.

Findings

Comparison of the treatment and control groups showed that quitting SNS does not change either feeling of social/emotional loneliness. This paper also found that feelings of social and emotional loneliness did not depend on freshmen's positive/negative attitudes toward being alone.

Originality/value

This study is one of the few that uses experimental design to study the effects of using social networks on the psychological state of students in the context of higher education. The results showed that refusing SNS use can have a positive potential for psychological well-being of freshmen since solitude can be used by them as time for self-discovery and self-development. According to the results, social networks neither increase nor decrease the feeling of loneliness, and offline learning and communication environment plays a more significant role in the adaptation of freshmen. These results allow to take a new look at the studies related to the relationship between SNS use and loneliness and the role of social networks in the adaptation of freshmen.
How the effects of latitude on daylight availability may have influenced the evolution of migration and photoperiodism
Authors: Sockman Keith W. , Hurlbert Allen H.
Published: May 2020

Date and latitude interact to determine photoperiod, the daily period of daylight. This interaction has important implications for latitudinal migrants for whom daylight may be a resource or for whom photoperiod regulates annual transitions in life‐history stages (i.e. birds).

Using an established formula, we developed user‐interactive, animated models that enable the visualization of how latitude and date determine photoperiod for latitudinal migrants. We also calculated the photoperiodic schedules for a broad range of hypothetical migratory programmes and real migratory programmes newly available through the proliferation of citizen‐science data. This enabled us to infer the limitations some migratory programmes place on mechanisms for photoperiodic regulation of annual breeding.

In the vast majority of cases, the act of migrating elevates annual daylight exposure. This raises the hypothesis that daylight availability selects for latitudinal migration, potentially contributing to its evolution in animals such as diurnal birds with limited time during the spring and summer to feed young. However, photoperiodic mechanisms regulating annual cycles could constrain the evolution of such migrations, depending on how they affect photoperiodic schedules. Most migratory programmes are consistent with known mechanisms of avian photoperiodism, but the range of feasible mechanisms declines for transequatorial migrants, which experience semi‐annual, 180°‐phase‐shifts in their photoperiodic cycles.

Understanding photoperiodic constraints on migration is particularly important in this age of changing latitudinal distributions and phenologies driven by climate change.

A free Plain Language Summary can be found within the Supporting Information of this article.
Seasonal survival and reversible state effects in a long‐distance migratory shorebird
Authors: Swift Rose J. , Rodewald Amanda D. , Johnson James A. , Andres Brad A. , Senner Nathan R.
Published: May 2020

Events during one stage of the annual cycle can reversibly affect an individual's condition and performance not only within that stage, but also in subsequent stages (i.e. reversible state effects). Despite strong conceptual links, however, few studies have been able to empirically link individual‐level reversible state effects with larger‐scale demographic processes.

We studied both survival and potential reversible state effects in a long‐distance migratory shorebird, the Hudsonian GodwitLimosa haemastica. Specifically, we estimated period‐specific survival probabilities across the annual cycle and examined the extent to which an individual's body condition, foraging success and habitat quality during the nonbreeding season affected its subsequent survival and reproductive performance.

Godwit survival rates were high throughout the annual cycle, but lowest during the breeding season, only slightly higher during southbound migration and highest during the stationary nonbreeding season. Our results indicate that overwintering godwits foraging in high‐quality habitats had comparably better nutritional status and pre‐migratory body condition, which in turn improved their return rates and the likelihood that their nests and chicks survived during the subsequent breeding season.

Reversible state effects thus appeared to link events between nonbreeding and breeding seasons via an individual's condition, in turn affecting their survival and subsequent reproductive performance. Our study thus provides one of the few empirical demonstrations of theoretical predictions that reversible state effects have the potential to influence population dynamics.
Obstetric admissions to intensive care units in Australia and New Zealand: a registry‐based cohort study
Authors: Maiden MJ , Finnis ME , Duke GJ , Huning EYS , Crozier TME , Nguyen N , Biradar V , McArthur C , Pilcher D
Published: May 2020

Objective

Describe the epidemiology of obstetric patients admitted to an Intensive Care Unit (ICU).

Design

Registry‐based cohort study.

Setting

One hundred and eighty‐three ICUs in Australia and New Zealand.

Population

Women aged 15–49 years, admitted to ICU between 2008 and 2017, classified as pregnant, postpartum or with an obstetric‐related diagnosis.

Methods

Data were extracted from the Australia and New Zealand Intensive Care Society (ANZICS) Adult Patient Database and national agencies.

Main outcome measures

Incidence of ICU admission, cohort characteristics, maternal outcomes and changes over time.

Results

The cohort comprised 16 063 patients. The annual number of obstetric ICU admissions increased, whereas their proportion of total ICU admissions (1.3%) did not change (odds ratio 1.02, 95% CI 0.99–1.04, P = 0.14). There were 10 518 (65%) with an obstetric‐related ICU diagnosis, and 5545 (35%) with a non‐obstetric ICU diagnosis. Mean (SD) age was 31 (6.4) years, 1463 (9.1%) were Indigenous, 2305 (14%) were transferred from another hospital, and 3008 (19%) received mechanical ventilation. Median [IQR] length of stay in hospital was 5.2 [3.1–7.9] days, which included 1.1 [0.7–1.8] days in ICU. There were 108 (0.7%) maternal deaths, most (n = 97, 90%) having a non‐obstetric diagnosis. There was no change in risk‐adjusted length of stay or mortality over time.

Conclusions

Obstetric patients account for a stable proportion of ICU admissions in Australia and New Zealand. These patients typically have a short length of ICU stay and low hospital mortality.

Tweetable abstract

Obstetric patients in Australia/New Zealand ICUs have a short length of ICU stay and low mortality.
Hemiptera phylogenomic resources: Tree‐based orthology prediction and conserved exon identification
Authors: Owen Christopher L. , Stern David B. , Hilton Sarah K. , Crandall Keith A.
Published: May 2020

High‐throughput sequencing of transcriptomes and targeted genomic regions are advancing our knowledge of The Tree of Life. Building phylogenies with regions of the genome requires 1‐to‐1 orthologue resources of genes and noncoding loci. One organismal group that has received little attention in this area is the Hemiptera, the fifth largest insect order represented by ~103,590 named species. Here, we present a set of 3,872 Hemiptera 1‐to‐1 orthogroups based on tree‐based orthology inference of eight Hemiptera species with publicly available genome sequences. We also estimate a set of 406 orthologous exons with similar mRNA splice sites that can be used for Sanger sequencing and develop enrichment probes for targeted genome sequencing for phylogenomic inference. We show this novel set of orthologues is informative at the protein, coding sequence and exon molecular levels and provides robust branch support in both gene tree–species tree methods and concatenated sequence phylogenies. In addition, we demonstrate the utility of these loci to resolve relationships in whiteflies, Bemisia tabaci, a large species complex with few phylogenomic resources. Last, we compare our Hemiptera phylogeny with previously published phylogenies and other orthologue databases, while providing suggestions on further improvement to this phylogenomic resource.
The genetic adaptations of fall armyworm Spodoptera frugiperda facilitated its rapid global dispersal and invasion
Authors: Xiao Huamei , Ye Xinhai , Xu Hongxing , Mei Yang , Yang Yi , Chen Xi , Yang Yajun , Liu Tao , Yu Yongyi , Yang Weifei , Lu Zhongxian , Li Fei
Published: May 2020

The fall armyworm (Spodoptera frugiperda) is a lepidopteran insect pest that causes huge economic losses. This notorious insect pest has rapidly spread over the world in the past few years. However, the mechanisms of rapid dispersal are not well understood. Here, we report a chromosome‐level assembled genome of the fall armyworm, named the ZJ‐version, using PacBio and Hi‐C technology. The sequenced individual was a female collected from the Zhejiang province of China and had high heterozygosity. The assembled genome size of ZJ‐version was 486 Mb, containing 361 contigs with an N50 of 1.13 Mb. Hi‐C scaffolding further assembled the genome into 31 chromosomes and a portion of W chromosome, representing 97.4% of all contigs and resulted in a chromosome‐level genome with scaffold N50 of 16.3 Mb. The sex chromosomes were identified by genome resequencing of a single male pupa and a single female pupa. About 28% of the genome was annotated as repeat sequences, and 22,623 protein‐coding genes were identified. Comparative genomics revealed the expansion of the detoxification‐associated gene families, chemoreception‐associated gene families, nutrition metabolism and transport system gene families in the fall armyworm. Transcriptomic and phylogenetic analyses focused on these gene families revealed the potential roles of the genes in polyphagia and invasion of fall armyworm. The high‐quality of the fall armyworm genome provides an important genomic resource for further explorations of the mechanisms of polyphagia and insecticide resistance, as well as for pest management of fall armyworm.
Splitting Urban Waters: The Politicisation of Water in Barcelona between Populism and Anti‐Populism
Authors: Popartan Lucia Alexandra , Ungureanu Camil , Velicu Irina , Amores Maria José , Poch Manuel
Published: May 2020

The current literature on remunicipalisation is focused either on theoretical concepts (e.g. right to the city, commons, return of the political) or on the “insurgent” actors involved in this process, overlooking the counter‐politicisation of the economic agents and the resulting struggles for power and legitimation. This paper examines, by means of an interpretative qualitative methodology and by critically engaging with Ernesto Laclau’s approach to populism, the complexities of the ongoing dialectic of populist and anti‐populist antagonism between socio‐political actors and private companies, with a focus on the discourse on remunicipalisation of water in Barcelona.
2019 novel coronavirus disease (COVID‐19) in patients with inflammatory bowel diseases
Authors: Taxonera Carlos , Sagastagoitia Iñigo , Alba Cristina , Mañas Norberto , Olivares David , Rey Enrique
Published: May 2020

Background

Data on patients with inflammatory bowel diseases (IBD) who have had 2019 novel coronavirus (SARS‐CoV‐2) disease (COVID‐19) are needed.

Aims

To report the clinical characteristics, including gastrointestinal symptoms, of COVID‐19 in IBD patients, and to assess the risk of COVID‐19 in IBD.

Methods

This case series included consecutive IBD patients with laboratory‐confirmed COVID‐19. Age‐adjusted cumulative incidences were compared with the general population in the Madrid region.

Results

Through April 8, 12 of 1918 IBD patients were diagnosed with COVID‐19. The average age was 52 years, 75% of the patients were female and 58.3% had Crohn’s disease. Seven patients (58%) were on maintenance treatment with immunomodulators/biologics, of these four with combined therapy (33%). Eight patients (66%) required hospitalisation (one intensive care unit admission, and two deaths), and four patients were isolated at home. Nine patients had diarrhoea ranging between 4 and 10 loose stools per day (mean 5.4, SD 1.6). In five patients (42%) diarrhoea was a presenting symptom. In two patients, diarrhoea was the only symptom at debut. Cumulative incidence of COVID‐19 was 6.2 per 1000 IBD patients. IBD patients had a lower adjusted incidence ratio of COVID‐19 (OR 0.74, 95% CI 0.70‐0.77; P < 0.001), and a similar associated mortality ratio (OR 0.95, 95% CI: 0.84‐1.06; P = 0.36), compared with the general population.

Conclusions

IBD patients do not have an increased risk of COVID‐19 and associated mortality compared with the general population. In many IBD patients, diarrhoea was a presenting symptom, and sometimes, was the only symptom at onset of COVID‐19.
Me‐too pharmaceutical products: History, definitions, examples, and relevance to drug shortages and essential medicines lists
Authors: Aronson Jeffrey K. , Green A. Richard
Published: May 2020

We define a me‐too drug as a pharmacologically active compound that is structurally related to a first‐in‐class compound, regarded as belonging to the same therapeutic class as the original compound, and used for the same therapeutic purposes, but which may differ in some respects, such as specificity of pharmacological action, adverse reactions profile, or drug–drug interactions. We also offer definitions of related terms, including follow‐on drug and first‐in‐class. The therapeutic advantages of me‐too drugs may include improved target specificity, reduced risks of off‐target adverse reactions and drug–drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics. Me‐too drugs can also demonstrate incremental innovation. Their availability may help in coping with drug shortages. However, they may occasionally cause unexpected adverse reactions that are not class effects. Tricyclic antidepressants, β‐blockers, and statins illustrate the diversity of me‐too drugs. Earlier compounds may be as effective as later ones, or more so. Tricyclic antidepressants have similar chemical structures, and compounds introduced after the first‐in‐class compound (imipramine) mostly offered little in the way of innovative features, but continue to be prescribed. In contrast, me‐too β‐blockers introduced after the first‐in‐class compound, pronethalol, have diverse structures and display several innovative features. Stereoisomers and biosimilars/biobetters provide special examples of me‐too drugs. Although many me‐too drugs offer no significant advantages over their predecessors, over 60% of the drugs listed on the World Health Organization's essential list are me‐toos. Different countries may choose different me‐too drugs when constructing essential medicines lists, partly explaining transnational differences between them.
Cost‐effectiveness and financial risks associated with immune checkpoint inhibitor therapy
Authors: Kim Hansoo , Liew Danny , Goodall Stephen
Published: May 2020

The reimbursement of immune checkpoint inhibitors is challenging. Funding these technologies involves the careful balance between awarding innovation and ensuring affordability as increases in drug spending compete directly with other health care and social expenditure. This narrative review examines the recommendations of 2 health technology assessment agencies—the Australian Pharmaceutical Benefits Advisory Committee and the British National Institute of Clinical Excellence—to determine the factors that contribute to the approval and rejection of immune checkpoint inhibitors as well as the use of manage entry schemes and risk management strategies to control expenditure. Reimbursement decisions from 6 immune checkpoint inhibitor drugs (ipilimumab,pembrolizumab,nivolumab,durvalumab,atezolizumab,avelumab) covering 10 different cancers were examined. The extrapolation of survival beyond the clinical trial and lack of head‐to‐head evidence are some of the main issues relating to cost effectiveness. Payers managed financial risks using different mechanisms such as risk share agreements and financial caps. This review of the reimbursement decisions and subsequent financial impact in Australia and the UK suggests budgets for immune checkpoint inhibitor therapy have been well managed so far. Through risk agreements and managed entry programmes, the example of immune checkpoint inhibitor therapies illustrates that industry and payers can effectively collaborate to ensure that innovative, but expensive, drugs can be made readily available to patients.
Upsetting the apple CAR‐T (chimeric antigen receptor T‐cell therapy) ‐ sustainability mandates USA innovation
Authors: Pantin Jeremy , Battiwalla Minoo
Published: May 2020

Seldom has a medical advance in cancer therapy been as pivotal as the advent of chimeric antigen receptor (CAR)‐T‐cell immunotherapy. While the first applications targeted the CD19 antigen on lymphoid malignancies, the incredible specificity of these ‘living drugs’, curative potential and generalisability to other targets have richly justified their declaration as 2019’s breakthrough of the year by Science magazine. Two CAR‐T products, Yescarta (axicabtagene ciloleucel) and Kymriah (tisagenlecleucel) were Food and Drug Administration (FDA)‐approved in the USA in late 2017, with the FDA commissioner Scott Gottlieb heralding ‘a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer’. Building upon early enthusiasm, nearly 1000 cell‐ and gene‐therapy investigational new drug applications are pending with the FDA, which expects to review and approve between 10 and 20 such treatments annually by 2025. Despite the enormous promise and urgent unmet need fulfilled by CAR‐T cells, the real‐world adoption of the two FDA‐approved treatments has been slow.
COVID‐19: impact on colorectal surgery
Authors: Wexner S. D. , Cortés‐Guiral D. , Gilshtein H. , Kent I. , Reymond M. A.
Published: May 2020

Aim

The rapid spread of the COVID‐19 pandemic has created unprecedented challenges for the medical and surgical healthcare systems. With the ongoing need for urgent and emergency colorectal surgery, including surgery for colorectal cancer, several questions pertaining to operating room (OR) utilization and techniques needed to be rapidly addressed.

Method

This manuscript discusses knowledge related to the critical considerations of patient and caregiver safety relating to personal protective equipment (PPE) and the operating room environment.

Results

During the COVID‐19 pandemic, additional personal protective equipment (PPE) may be required contingent upon local availability of COVID‐19 testing and the incidence of known COVID‐19 infection in the respective community. In addition to standard COVID‐19 PPE precautions, a negative‐pressure environment, including an OR, has been recommended, especially for the performance of aerosol‐generating procedures (AGPs). Hospital spaces ranging from patient wards to ORs to endoscopy rooms have been successfully converted from standard positive‐pressure to negative‐pressure spaces. Another important consideration is the method of surgical access; specifically, minimally invasive surgery with pneumoperitoneum is an AGP and thus must be carefully considered. Current debate centres around whether it should be avoided in patients known to be infected with SARS‐CoV‐2 or whether it can be performed under precautions with safety measures in place to minimize exposure to aerosolized virus particles. Several important lessons learned from pressurized intraperitoneal aerosolized chemotherapy procedures are demonstrated to help improve our understanding and management.

Conclusion

This paper evaluates the issues surrounding these challenges including the OR environment and AGPs which are germane to surgical practices around the world. Although there is no single universally agreed upon set of answers, we have presented what we think is a balanced cogent description of logical safe approaches to colorectal surgery during the COVID‐19 pandemic.
Short‐term mechanical circulatory support devices as bridge to heart transplantation: A prospective single‐center experience in Argentina
Authors: Giordanino Elian F. , Absi Daniel O. , Favaloro Liliana E. , Renedo Maria F. , Ratto Roxana D. , Rubira Daniela M. , Ameri Aldana , Giunta Gustavo , Favaloro Roberto R. , Bertolotti Alejandro M.
Published: May 2020

Background

Patients with cardiogenic shock may require hemodynamic stabilization with short‐term mechanical circulatory support devices (ST‐MCS) such as extracorporeal membrane oxygenation (ECMO) and centrifugal pump (CP) as bridge to transplantion (BTT). This study aimed to describe ECMO and CP during BTT and after heart transplant.

Methods

A cohort of patients on ECMO or CP as BTT between April 2006 and April 2018 in a single hospital.

Results

Thirty‐seven consecutive patients with ECMO (n = 14) or CP (n = 23) were included. Acute kidney injury was more prevalent during CP (28.6% vs 69.6%, P = .02). There were no differences in stroke, thrombosis, sepsis, or vasoplegia. Bleeding (0% vs 56.5%, P = .0003) and reoperation (0% vs 47.8%, P = .002) were more frequent in CP group as well as mortality (0 vs 7 [30.4%], P = .03). The remaining 30 patients (81.1%) underwent heart transplantation, without differences in primary graft dysfunction, vasoplegia, reoperation for bleeding, or hospital stay. Mortality was 23.3% at 30 days, similar in both groups, with no further deaths at median follow‐up of 44.2 months.

Conclusions

In patients with cardiogenic shock, ST‐MCS with ECMO or CP as BTT are a lifesaving approach allowing successful transplantation in the majority of cases, with good short‐ and long‐term survival.
Prediabetes and older age increase the risk of post‐transplantation diabetes mellitus: Qatar experience
Authors: Alkadi Mohamad M. , Abuhelaiqa Essa , Jerobin Jayakumar , Thappy Shaefiq , Khan Saifatullah , Abdelhalim Mohamed F. , Asim Muhammad , Fituri Omar , Hamdi Ahmed , Ashour Adel , Nauman Awais , Al‐Maslamani Yousuf K. , Jarman Mona , Dargham Soha R. , Abou‐Samra Abdul Badi , Al‐Malki Hassan
Published: May 2020

Post‐transplantation diabetes mellitus (PTDM) is a major complication in kidney transplant recipients leading to reduced allograft and patient survival. Given the high prevalence of diabetes in Qatar, which is twice the global average, we were interested in determining the incidence of PTDM, identifying risk factors, and comparing clinical outcomes in kidney transplant recipients with and without diabetes. We retrospectively followed up 191 adult kidney allograft recipients transplanted between January 1, 2012, and December 31, 2016, for a median of 41 months. A total of 76 patients (40%) had pre‐existing diabetes. A total of 39 patients developed PTDM during follow‐up; they represent 34% of patients who did not have diabetes prior to transplantation. Two thirds of PTDM occurred within 3‐6 months post‐transplantation. Prediabetes before transplant [OR = 6.07 (1.24‐29.74), P = .026] older recipient's age at the time of transplantation [OR = 1.10 (1.00‐1.20), P = .039] and average fasting blood sugar during 3‐6 months post‐transplant [OR = 1.06 (1.01‐1.11), P = .010] were independently associated with PTDM. Patient and kidney allograft survival rates exceeded 97% in all groups. The incidence of PTDM in kidney transplant recipients living in Qatar is high. Older age and prediabetes are independent risk factors for developing PTDM.
Cornea donation in Germany: Obtaining consent
Authors: Schmidt Sabrina , Ghouzi Ammar , Petrov George , Hofmann Nicola , Boergel Martin , Sixt Stephan Urs
Published: May 2020

Tissue donation is important to reverse cornea‐related blindness. Unfortunately, the willingness to make a decision concerning organ and tissue donation while still alive remains low despite all efforts. By analyzing anonymized archived data from 25 654 next‐of‐kin interviews from our database over a period of 5 years (2013‐2018), it was found that only 20.8% of all potential cornea donors have declared their own wishes. While still alive, refusal was communicated more often than consent by potential donors. Overall consent rates were 39.2%, with parents and siblings consenting more often than other relatives and females refusing more often than male family members. Personal interviews and interviews via telephone handled by staff known to the family resulted in better consent rates (up to 75.6%) with male interviewers receiving higher consent rates in general. The gender of the approached relatives in relation to a male/female interviewer was of low importance. The results also show that it is important to allow discussion about that topic between family members—the more relatives that were involved the higher the probability of consent.
Is bacterial vaginosis associated with autoimmune antibody positivity?
Authors: Donmez Hanife Guler , Cagan Murat , Fadiloglu Erdem , Unal Canan , Onder Sevgen Celik , Beksac Mehmet Sinan
Published: May 2020

Objective

To evaluate the association between bacterial vaginosis (BV) and autoimmune antibody positivity.

Method

We evaluated Papanicolaou‐stained cervicovaginal smears of 210 patients with poor obstetric history who were admitted to a special preconception counselling programme. Cytological specimens with various types of microorganisms except for BV, epithelial cell abnormalities and other non‐neoplastic findings, including inflammation were excluded from the cohort in addition to patients with autoimmune and chronic inflammatory diseases. The remaining study population (n = 121) was divided into two groups of patients with autoimmune antibody positivity (study group, n = 80) and patients without antibody positivity (control group, n = 41).

Results

The rate of BV was demonstrated to be 13.8% and 2.4% in the study and control groups respectively (P = .042). We also demonstrated that the anti‐nuclear antibody was positive in 58.3% of the cases with BV.

Conclusion

BV was found more frequently in patients with autoimmune antibody positivity to a statistically significant degree.
Getting under the skin of hair aging: the impact of the hair follicle environment
Authors: Williams Rachael , Pawlus Alison D. , Thornton M. Julie
Published: May 2020

Like the skin, our hair shows striking changes with age, producing hairs with altered diameter, lustre and texture. The biology of hair aging has focused predominately on various aspects of the hair cycle, follicle size and the fibre produced, but surprisingly the impact of the aging scalp dermal environment on the hair follicle and fibre has been generally overlooked. Hair loss affects both sexes with incidence increasing with age. In men, male pattern‐balding (androgenetic alopecia) is driven by androgens and follows a specific pattern of frontotemporal and vertex regression. Women also experience female pattern hair loss (FPHL), presenting as more general, diffuse hair thinning. Hair thinning in women is commonly associated with the menopause, corresponding with other age‐related changes in skin. The rapidly growing hair follicle undergoes continued renewal throughout the life span of an individual, where it is exposed to a substantial number of extrinsic and intrinsic stressors. As the hair follicle sits deep within the dermis with its bulb residing in the hypodermis, detrimental age‐related changes in the surrounding scalp skin may likely disrupt the hair follicle machinery. The impacts of these changes are unknown, but evidence suggests that scalp skin aging and hair follicle aging go hand‐in‐hand. Herein, we summarize the evidence that the age‐related changes observed in sun‐exposed human skin also occur in scalp skin and that these changes are likely to play a contributing role in the aging hair phenotype.
Evaluation of an interactive educational system in urban knowledge acquisition and representation based on students' profiles
Authors: Sanchez‐Sepulveda Monica V. , Fonseca David , García‐Holgado Alicia , García‐Peñalvo Francisco José , Franquesa Jordi , Redondo Ernesto , Moreira Fernando
Published: May 2020

The aim of this article is to study how students currently understand the conception of space through different media and how that understanding helps them to intervene in the space. Firstly, the process of teaching and learning as well as innovative supporting technologies are analysed, revealing the characteristics of the contemporary student profile and better ways of teaching according to it. Secondly, we describe the evaluation of an experiment with a virtual reality (VR) system for urban project design with students of architecture from two universities. The premise is that the technology used in VR is familiar to the current profile of students. This paper aims to study the advantages and disadvantages of this trend and to find a balance. To do so, we use a quantitative method to evaluate students' profiles and their level of satisfaction with the system. The results were obtained by a questionnaire and a survey, which show the role and use of technologies in the students' environment and the degree of satisfaction when using it in the educational processes. In line with our assumptions, the value of satisfaction in the use of an advanced visualization technology in the classroom reveals a high level of motivation, in general, with differentiation between students in their first and last phases of studies.
Network learning and trust: A case study of a benchmarking network
Authors: Dietrichson Lars G. , Bukh Per Nikolaj
Published: May 2020

When organizations engage in learning from each other through self‐governed networks, they may encounter challenges regarding confidentiality. This is particularly true if external accountability needs of the network participants conflict with internal accountability among participants and/or network‐level objectives. This study shows how important it is to have specific agreements about not using findings for accountability outside the network. Empirical evidence comes from a longitudinal case study of a benchmarking project involving six independent public sector companies. Based on reciprocal trust among the participants, the promise of confidentiality was made up front and enforced throughout the network collaboration by the participants themselves.
A conserved sequence motif bridges two protein kinases for enhanced phosphorylation and nuclear function of a splicing factor
Authors: Aubol Brandon E. , Fattet Laurent , Adams Joseph A.
Published: May 2020

The assembly and activation of the spliceosome rely upon the phosphorylation of an essential family of splicing factors known as the serine–arginine (SR) proteins. Although it has been demonstrated recently that two enzyme families, the SR protein kinases (SRPKs) and the Cdc2‐like kinases (CLKs), can function as a complex to efficiently phosphorylate these SR proteins in the nucleus, the molecular features involved in such a connection are unknown. In this study, we identified a group of conserved residues in the large lobe of SRPK1 that interact with the N terminus of CLK1 stabilizing the SRPK1‐CLK1 complex. Mutations in this motif not only disrupt formation of the kinase–kinase complex but also impair SRPK1‐dependent release of the phospho‐SR protein from CLK1. The binding motif potently up‐regulates CLK1‐specific phosphorylation sites, enhances SR protein diffusion from nuclear speckles, and impacts the alternative splicing of several target genes. These results indicate that CLK1 binds a conserved, electronegative surface on SRPK1, thereby controlling SR protein phosphorylation levels for enhanced subnuclear trafficking and alternative splicing regulation.
Applying machine learning methods to develop a successful aging maintenance prediction model based on physical fitness tests
Authors: Cai TianPan , Long JingWen , Kuang Jie , You Fu , Zou TingTing , Wu Lei
Published: May 2020

Aim

The purpose of this study was to develop a machine learning prediction model for successful aging (SA) based on physical fitness tests.

Methods

A total of 3657 community‐dwelling adults aged ≥60 years from Nanchang city were recruited in this study. A 3‐year follow‐up test was carried out for all the participants to determine whether they turn to non‐SA. Developed questionnaires and physical fitness tests were used to obtain overall health condition, balance, agility, speed, reactions and gait. Four machine learning models (logistic regression, deep learning, random forest and gradient boosting decision tree) were applied to develop the prediction models, the analyzed sample was 890.

Results

The baseline prevalence of successful aging was 26.99%, The average annual incidence rate of SA to non‐SA was 11.04%. There were significant differences between the SA and non‐SA groups for all physical fitness tests at baseline. The accuracy and area under the curve of all four machine learning models was >85%, the positive predictive value and sensitivity was >75%, and the specificity was >86% on the average. The deep learning model outperformed the other model, with area under the curve 90.00%, accuracy 89.3%, positive predictive value 85.8% and specificity 93.1%, respectively. Compared with other models, the logistic regression model performed best in sensitivity. Age, arm curl, 30‐s sit‐to‐stand and reaction time were important predictors in all models.

Conclusion

The deep learning model is ideal in the prediction of SA maintenance, and the corresponding physical fitness interventions are essential to ensuring SA. Geriatr Gerontol Int 2020; ••: ••–••.