bluuebunny/crossref_metadata_2025 huggingface dataset:
It’s Not Just the Prices: Time-Driven Activity-Based Costing for Initiation of Veno-Venous Extracorporeal Membrane Oxygenation at Three International Sites—A Case Review
Authors: Nurok Michael , Pellegrino Vin , Pineton de Chambrun Marc , Warsh Jonathan , Young Meredith , Dong Erik , Parrish Neil , Shehab Syed , Combes Alain , Kaplan Robert S.
Published: June 2022

The United States spends more for intensive care units (ICUs) than do other high-income countries. We used time-driven activity-based costing (TDABC) to analyze ICU costs for initiation of veno-venous extracorporeal membrane oxygenation (VV ECMO) for respiratory failure to estimate how much of the higher ICU costs at 1 US site can be attributed to the higher prices paid to ICU personnel, and how much is caused by the US site’s use of a higher cost staffing model. We accompanied our TDABC approach with narrative review of the ECMO programs, at Cedars-Sinai (Los Angeles), Hôpital Pitié-Salpêtrière (Paris), and The Alfred Hospital (Melbourne) from 2017 to 2019. Our primary outcome was daily ECMO cost, and we hypothesized that cost differences among the hospitals could be explained by the efficiencies and skill mix of involved clinicians and prices paid for personnel, equipment, and consumables. Our results are presented relative to Los Angeles’ total personnel cost per VV ECMO patient day, indexed at 100. Los Angeles’ total indexed daily cost of care was 147 (personnel: 100, durables: 5, and disposables: 42). Paris’ total cost was 39 (26% of Los Angeles) (personnel: 12, durables: 1, and disposables: 26). Melbourne’s total cost was 53 (36% of Los Angeles) (personnel: 32, durables: 2, and disposables: 19) (rounded). The higher personnel prices at Los Angeles explained only 26% of its much higher personnel costs than Paris, and 21% relative to Melbourne. Los Angeles’ higher staffing levels accounted for 49% (36%), and its costlier mix of personnel accounted for 12% (10%) of its higher personnel costs relative to Paris (Melbourne). Unadjusted discharge rates for ECMO patients were 46% in Los Angeles (46%), 56% in Paris, and 52% in Melbourne. We found that personnel salaries explained only 30% of the higher personnel costs at 1 Los Angeles hospital. Most of the cost differential was caused by personnel staffing intensity and mix. This study demonstrates how TDABC may be used in ICU administration to quantify the savings that 1 US hospital could achieve by delivering the same quality of care with fewer and less-costly mix of clinicians compared to a French and Australian site. Narrative reviews contextualized how the care models evolved at each site and helped identify potential barriers to change.
Natural history study and statistical modeling of disease progression in a preclinical model of myotubular myopathy
Authors: Buono Suzie , Monseur Arnaud , Menuet Alexia , Robé Anne , Koch Catherine , Laporte Jocelyn , Thielemans Leen , Depla Marion , Cowling Belinda S.
Published: June 2022

Generating reliable preclinical data in animal models of disease is essential in therapy development. Here, we performed statistical analysis and joint longitudinal–survival modeling of the progressive phenotype observed in Mtm1−/y mice, a reliable model for myotubular myopathy. Analysis of historical data was used to generate a model for phenotype progression, which was then confirmed with phenotypic data from a new colony of mice derived via in vitro fertilization in an independent animal house, highlighting the reproducibility of disease phenotype in Mtm1−/y mice. These combined data were used to refine the phenotypic parameters analyzed in these mice and improve the model generated for expected disease progression. The disease progression model was then used to test the therapeutic efficacy of Dnm2 targeting. Dnm2 reduction by antisense oligonucleotides blocked or postponed disease development, and resulted in a significant dose-dependent improvement outside the expected disease progression in untreated Mtm1−/y mice. This provides an example of optimizing disease analysis and testing therapeutic efficacy in a preclinical model, which can be applied by scientists testing therapeutic approaches using neuromuscular disease models in different laboratories.

This article has an associated First Person interview with the joint first authors of the paper.
The Commitment Benefit of Consols in Government Debt Management
Authors: Debortoli Davide , Nunes Ricardo , Yared Pierre
Published: June 2022

We consider optimal government debt maturity in a deterministic economy in which the government can issue any arbitrary debt maturity structure and in which bond prices are a function of the government’s current and future primary surpluses. The government sequentially chooses policy, taking into account how current choices—which impact future policy—feed back into current bond prices. We show that issuing consols constitutes the unique stationary optimal debt portfolio, as it boosts government credibility to future policy and reduces the debt financing costs. (JEL E62, G12, H61, H63)
New records and review of the occurrence of the oriental hornet Vespa orientalis Linnaeus, 1771 in the islands of Greece (Hymenoptera: Vespidae: Vespinae)
Authors: Ceccolini Filippo
Published: June 2022

Records of Vespa orientalis Linnaeus, 1771 for 28 islands of Greece are given: in 18 islands (Agistri, Euboea, Folegandros, Kalamos, Kalymnos, Karpathos, Kos, Leros, Lefkada, Naxos, Nisyros, Paros, Patmos, Pserimos, Telendos, Tilos, Tinos, Sifnos), these occurrences are the first record of the species for them. The total number of Greek islands in which V. orientalis is known becomes 33.
Association between the body mass index, waist circumference, and body fat percentage with erosive esophagitis in adults with obesity after sleeve gastrectomy
Authors: Zevallos-Ventura Alba S. , de la Cruz-Ku Gabriel , Runzer-Colmenares Fernando M. , Pinto-Elera Jesús , Toro-Huamanchumo Carlos J.
Published: June 2022

Background: High anthropometric indexes before sleeve gastrectomy (SG) are associated with an increased risk of erosive esophagitis (EE) in bariatric surgery candidates. Reasons that explain how these indexes influence the development of esophageal pathology after surgery remains unclear.

Objectives: To assess the association between the body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) with the development of EE in adults with obesity three months after SG.

Setting: Clínica Avendaño, Lima, Peru.

Methods: Retrospective cohort using a database including adults with obesity who underwent SG during 2017-2020. All the patients included had an endoscopy before and after the surgery. Sociodemographic, clinical and laboratory characteristics were compared according to BMI, WC and BFP, as well as by the development of de novo esophagitis. The association was evaluated by crude and adjusted generalized linear models with the log-Poisson family.

Results: From a total of 106 patients, 23 (21.7%) developed EE. We did not find significant differences in sociodemographic, clinical and laboratory characteristics between patients with de novo EE compared to those who did not develop EE. After adjustment, BMI (aRR = 0.59, 95% CI = 0.18-1.40), BFP (aRR = 0.41, 95% CI = 0.15-1.19) and WC (aRR = 0.91, 95% CI = 0.69-1.16) were not associated with the development of EE three months post SG.

Conclusions: We found no association between preoperative anthropometric indexes and the development of de novo EE; therefore, morbid obesity should not be a criterion to exclude the patients to undergo SG as primary surgery because of the risk of developing EE.
Association between dermatoglyphic patterns and growth patterns of subjects with skeletal class I relation: A cross sectional study
Authors: Shashidhar Keerthan , M N Kuttappa , Nayak U S Krishna , D'Souza Neevan , Shetty Mahabalesh , Achalli Sonika
Published: June 2022

Background: To assess the relationship between dermatoglyphic patterns and various growth patterns of the mandible.

Methods: Patients with Class I Skeletal relation were selected after clinical diagnosis followed by digitally tracing the cephalogram. The patients were subdivided into three groups of mandibular divergence patterns ie Average, Horizontal and Vertical. 90 samples ie 30 in each group were selected for the study. The fingerprints of all the selected subjects were then extracted digitally and analysed for the most dominant pattern in each hand.

Results: For the left hand, there was a statistically significant (P<0.05) association between fingerprint pattern and growth pattern when Horizontal growers were compared to Average and Vertical Growers. For the right hand, there was a statistically significant (P<0.05) association between fingerprint pattern and growth pattern when Horizontal growers were compared to Average Growers. A significant association (P<0.05) between fingerprint pattern and growth pattern was also found when average growers were compared to vertical growers.

Conclusions: Horizontal growers had 80% frequency of appearance of whorls in their left hand and 67% in their right hand. Horizontal growers could easily be differentiated from the average and vertical growers because of the dominance of whorl pattern in their hands.

Composite and arch pattern were more frequent in vertical growers when compared to horizontal and average growers.
Pharmaceutical pollution: Prediction of environmental concentrations from national wholesales data
Authors: Welch Samuel A. , Olsen Kristine , Nouri Sharikabad Mohammad , Tollefsen Knut Erik , Grung Merete , Moe S. Jannicke
Published: June 2022

The regulation and monitoring of pharmaceutical pollution in Europe lag behind that of more prominent groups. However, the repurposing of sales data to predict surface water environmental concentrations is a promising supplement to more commonly used market-based risk assessment and measurement approaches. The Norwegian Institute of Public Health (NIPH) has since the 1980s compiled the Drug Wholesale Statistics database - covering all sales of both human and veterinary pharmaceuticals to retailers, pharmacies, and healthcare providers.

To date, most similar works have focused either on a small subset of Active Pharmaceutical Ingredients (APIs) or used only prescription data, often more readily available than wholesale data, but necessarily more limited. By using the NIPH’s product wholesale records, with additional information on API concentrations per product from, we have been able to calculate sales weights per year for almost 900 human and veterinary APIs for the period 2016–2019.

In this paper, we present our methodology for converting the provided NIPH data from a public health to an ecotoxicological resource. From our derived dataset, we have used an equation to calculate Predicted Environmental Concentration per API for inland surface waters, a key component of environmental risk assessment. We further describe our filtering to remove ecotoxicological-exempt and data deficient APIs. Lastly, we provide a limited comparison between our dataset and similar publicly available datasets for a subset of APIs, as a validation of our approach and a demonstration of the added value of wholesale data.

This dataset will provide the best coverage yet of pharmaceutical sales weights for an entire nation. Moreover, our developed routines for processing 2016–2019 data can be expanded to older Norwegian wholesales data (1974–present). Consequently, our work with this dataset can contribute to narrowing the gap between desk-based predictions of exposure from consumption, and empirical but expensive environmental measurement.
Saussure’s dichotomies and the shapes of structuralist semiotics
Authors: Joseph John E.
Published: June 2022

The Cours de linguistique générale (1916), which became the master text for structuralist linguistics and semiotics, is characterized by a series of dichotomies. Some of them, e.g. langue and parole, signified and signifier, arbitrary and motivated, are very well known, others less so. This paper looks at Saussure’s semiotics in terms of these dichotomies, and considers how later critiques, such as Voloshinov’s (1929), and reformulations, particularly Hjelmslev’s (1935, 1942) and the concept of enunciation which emerged conjointly in the work of Jakobson, Lacan, Dubois, Benveniste and others, were shaped as responses to the Saussurean dichotomies. Also examined in terms of its contrast with Saussure is Bally’s stylistics. The aim is a fuller understanding of the shapes taken by structuralist semiotics, in view of the heritage on which they were based and the broader intellectual climate, including phenomenology and Marxism, in which they developed.
Can linguistics and semiotics conceive man without language?
Authors: Fadda Emanuele
Published: June 2022

Saussure’s refusal to adopt a biological perspective in linguistics and to consider the problem of the origin of language does not imply a struggle against the natural and biological aspects of language. Rather, it derives from the awareness that it is impossible to look at language “from the outside” if one wants (as Saussure considers obligatory for the linguist) to drop into the perspective of the speaking subjects. This tendency to consider the nature of language “from within” has a strong philosophical importance.
Language as an “independent unit”: Ferdinand de Saussure vs. Paul Boyer
Authors: Zalesskaya Daria
Published: June 2022

Didactics and semiotics are two fields that have been interconnected for a long time. Russian language teaching in France in the 20th century, especially in its first half, had several interesting didactic features closely related to the understanding of Ferdinand de Saussure’s theoretical conceptions. Through the works of influential Slavist professor Paul Boyer (1864–1949), some of Ferdinand de Saussure’s ideas became reflected in French didactics in a particular way, providing the basis for a new method of teaching Russian as a foreign language. The article offers an analysis of the textbook Manuel pour l’étude de la langue russe by Boyer and Nicolas Spéransky, as well as of the teaching method “language-in-itself ”, with the objective to identify the references to the Course in General Linguistics and to consider their reflection in didactics.
Is language a system of signs? Lenin, Saussure and the theory of hieroglyphics
Authors: Sériot Patrick
Published: June 2022

This paper strives to pursue two goals at the same time: how can one get to know in depth the intellectual life of the USSR in the 1930s–1950s; and, what can the virulent anti-Saussurean criticism in Russia at that time tell us about the specificity of the Marxist-Leninist theory of signs?

We propose the following angle of attack: the recurring theme of this criticism, namely that Saussure’s Cours presents a “theory of hieroglyphics”, therefore a type of “bourgeois idealist” theory that Lenin assailed in his 1909 book Materialism and Empiriocriticism about Ernst Mach. Yet thinking about hieroglyphics is based on much older controversies, dating back to the 17th century and concerning the deciphering of Egyptian writing. The issue which arises here is semiotic in nature: it is the scalar opposition between transparency and opacity of the sign that is at stake. Does the sign hide or reveal? The Soviet discourse on language and signs in the 1930s–1950s seems to be based on an interrogation of the sign/referent, language/ thought, form/content relationship. A part of the history of semiotics can thus be discovered from the critique of the “hieroglyphic theory”, a little-known episode in a debate on the interpretation of Saussurism.
Supply Chain Practices - OLA Cabs Users’ Perception
Authors: Nallasivam Anitha , C Selvaraj
Published: June 2022

Supply chain practices of any organisation a plays vital role to satisfy the Customer expectation. Supply chain management of an organisation is taking care from suppliers to end users. The chain must move in smooth way based on the prescribed standards is the key for exceeding the customer expectations. The supply chain practices of Mobile application-based cab operators are based on the triangle relationship. The triangle includes the Customers, Drivers and App service providers. The technology is connecting the all the corners of the triangle. This paper is trying to provide an insight about the OLA Cabs users’ perception over the supply chain practices of OLA cabs in White field, Bangalore city. It tries to identify the Key factors of Customer Perception over the supply chain practices of OLA Cabs.
History of treatment of labor pains
Authors: Janowski Jacek , Zwierzyńska Anna , Adamczyk-Gruszka Olga
Published: June 2022

Pain is both a mental and a physical condition. It is considered by many experts to be a serious health problem or even a disease one. WHO describes it as a multidimensional phenomenon consisting of sensory, physiological, affective, spiritual and behavioral factors. Childbirth has always been associated with severe pain. The pain of childbirth has been known for centuries and is presented in every possible way as a very unpleasant sensation, not only physical but also mental. Over the years, efforts have been made to develop the best possible methods of relieving labor pain. These include non-pharmacological, such as: acupuncture, TENS or hypnosis, and pharmacological: administration of opioids and inhalation anesthetics, ending with regional analgesia techniques such as: epidural, subarachnoid anesthesia, etc. The article presents the history of the treatment of labor pain.
The desire and fear of discharge from mental health units by people with autistic spectrum conditions: a phenomenological study
Authors: Maloret Paul , Scott Patricia , Sharma Shivani
Published: June 2022

Background/Aims

Anxiety is a common characteristic for people who live with an autistic spectrum condition and while studies on anxiety in this population are commonplace and case studies correlate anxiety with mental health service experience, little is known about the actual triggers of anxiety and its manifestations, particularly during the discharge process. This aim of this study was to explore how mental health inpatients with autistic spectrum conditions experienced and coped with discharge from a UK acute mental health inpatient facility.

Methods

Between 2018 and 2019, audio-recorded semi-structured interviews captured the experiences of 20 adults from the east of England, who were former psychiatric inpatients with an established diagnosis of an autistic spectrum condition.

Results

Themes were identified through interpretative phenomenological data analysis, which explained participants' reflections regarding the situations and events within the acute care mental health facility that triggered their anxiety, behavioural manifestations of anxiety and responses to the discussion of discharge. Broad behavioural patterns were established that could be associated with their anxiety, such as self-harming or exhibiting aggressive and violent behaviours.

Conclusions

The anxiety caused by the discussion of the discharge process appears to be overlooked by mental health practitioners, so attention to potentially anxiety-inducing dialogue is needed when planning discharge from acute care mental health services. The nature of patient–practitioner interactions and dialogue leading up to discharge needs to be handled with sensitivity to the unique needs of the patient so that the experience of discharge becomes less daunting. Transformative research is required to clearly understand the experiences of this vulnerable group and to act as a vehicle to enhance pre-discharge dialogue and support.
High-bandwidth CMOS-voltage-level electro-optic modulation of 780 nm light in thin-film lithium niobate
Authors: Celik Oguz Tolga , Sarabalis Christopher J. , Mayor Felix M. , Stokowski Hubert S. , Herrmann Jason F. , McKenna Timothy P. , Lee Nathan R. A. , Jiang Wentao , Multani Kevin K. S. , Safavi-Naeini Amir H.
Published: June 2022

Integrated photonics operating at visible-near-infrared (VNIR) wavelengths offer scalable platforms for advancing optical systems for addressing atomic clocks, sensors, and quantum computers. The complexity of free-space control optics causes limited addressability of atoms and ions, and this remains an impediment on scalability and cost. Networks of Mach-Zehnder interferometers can overcome challenges in addressing atoms by providing high-bandwidth electro-optic control of multiple output beams. Here, we demonstrate a VNIR Mach-Zehnder interferometer on lithium niobate on sapphire with a CMOS voltage-level compatible full-swing voltage of 4.2 V and an electro-optic bandwidth of 2.7 GHz occupying only 0.35 mm2. Our waveguides exhibit 1.6 dB/cm propagation loss and our microring resonators have intrinsic quality factors of 4.4 × 105. This specialized platform for VNIR integrated photonics can open new avenues for addressing large arrays of qubits with high precision and negligible cross-talk.
Ultra-low dark current back-illuminated AlGaN-based solar-blind ultraviolet photodetectors with broad spectral response
Authors: Xie Feng , Gu Yan , Hu Zhijia , Yu Benli , Yang Guofeng
Published: June 2022

A high performance AlGaN-based back-illuminated solar-blind ultraviolet (UV) p-i-n photodetectors (PDs) are fabricated on sapphire substrates. The fabricated PD exhibits ultra-low dark current of less than 0.15 pA under -5 V bias, which corresponds to a dark current density of <1.5×10−11 A/cm2. In particular, the PD shows broad spectral response from 240 nm to 285 nm with an excellent solar-blind/UV rejection ratio of more than 103. The peak responsivity at the wavelength of 275 nm reaches 0.19 A/W at -5 V, corresponding to a maximum quantum efficiency of approximately 88%. Based on the absence of any anti-reflection coating, this corresponds to nearly 100% internal quantum efficiency. In addition, the PD shows a quite fast response of 0.62 ms. To the best of our knowledge, this is the record low dark current density and broadest response band reported for the back-illuminated AlGaN-based solar-blind UV detectors.
Why does viral RNA sometimes persist after recovery from acute infections?
Authors: Griffin Diane E.
Published: June 2022

DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?
Improved transcriptome assembly using a hybrid of long and short reads with StringTie
Authors: Shumate Alaina , Wong Brandon , Pertea Geo , Pertea Mihaela
Published: June 2022

Short-read RNA sequencing and long-read RNA sequencing each have their strengths and weaknesses for transcriptome assembly. While short reads are highly accurate, they are rarely able to span multiple exons. Long-read technology can capture full-length transcripts, but its relatively high error rate often leads to mis-identified splice sites. Here we present a new release of StringTie that performs hybrid-read assembly. By taking advantage of the strengths of both long and short reads, hybrid-read assembly with StringTie is more accurate than long-read only or short-read only assembly, and on some datasets it can more than double the number of correctly assembled transcripts, while obtaining substantially higher precision than the long-read data assembly alone. Here we demonstrate the improved accuracy on simulated data and real data from Arabidopsis thaliana, Mus musculus, and human. We also show that hybrid-read assembly is more accurate than correcting long reads prior to assembly while also being substantially faster. StringTie is freely available as open source software at https://github.com/gpertea/stringtie.
Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers
Authors: Wibisana Johannes N. , Inaba Takehiko , Shinohara Hisaaki , Yumoto Noriko , Hayashi Tetsutaro , Umeda Mana , Ebisawa Masashi , Nikaido Itoshi , Sako Yasushi , Okada Mariko
Published: June 2022

The transcription factor NF-κB, which plays an important role in cell fate determination, is involved in the activation of super-enhancers (SEs). However, the biological functions of the NF-κB SEs in gene control are not fully elucidated. We investigated the characteristics of NF-κB-mediated SE activity using fluorescence imaging of RelA, single-cell transcriptome and chromatin accessibility analyses in anti-IgM-stimulated B cells. The formation of cell stimulation-induced nuclear RelA foci was abolished in the presence of hexanediol, suggesting an underlying process of liquid-liquid phase separation. The gained SEs induced a switch-like expression and enhanced cell-to-cell variability in transcriptional response. These properties were correlated with the number of gained cis-regulatory interactions, while switch-like gene induction was associated with the number of NF-κB binding sites in SE. Our study suggests that NF-κB SEs have an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions.
Suicide and self-harm in low- and middle- income countries during the COVID-19 pandemic: A systematic review
Authors: Knipe Duleeka , John Ann , Padmanathan Prianka , Eyles Emily , Dekel Dana , Higgins Julian P. T. , Bantjes Jason , Dandona Rakhi , Macleod-Hall Catherine , McGuinness Luke A. , Schmidt Lena , Webb Roger T. , Gunnell David
Published: June 2022

There is widespread concern over the potential impact of the COVID-19 pandemic on suicide and self-harm globally, particularly in low- and middle-income countries (LMIC) where the burden of these behaviours is greatest. We synthesised the evidence from the published literature on the impact of the pandemic on suicide and self-harm in LMIC. This review is nested within a living systematic review (PROSPERO ID CRD42020183326) that continuously identifies published evidence (all languages) through a comprehensive automated search of multiple databases (PubMed; Scopus; medRxiv, PsyArXiv; SocArXiv; bioRxiv; the WHO COVID-19 database; and the COVID-19 Open Research Dataset by Semantic Scholar (up to 11/2020), including data from Microsoft Academic, Elsevier, arXiv and PubMed Central.) All articles identified by the 4th August 2021 were screened. Papers reporting on data from a LMIC and presenting evidence on the impact of the pandemic on suicide or self-harm were included. Methodological quality was assessed using an appropriate tool, and a narrative synthesis presented. A total of 22 studies from LMIC were identified representing data from 12 countries. There was an absence of data from Africa, the Pacific, and the Caribbean. The reviewed studies mostly report on the early months of COVID-19 and were generally methodologically poor. Few studies directly assessed the impact of the pandemic. The most robust evidence, from time-series studies, indicate either a reduction or no change in suicide and self-harm behaviour. As LMIC continue to experience repeated waves of the virus and increased associated mortality, against a backdrop of vaccine inaccessibility and limited welfare support, continued efforts are needed to track the indirect impact of the pandemic on suicide and self-harm in these countries.
Efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever in patients with acute dengue: A randomised, double blind, placebo-controlled trial
Authors: Malavige Gathsaurie Neelika , Jeewandara Chandima , Wijewickrama Ananda , Gunasinghe Dumni , Mahapatuna Sameera D. , Gangani Chathurika , Vimalachandran Vimalahan , Jayarathna Geethal , Perera Yashoda , Wanigatunga Chandanie , Dissanayake Harsha , Prathapan Shamini , Narangoda Eranga , Idampitiya Damayanthi , Gomes Laksiri , Wickramanayake Samurdhi , Sahabandu Pramodth , Ogg Graham S.
Published: June 2022

Background

Rupatadine was previously shown to reduce endothelial dysfunction in vitro, reduced vascular leak in dengue mouse models and to reduce the extent of pleural effusions and thrombocytopenia in patients with acute dengue. Therefore, we sought to determine the efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever (DHF) in patients with acute dengue.

Methods and findings

A phase 2, randomised, double blind, placebo controlled clinical trial was carried out in patients with acute dengue in Sri Lanka in an outpatient setting. Patients with ≤3 days since the onset of illness were either recruited to the treatment arm of oral rupatadine 40mg for 5 days (n = 123) or the placebo arm (n = 126). Clinical and laboratory features were measured daily to assess development of DHF and other complications. 12 (9.7%) patients developed DHF in the treatment arm compared to 22 (17.5%) who were on the placebo although this was not significant (p = 0.09, relative risk 0.68, 95% CI 0.41 to 1.08). Rupatadine also significantly reduced (p = 0.01) the proportion of patients with platelet counts <50,000 cells/mm3 and significantly reduced (p = 0.04) persisting vomiting, headache and hepatic tenderness (p<0.0001) in patients. There was a significant difference in the duration of illness (p = 0.0002) although the proportion of individuals who required hospital admission in both treatment arms. Only 2 patients on rupatadine and 3 patients on the placebo developed shock, while bleeding manifestations were seen in 6 patients on rupatadine and 7 patients on the placebo.

Conclusions

Rupatadine appeared to be safe and well tolerated and showed a trend towards a reducing proportion of patients with acute dengue who developed DHF. Its usefulness when used in combination with other treatment modalities should be explored.

Trial registration

International Clinical Trials Registration Platform: SLCTR/2017/024.
Prevalence and diversity of small rodent-associated Bartonella species in Shangdang Basin, China
Authors: Yu Juan , Xie Bing , Bi Ge-Yue , Zuo Hui-Hui , Du Xia-Yan , Bi Li-Fang , Li Dong-Mei , Rao Hua-Xiang
Published: June 2022

The aim of this study was to investigate the occurrence and molecular characteristics of Bartonella infections in small rodents in the Shangdang Basin, China. Small rodents were captured using snap traps, and their liver, spleen, and kidney tissues were harvested for Bartonella detection and identification using a combination of real-time PCR of the ssrA gene (296 bp) and conventional PCR and sequencing of the gltA gene (379 bp). Results showed that 55 of 147 small rodents to be positive for Bartonella, with a positivity rate of 37.41%, and 95% confidence interval of 29.50%- 45.33%. While the positivity rate across genders (42.62% in males and 33.72% in females, χ2 = 1.208, P = 0.272) and tissues (28.57% in liver, 33.59% in spleen, and 36.76% in kidney, χ2 = 2.197, P = 0.333) of small rodents was not statistically different, that in different habitats (5.13% in villages, 84.44% in forests, and 54.17% in farmlands, χ2 = 80.105, P<0.001) was statistically different. There were 42 Bartonella sequences identified in six species, including 30 B. grahamii, three B. phoceensis, two B. japonica, two B. queenslandensis, one B. fuyuanensis and four unknown Bartonella species from Niviventer confucianus, Apodemus agrarius and Tscherskia triton. In addition to habitat, Bartonella species infection could be affected by the rodent species as well. Among the Bartonella species detected in this area, B. grahamii was the dominant epidemic species (accounting for 71.43%). B. grahamii exhibited four distinct clusters, and showed a certain host specificity. In addition, 11 haplotypes of B. grahamii were observed using DNASP 6.12.03, among which nine haplotypes were novel. Overall, high occurrence and genetic diversity of Bartonella were observed among small rodents in the Shangdang Basin; this information could potentially help the prevention and control of rodent-Bartonella species in this area.
Role of TLR4 signaling on Porphyromonas gingivalis LPS-induced cardiac dysfunction in mice
Authors: Matsuo Ichiro , Kawamura Naoya , Ohnuki Yoshiki , Suita Kenji , Ishikawa Misao , Matsubara Takehiro , Mototani Yasumasa , Ito Aiko , Hayakawa Yoshio , Nariyama Megumi , Morii Akinaka , Kiyomoto Kenichi , Tsunoda Michinori , Gomi Kazuhiro , Okumura Satoshi
Published: June 2022

Oral infections, particularly periodontitis, are a well-established risk factor for cardiovascular diseases, although the molecular mechanisms involved remain elusive. The aims of the present study were to investigate the effects of lipopolysaccharide derived from Porphyromonas gingivalis (PG-LPS) on cardiac function in mice, and to elucidate the underlying mechanisms. Mice (C57BL/6) were injected with PG-LPS (0.8 mg/kg/day) with or without an inhibitor of Toll-like receptor 4 (TLR4) signaling (TAK-242, 0.8 mg/kg/day) for 4 weeks. Left ventricular ejection function was significantly decreased at 1 week (from 67 ± 0.5 to 58 ± 1.2%) and remained low at 4 weeks (57 ± 1.0%). The number of apoptotic myocytes was increased (approximately 7.4-fold), the area of fibrosis was increased (approximately 3.3-fold) and the number of 8-hydroxydeoxyguanosine-positive myocytes, a sensitive indicator of oxidative DNA damage, was increased (approximately 7.6-fold) at 4 weeks in the heart of PG-LPS treated mice. However, levels of various serum pro-inflammatory cytokines in PG-LPS-treated mice were similar to those in control mice. The impairment of cardiac function in PG-LPS-treated mice appears to involve activation of TLR4-NADPH oxidase (NOX) 4 signaling, leading to abundant production of reactive oxygen species and Ca2+ leakage from sarcoplastic reticulumn induced by calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (at Thr-17) and ryanodine receptor 2 (at Ser-2448). Pharmacological inhibition of TLR4 with TAK-242 attenuated the changes in cardiac function in PG-LPS-treated mice. Our results indicate that TLR4-NOX4 signaling may be a new therapeutic target for treatment of cardiovascular diseases in patients with periodontitis.
The nature and chronology of human occupation at the Galerías Bajas, from Cueva de Ardales, Malaga, Spain
Authors: Ramos-Muñoz José , Cantalejo Pedro , Blumenröther Julia , Bolin Viviane , Otto Taylor , Rotgänger Miriam , Kehl Martin , Nielsen Trine Kellberg , Espejo Mar , Fernández-Sánchez Diego , Moreno-Márquez Adolfo , Vijande-Vila Eduardo , Cabello Lidia , Becerra Serafín , Martí África Pitarch , Riquelme José A. , Cantillo-Duarte Juan J. , Domínguez-Bella Salvador , Ramos-García Pablo , Tafelmaier Yvonne , Weniger Gerd-Christian
Published: June 2022

The Cueva de Ardales is a hugely important Palaeolithic site in the south of the Iberian Peninsula owing to its rich inventory of rock art. From 2011–2018, excavations were carried out in the cave for the first time ever by a Spanish-German research team. The excavation focused on the entrance area of the cave, where the largest assemblage of non-figurative red paintings in the cave is found. A series of 50 AMS dates from the excavations prove a long, albeit discontinuous, occupation history spanning from the Middle Palaeolithic to the Neolithic. The dating of the Middle Palaeolithic layers agrees with the U/Th dating of some red non-figurative paintings in the entrance area. In addition, a large assemblage of ochre lumps was discovered in the Middle Palaeolithic layers. Human visits of the cave in the Gravettian and Solutrean can be recognized, but evidence from the Aurignacian and Magdalenian cannot be confirmed with certainty. The quantity and nature of materials found during the excavations indicate that Cueva de Ardales was not a campsite, but was mainly visited to carry out non-domestic tasks, such as the production of rock art or the burial of the dead.
Conditioned medium from human tonsil-derived mesenchymal stem cells inhibits glucocorticoid-induced adipocyte differentiation
Authors: Kim Yu-Hee , Lee Hyun-Ji , Cho Kyung-Ah , Woo So-Youn , Ryu Kyung-Ha
Published: June 2022

Obesity, which has become a major global health problem, involves a constitutive increase in adipocyte differentiation signaling. Previous studies show that mesenchymal stem cells (MSCs) induce weight loss and glycemic control. However, the mechanisms by which MSCs regulate adipocyte differentiation are not yet known. In this study, we investigated the effects of conditioned medium obtained from human tonsil-derived MSCs (T-MSC CM) on adipocyte differentiation. We found that T-MSC CM attenuated adipocyte differentiation from early stages via inhibiting glucocorticoid signaling. T-MSC CM also increased the phosphorylation of p38 mitogen-activated protein kinase and glucocorticoid receptors and decreased the subsequent nucleus translocation of glucocorticoid receptors. Chronic treatment of mice with synthetic glucocorticoids induced visceral and bone marrow adipose tissue expansion, but these effects were not observed in mice injected with T-MSC CM. Furthermore, T-MSC CM injection protected against reductions in blood platelet counts induced by chronic glucocorticoid treatment, and enhanced megakaryocyte differentiation was also observed. Collectively, these results demonstrate that T-MSC CM exerts inhibitory effects on adipocyte differentiation by regulating glucocorticoid signal transduction. These findings suggest that the therapeutic application of T-MSC CM could reduce obesity by preventing adipose tissue expansion.
Transcriptomic analysis reveals high ITGB1 expression as a predictor for poor prognosis of pancreatic cancer
Authors: Iwatate Yosuke , Yokota Hajime , Hoshino Isamu , Ishige Fumitaka , Kuwayama Naoki , Itami Makiko , Mori Yasukuni , Chiba Satoshi , Arimitsu Hidehito , Yanagibashi Hiroo , Takayama Wataru , Uno Takashi , Lin Jason , Nakamura Yuki , Tatsumi Yasutoshi , Shimozato Osamu , Nagase Hiroki
Published: June 2022

Transcriptomic analysis of cancer samples helps identify the mechanism and molecular markers of cancer. However, transcriptomic analyses of pancreatic cancer from the Japanese population are lacking. Hence, in this study, we performed RNA sequencing of fresh and frozen pancreatic cancer tissues from 12 Japanese patients to identify genes critical for the clinical pathology of pancreatic cancer among the Japanese population. Additionally, we performed immunostaining of 107 pancreatic cancer samples to verify the results of RNA sequencing. Bioinformatics analysis of RNA sequencing data identified ITGB1 (Integrin beta 1) as an important gene for pancreatic cancer metastasis, progression, and prognosis. ITGB1 expression was verified using immunostaining. The results of RNA sequencing and immunostaining showed a significant correlation (r = 0.552, p = 0.118) in ITGB1 expression. Moreover, the ITGB1 high-expression group was associated with a significantly worse prognosis (p = 0.035) and recurrence rate (p = 0.028). We believe that ITGB1 may be used as a drug target for pancreatic cancer in the future.
Efficacy and safety of Xuebijing injection for radiation pneumonitis: A meta-analysis
Authors: Li Zheng , Wang Dandan , Zhang Ying , Wang Shuo , Wang Xueqian , Li Yuxiao , Gui Yuerong , Dong Jun , Hou Wei
Published: June 2022

Background

Currently, the treatment of radiation pneumonitis (RP) remains a clinical challenge. Although glucocorticoids are used for RP treatment, they have associated side effects. Xuebijing injection (XBJ) has been widely used for RP treatment in China, but so far no meta-analysis has evaluated its efficacy and safety.

Methods

PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, WANFANG database, SinoMED, and China Science and Technology J Database were searched for randomized controlled trials related to XBJ in RP treatment. Two researchers independently conducted literature screening, data extraction, and risk of bias assessment. The outcomes were synthesized and analyzed using the Cochrane Review Manager (RevMan 5.3) software, and a forest plot generated.

Result

Eight articles met the eligibility criteria for further data extraction and meta-analysis. A total of 578 patients with RP participated in these studies, including 296 in the experimental group (XBJ+BT), and 282 in the control group (BT). The results of the meta-analysis revealed that compared to the BT group, XBJ+BT significantly increased the total effective rate (n = 578; RR = 1.45, 95% CI: 1.30 to 1.61, p<0.0001), and IL-10 expression (n = 296; MD = 17.62, 95% CI:13.95 to 21.29, p<0.00001), decreased interleukin-6 (IL-6) expression (n = 296; MD = -21.56, 95% CI:-27.37 to -15.76, p<0.00001), that of tumor necrosis factor alpha (n = 246; MD = -25.63, 95% CI:-30.77 to -20.50, p<0.00001), and that of C-reactive protein (n = 296; MD = -48.61, 95% CI:-56.49–40.73, p< 0.00001).

Conclusion

Based on our results, we do not recommend XBJ as an adjuvant treatment for RP. Further randomized controlled trials with rigorous design, strict implementation, and standard reporting are needed to further evaluate the efficacy and safety of XBJ for RP treatment.

Systematic review registration

INPLASY registration number:INPLASY2020120037.
Performance barriers of Civil Registration System in Bihar: An exploratory study
Authors: Kumar Krishna , Saikia Nandita , Diamond-smith Nadia
Published: June 2022

Objectives

Vital statistics generated by the Civil Registration System (CRS) are essential for developing healthcare interventions at all administrative levels. Bihar had one of the lowest levels of mortality registration among India’s states. This study investigates CRS’s performance barriers from the perspective of CRS staff and community members in Bihar.

Methods

We conducted a primary qualitative survey in the two districts of Bihar during February-March 2020 with CRS staff (n = 15) and community members (n = 90). We purposively selected the Patna and Vaishali districts of Bihar for the survey. Thematic analysis was done to identify the pattern across the data using the Atlas-ti software.

Results

Most participants showed a good understanding of registration procedures and birth and death registration benefits. The perceived need for death registration is lower than birth registration. Birth registration was higher among female children than male children. We found that most participants did not report children or adult female death due to lack of financial or property-related benefits. Most participants faced challenges in reporting birth and death due to poor delivery of services at the registration centres, higher indirect opportunity cost, and demand of bribes by the CRS staff for providing certificates. We found a lack of adequate investment, shortage of dedicated staff, and limited computer and internet services at the registration centres.

Conclusions

Poor data on birth and death registration could lead decision-makers to target health services inappropriately. Strengthening health institutions’ linkage with the registration centres, mobile registration in far-flung areas and regular CRS staff training could increase death registration levels. An adequate awareness campaign on the benefits of birth and death registration is required to increase the reporting of vital events.
Treatment failure, death, and predictors among PLWHIV on second-line antiretroviral therapy in Dessie Comprehensive Specialized Hospital, northeast Ethiopia: A retrospective cohort study
Authors: Wedajo Shambel , Degu Getu , Deribew Amare , Ambaw Fentie
Published: June 2022

Background

The proportion of HIV patients on second-line antiretroviral therapy is becoming a growing public health concern, especially in a low-income country setting. However, unlike first-line therapy, to date, very little is known about the outcomes of second-line therapy in the Ethiopia context. Thus, this study was conducted to determine the rate of treatment failure, death, and their predictors among HIV patients receiving second-line therapy.

Methods

A retrospective cohort study was conducted on 642 people living with HIV in Dessie Comprehensive Specialized Hospital from October 2016 to November 2019. Poisson and competitive risk survival models were computed to explore predictors of treatment failure and death, respectively.

Results

During follow-up period, 39 (6.87%, 95% CI: 5–9.2%) of 568 patients had second-line treatment failure with 4.07 per 100 person-year rate of failure. Being on anti-TB treatment [Rate ratio, RR = 2.57 (95% CI: 1.25–5.25)], not having optimal medication adherence [RR = 2.29 (95% CI: 1.09–4.78)], and not timely switched [RR = 5.89 (95% CI: 1.36–25.54)] were positively associated with treatment failure. Similarly, 44 (6.85%, 95% CI: 5–9%) of 642 patients died with 4.5 per 100 person-year rate of death. Being on advanced clinical condition [Sub distribution Hazard ratio, SHR = 2.49 (95% CI: 1.31–4.74)], not having optimal medication adherence [SHR = 2.65 (95% CI: 1.31–4.74)], lower CD4 cell counts, and high viral load measurement were positively associated with death.

Conclusions

A significant number of patients had failed to respond to second-line therapy. A large number of patients had also died. Patient medical profile and monitoring practice were associated with treatment failure and death. Hence, patient-centered monitoring and interventions should be strengthened, besides treatment switch.
Data-driven long-term glycaemic control trajectories and their associated health and economic outcomes in Finnish patients with incident type 2 diabetes
Authors: Lavikainen Piia , Aarnio Emma , Linna Miika , Jalkanen Kari , Tirkkonen Hilkka , Rautiainen Päivi , Laatikainen Tiina , Martikainen Janne
Published: June 2022

Background

Treatments should be customized to patients to improve patients’ health outcomes and maximize the treatment benefits. We aimed to identify meaningful data-driven trajectories of incident type 2 diabetes patients with similarities in glycated haemoglobin (HbA1c) patterns since diagnosis and to examine their clinical and economic relevance.

Materials and methods

A cohort of 1540 patients diagnosed in 2011–2012 was retrieved from electronic health records covering primary and specialized healthcare in the North Karelia region, Finland. EHRs data were compiled with medication purchase data. Average HbA1c levels, use of medications, and incidence of micro- and macrovascular complications and deaths were measured annually for seven years since T2D diagnosis. Trajectories were identified applying latent class growth models. Differences in 4-year cumulative healthcare costs with 95% confidence intervals (CIs) were estimated with non-parametric bootstrapping.

Results

Four distinct trajectories of HbA1c development during 7 years after T2D diagnosis were extracted: patients with “Stable, adequate” (66.1%), “Slowly deteriorating” (24.3%), and “Rapidly deteriorating” glycaemic control (6.2%) as well as “Late diagnosed” patients (3.4%). During the same period, 2.2 (95% CI 1.9–2.6) deaths per 100 person-years occurred in the “Stable, adequate” trajectory increasing to 3.2 (2.4–4.0) in the “Slowly deteriorating”, 4.7 (3.1–6.9) in the “Rapidly deteriorating” and 5.2 (2.9–8.7) in the “Late diagnosed” trajectory. Similarly, 3.5 (95% CI 3.0–4.0) micro- and macrovascular complications per 100 person-years occurred in the “Stable, adequate” trajectory increasing to 5.1 (4.1–6.2) in the “Slowly deteriorating”, 5.5 (3.6–8.1) in the “Rapidly deteriorating” and 7.3 (4.3–11.8) in the “Late diagnosed” trajectory. Patients in the “Stable, adequate” trajectory had lower accumulated 4-year medication costs than other patients.

Conclusions

Data-driven patient trajectories have clinical and economic relevance and could be utilized as a step towards personalized medicine instead of the common “one-fits-for-all” treatment practices.