bluuebunny/crossref_metadata_2025 huggingface dataset:
A clinical focus on the use of extended-duration thromboprophylaxis in medically ill patients
Authors: Snoga Jenna L , Benitez Rebekah M , Kim Subin , Creager Olivia , Lusk Kathleen A
Published: February 2021

Purpose

This review describes and analyzes literature to provide recommendations for use of extended-duration thromboprophylaxis (EDT) in medically ill patients.

Guidelines recommend pharmacologic thromboprophylaxis for patients at increased thrombosis risk during hospitalization and recommend against extending thromboprophylaxis beyond hospitalization. Despite these recommendations, observational data demonstrate that venous thromboembolism (VTE) risk persists following hospital discharge. A MEDLINE literature search was performed to identify original research evaluating the safety and efficacy of EDT. Eight meta-analyses and 5 randomized controlled trials—each varying in the agents studied (enoxaparin, rivaroxaban, apixaban, and betrixaban)—were selected for inclusion. Collectively, the evaluated data demonstrates that EDT reduces the incidence of VTE at the expense of increasing the risk of major bleeding and without providing mortality reduction. Variations in enrollment criteria, differences in EDT strategies, and uncertainty regarding proper patient selection limit the applicability of EDT in practice. Rivaroxaban and betrixaban gained Food and Drug Administration (FDA) approval on the basis of results of the APEX and MARINER trials and a post hoc analysis of the MAGELLEN trial results. Although a number of agents are FDA approved for use in EDT, clinicians must carefully weigh the risks vs benefits of EDT with these agents until studies demonstrate a more favorable risk-benefit profile.

Conclusion

Evidence to support EDT in medically ill patients is inconclusive and has highlighted the need for an individualized approach. The reviewed evidence supports guideline recommendations from both the American College of Chest Physicians and the American Society of Hematology that recommend against routine use of EDT in the majority of medically ill patients. Future studies are needed to optimize the risk-benefit profile of EDT and to ensure proper patient selection.
Anatomical patterns of condensed tannin in fine roots of tree species from a cool-temperate forest
Authors: Endo Izuki , Kobatake Miwa , Tanikawa Natsuko , Nakaji Tatsuro , Ohashi Mizue , Makita Naoki
Published: February 2021

Background and Aims

Condensed tannin (CT) is an important compound in plant biological structural defence and for tolerance of herbivory and environmental stress. However, little is known of the role and location of CT within the fine roots of woody plants. To understand the role of CT in fine roots across diverse species of woody dicot, we evaluated the localization of CT that accumulated in root tissue, and examined its relationships with the stele and cortex tissue in cross-sections of roots in 20 tree species forming different microbial symbiotic groups (ectomycorrhiza and arbuscular mycorrhiza).

Methods

In a cool-temperate forest in Japan, cross-sections of sampled roots in different branching order classes, namely, first order, second to third order, fourth order, and higher than fourth order (higher order), were measured in terms of the length-based ratios of stele diameter and cortex thickness to root diameter. All root samples were then stained with ρ-dimethylaminocinnamaldehyde solution and we determined the ratio of localized CT accumulation area to the root cross-section area (CT ratio).

Key Results

Stele ratio tended to increase with increasing root order, whereas cortex ratio either remained unchanged or decreased with increasing order in all species. The CT ratio was significantly positively correlated to the stele ratio and negatively correlated to the cortex ratio in second- to fourth-order roots across species during the shift from primary to secondary root growth. Ectomycorrhiza-associated species mostly had a higher stele ratio and lower cortex ratio than arbuscular mycorrhiza-associated species across root orders. Compared with arbuscular mycorrhiza species, there was greater accumulation of CT in response to changes in the root order of ectomycorrhiza species.

Conclusions

Different development patterns of the stele, cortex and CT accumulation along the transition from root tip to secondary roots could be distinguished between different mycorrhizal associations. The CT in tissues in different mycorrhizal associations could help with root protection in specific branching orders during shifts in stele and cortex development before and during cork layer formation.
An Innovative Approach for Facial Rejuvenation and Contouring Injections in Asian Patients
Authors: Cui Haiyan , Zhao Haiguang , Xu Haisong , Wang Guobao , Tan Linlin
Published: February 2021

An increasing number of Asian people are seeking nonsurgical facial aesthetic treatments. Ethnic Asians differ from Western populations in both facial appearance and baseline structural facial anatomy. And there is a lack of clinical instruction to doctors who provide facial aesthetic treatment for Asian patients. The authors proposed the “未来 Future Codes” design in Chinese calligraphy describing the art of facial injection in Asians to help doctors perform well. “未来” are pictograph of 2 Chinese characters, translated into English as “Future,” which represent beautiful meanings and vividly describe the procedure and operating area of the design methods. The concept encompasses a systematic overall design for the art of facial injection in Asians, and these procedures are easy to learn and perform safely. This is the first systematic solution available in the clinic that can be used to design facial aesthetics and rejuvenation in Asians through Eastern philosophy and culture.

Level of Evidence: 5
Insight into the collagen-degrading activity of a serine protease in the latex of Ficus carica cultivar Masui Dauphine
Authors: Nishimura Kosaku , Higashiya Keisuke , Ueshima Naoki , Kojima Kenji , Takita Teisuke , Abe Tatsuya , Takahashi Toru , Yasukawa Kiyoshi
Published: February 2021

Ficus carica produces, in addition to the cysteine protease ficin, a serine protease. Earlier study on a serine protease from F. carica cultivar Brown Turkey showed that it specifically degraded collagen. In this study, we characterized the collagenolytic activity of a serine protease in the latex of F. carica cultivar Masui Dauphine. The serine protease degraded denatured, but not undenatured, acid-solubilized type I collagen. It also degraded bovine serum albumin, while the collagenase from Clostridium histolyticum did not. These results indicated that the serine protease in Masui Dauphine is not collagen-specific. The protease was purified to homogeneity by two-dimensional gel electrophoresis, and its partial amino acid sequence was determined by liquid chromatography-tandem mass spectrometry. BLAST searches against the Viridiplantae (green plants) genome database revealed that the serine protease was a subtilisin-like protease. Our results contrast with the results of the earlier study stating that the serine protease from F. carica is collagen-specific.
CD38+CD27–TNF-α + on Mtb-specific CD4+ T Cells Is a Robust Biomarker for Tuberculosis Diagnosis
Authors: Acharya Muthya Pragun , Pradeep Sai Pallavi , Murthy Venkataramappa Srinivasa , Chikkannaiah Panduranga , Kambar Vivekanand , Narayanashetty Satyanarayana , Burugina Nagaraja Sharath , Gangadhar Niveditha , Yoganand Raksha , Satchidanandam Vijaya
Published: February 2021

Background

Early and accurate diagnosis followed by timely treatment are the key prerequisites to fight tuberculosis (TB) and reduce its global burden. Despite scientific advances, the rapid and correct diagnosis of both pulmonary and extrapulmonary tuberculosis remains a challenge because of traditional reliance on detection of the elusive bacilli. Mycobacterium tuberculosis (Mtb)-specific host immune activation and cytokine production have shown significant promise as alternative means of detecting and distinguishing active disease from latent infection. We queried the diagnostic ability of phenotypic markers on Mtb-specific cytokine-producing immune cell subsets for identifying active TB.

Methods

Subjects belonging to the following groups were recruited: pulmonary and extrapulmonary TB, latent TB, cured TB, sick controls, and healthy controls. Polychromatic flow cytometry was used to identify host immune biomarkers in an exploratory cohort comprising 56 subjects using peripheral blood mononuclear cells. Clinical performance of the identified biomarker was evaluated using whole blood in a blinded validation cohort comprising 165 individuals.

Results

Cytokine secreting frequencies of Mtb-specific cluster of differentiation 4-positive (CD4+) T cells with CD38+CD27– phenotype clearly distinguished infected individuals with active tuberculosis from those without disease. Tumor necrosis factor-α (TNF-α) secretion from CD38+CD27–CD4+ T cells upon stimulation with ESAT6/CFP10 peptides had the best diagnostic accuracy at a cutoff of 9.91% (exploratory: 96.67% specificity, 88.46% sensitivity; validation: 96.15% specificity, 90.16% sensitivity). Additionally, this subset differentiated treatment-naive patients with TB from individuals cured of TB following completion of anti-TB therapy.

Conclusions

Mtb-specific CD38+CD27–TNF-α +CD4+ T-cell subset is a robust biomarker both for diagnosing TB and assessing cure.
Reliability and repeatability of a smartphone-based 6-min walk test as a patient-centred outcome measure
Authors: Mak Jonathan , Rens Neil , Savage Dasha , Nielsen-Bowles Helle , Triggs Doran , Talgo Julia , Gandhi Neil , Gutierrez Sebastian , Gutierrez Santiago , Aalami Oliver
Published: February 2021

Aims 

The 6-min-walk test (6MWT) is a validated proxy for frailty and a predictor of clinical outcomes, yet is not widely used due to implementation challenges. This comparative effectiveness study assesses the reliability and repeatability of a home-based 6MWT compared to in-clinic 6MWTs in patients with cardiovascular disease.

Methods and results 

One hundred and ten (110) patients scheduled for cardiac or vascular surgery were enrolled during a study period from June 2018 to December 2019 at the Palo Alto VA Hospital. Subjects were provided with an Apple iPhone 7 and Apple Watch Series 3 loaded with the VascTrac research study application and performed a supervised in-clinic 6MWT during enrolment, at 2 weeks, 1, 3, and 6 months post-operatively. Subjects also received notifications to perform at-home smartphone-based 6MWTs once a week for a duration of 6 months. Test–retest reliability of in-clinic measurements and at-home measurements was assessed with an industry standard Cronbach’s alpha reliability test. Test–retest reliability for in-clinic ground truth 6MWT steps vs. in-clinic iPhone 6MWT steps was 0·99, showing high reliability between the two tested measurements. When comparing for in-clinic ground truth 6MWT steps vs. neighbouring at-home iPhone 6MWT steps, reliability was 0·74.

Conclusion 

Running the test–reliability test on both measurements shows that an iPhone 6MWT test is reliable compared to an in-clinic ground truth measurement in patients with cardiovascular disease.
Casting Doubt: Image Concerns and the Communication of Social Impact
Authors: Foerster Manuel , van der Weele Joël J
Published: February 2021

We investigate strategic communication about the social impact of costly prosocial actions. A ‘sender’ with noisy information about impact sends a cheap-talk message to a ‘receiver’, upon which both agents choose whether to act. In the presence of social preferences and image concerns, the sender trades off persuasion, exaggerating impact to induce receiver action, and justification, downplaying impact to cast doubt on the effectiveness of action and excuse her own passivity. In an experiment on charitable giving we find evidence for both motives. In line with our theory and a justification motive, increasing image concerns reduces communication of positive impact.
Tricuspid valve detachment for ventricular septal defect closure in infants <5 kg: should we be hesitant?
Authors: Lee Jae Hong , Cho Sungkyu , Kwak Jae Gun , Kwon Hye Won , Kwak Yujin , Min Jooncheol , Kim Woong-Han , Lee Jeong Ryul
Published: February 2021

OBJECTIVES

We compared the clinical outcomes between tricuspid valve detachment (TVD) and non-TVD for ventricular septal defect (VSD) closure in infants <5 kg.

METHODS

From January 2004 to April 2020, 462 infants <5 kg with VSD without more complex intracardiac lesions and who had undergone VSD closure through the trans-atrial approach were enrolled. Propensity score-matching analysis was performed. Clinical outcomes were compared between the paired TVD group (group D) and paired non-TVD group (group N).

RESULTS

The median age and body weight at operation were 1.9 months [interquartile range(IQR), 1.4–2.5] and 4.2 kg (IQR, 3.7–4.6). The median follow-up duration was 83.4 months (IQR, 43.5–130.4). After matching, 44 pairs were extracted from each group. There were no significant differences in all-cause mortality (P = 0.176), reoperation (P = 0.172), postoperative morbidities, including residual VSD, aortic regurgitation, atrioventricular block and significant tricuspid regurgitation (TR) (P = 0.346) between group D and group N. However, group D showed significantly less TR progression during follow-up (P = 0.019).

CONCLUSIONS

In infants <5 kg, TVD can be a reasonable and valid option for successful VSD closure without morbidities, including TR progression if the indication exists.
Cardiac paraganglioma: stent in right coronary artery prior to surgery resection
Authors: Martinez Lopez Daniel , Goicolea Ruigomez Javier , Martín López Carlos Esteban , Forteza Gil Alberto
Published: February 2021

Cardiac paragangliomas are extremely rare. Sometimes surgical resection is a challenge owing to the proximity of vital structures and coronary arteries involvement. We report a case of a 34-year-old man with cardiac paragangliomas located between right atrium and right ventricle with a feeding blood supply from collaterals of the right coronary artery. In this case, we implanted a covered single stent (PK Papyrus®) in the right coronary artery with the objective of embolizing collateral branches and to reinforce the coronary artery wall. Although tumour mass was not reduced, vascularization was minimized, and this hybrid strategy made the surgery easier and safer.
Transcriptional response of Candida albicans to Pseudomonas aeruginosa in a polymicrobial biofilm
Authors: Fourie Ruan , Cason Errol D , Albertyn Jacobus , Pohl Carolina H
Published: February 2021

Candida albicans is frequently co-isolated with the Gram-negative bacterium, Pseudomonas aeruginosa. In vitro, the interaction is complex, with both species influencing each other. Not only does the bacterium kill hyphal cells of C. albicans through physical interaction, it also affects C. albicans biofilm formation and morphogenesis, through various secreted factors and cell wall components. The present study sought to expand the current knowledge regarding the interaction between C. albicans and P. aeruginosa, using transcriptome analyses of early static biofilms. Under these conditions, a total of 2,537 open reading frames (approximately 40% of the C. albicans transcriptome) was differentially regulated in the presence of P. aeruginosa. Upon deeper analyses it became evident that the response of C. albicans toward P. aeruginosa was dominated by a response to hypoxia, and included those associated with stress as well as iron and zinc homeostasis. These conditions may also lead to the observed differential regulation of genes associated with cell membrane synthesis, morphology, biofilm formation and phenotypic switching. Thus, C. albicans in polymicrobial biofilms with P. aeruginosa have unique transcriptional profiles that may influence commensalism as well as pathogenesis.
Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53
Authors: Beauchamp Marie-Claude , Djedid Anissa , Bareke Eric , Merkuri Fjodor , Aber Rachel , Tam Annie S , Lines Matthew A , Boycott Kym M , Stirling Peter C , Fish Jennifer L , Majewski Jacek , Jerome-Majewska Loydie A
Published: February 2021

EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3. Exon skipping in Mdm2 was also increased in O9-1 mouse neural crest cells after siRNA knock-down of Eftud2 and in MFDM patient cells. Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death. Finally, overactivation of the P53 pathway in Eftud2 knockdown cells was attenuated by overexpression of non-spliced Mdm2, and craniofacial development was improved when Eftud2-mutant embryos were treated with Pifithrin-α, an inhibitor of P53. Thus, our work indicates that the P53-pathway can be targeted to prevent craniofacial abnormalities and shows a previously unknown role for alternative splicing of Mdm2 in the etiology of MFDM.
Finiteness of ℚ-Fano Compactifications of Semisimple Groups with Kähler–Einstein Metrics
Authors: Li Yan , Li Zhenye
Published: February 2021

Let $G$ be a complex semisimple group. In this note, we give a method to classify $\mathbb Q$-Fano compactifications of $G$. We will prove that there are only finitely many $\mathbb Q$-Fano $G$-compactifications that admit (singular) Kähler–Einstein metrics. As an application, this improves a former result in [ 19].
Rethinking disease eradication: putting countries first
Authors: Gebre Teshome
Published: February 2021

There have been various infectious disease eradication programs implemented in various parts of the world with varying degrees of success since the early 1900s. Of all those programs, the one that achieved monumental success was the Smallpox Eradication Program (SEP). Most of the global health leaders and authorities that came up with the new idea of disease eradication in the 1980s tried to design and shape the new programs based on their experience in the SEP. The SEP had a very effective tool, vaccine, that did not require a cold chain system, and a relatively simple way of administration. The total cost of the eradication program was about US$300 million and the entire campaign took about 10 y. However, the Guinea worm and polio eradication programs that followed in the footsteps of SEP attained varying levels of success, consuming a huge amount of resources and taking a much longer time (>30 y each). This paper reviews the factors that played major roles in hindering the attainment of eradication goals and outlines possible recommendations for the way forward. Among other things, this paper strongly emphasizes that endemic countries should take the lead in all matters pertaining to making decisions for disease elimination and/or eradication initiatives and that ‘elimination as a public health problem’ is the preferred option rather than going for complete eradication at the expense of other health programs and thereby contributing to weakening of already fragile health systems, mainly in Africa.
Two New Species of Sucking Lice (Psocodea: Phthiraptera: Hoplopleuridae) from Chestnut Mice, Pseudomys gracilicaudatus and Pseudomys nanus (Rodentia: Muridae), in Australia
Authors: Wang Wei , Durden Lance A , Shao Renfu
Published: February 2021

We describe two new species of sucking lice in the genus Hoplopleura Enderlein, 1904 (Psocodea: Phthiraptera: Hoplopleuridae) from Australia: Hoplopleura gracilicaudatusa n. sp. from the eastern chestnut mouse Pseudomys gracilicaudatus (Gould) (Rodentia: Muridae), and Hoplopleura nanusa n. sp. from the western chestnut mouse Pseudomys nanus (Gould) (Rodentia: Muridae). Pseudomys Gray is the most speciose genus of rodents endemic to Australia with 24 species; however, only two Pseudomys species have been reported previously to be hosts of sucking lice. The description of the new species in the present study doubles the number of sucking louse species known to parasitize Pseudomys mice and increases the total number of sucking louse species known from endemic Australian rodents from 21 to 23. Pseudomys gracilicaudatus and P. nanus are closely related murines that diverged ~1 MYA with distinct and widely separated extant geographic distributions. The two new Hoplopleura species described in the present study share some morphological characters and likely co-evolved and co-speciated with their chestnut mouse hosts.
Systematic Classification of Spina Bifida
Authors: Schindelmann Kim Hannah , Paschereit Fabienne , Steege Alexandra , Stoltenburg-Didinger Gisela , Kaindl Angela M
Published: February 2021

Spina bifida (SB) is an umbrella term for multiple conditions characterized by misclosure of vertebral arches. Neuropathologic findings in SB cases are often reported with imprecise and overlapping terminology. In view of the increasing identification of SB-associated genes and pathomechanisms, the precise description of SB subtypes is highly important. In particular, the term “myelomeningocele” is applied to various and divergent SB subtypes. We reevaluated 90 cases with SB (58 prenatal; 32 postnatal). The most frequent SB phenotype in our cohort was myeloschisis, which is characterized by an open neural plate with exposed ependyma (n = 28; 31.1%). An open neural plate was initially described in only in two-thirds of the myeloschisis cases. An additional 21 cases (23.3%) had myelomeningocele; 2 cases (2.2%) had a meningocele; and 21 cases (23.3%) had an unspecified SB aperta (SBA) subtype. Overall, the SB phenotype was corrected in about one-third of the cases. Our findings highlight that “myelomeningocele” and “SB aperta” cannot be used as synonymous terms and that myeloschisis is an underreported SB phenotype. Based on our findings and a review of literature we propose a classification of SB subtypes in SB occulta and the 3 SBA subtypes, meningocele, myelomeningocele, and myeloschisis.
Hurricane Irma induces divergent behavioral and hormonal impacts on an urban and forest population of invasiveAnolislizards: evidence for an urban resilience hypothesis
Authors: Fokidis H Bobby , Brock Taylor
Published: February 2021

Hurricanes can have both profound short-term effects on animal populations and serve as long-term drivers of evolutionary change. Animals inhabiting varying habitats may differ in their response to hurricane impacts. Increasing evidence suggests that animals from urban areas exhibit different behavioral and physiological traits compared to rural counterparts, including attenuated hormonal stress responses and a lowered propensity for flight behavior. A unique opportunity was presented when Hurricane Irma hit Florida on 10 September 2017 and interrupted a study of invasive brown anoles (Anolis sagrei) at an urban and a forest. Using data collected before and after Hurricane Irma, we documented that forest anoles exhibited a greater avoidance of people and more male territorial behavior for a longer period of time following the hurricane. Post-hurricane both populations increased corticosterone concentrations post-capture stress, but urban anoles recovered 2 weeks faster than forest conspecifics. A dexamethasone suppression experiment suggested that these population differences were the result of forest anoles having a less effective negative feedback regulating corticosterone secretion. In the brain, forest anoles had higher corticosterone concentrations within the amygdala and parts of the cortex associated with stress than urban lizards. One explanation may be Hurricane Irma brought flooding and debris that altered the landscape leading to behavioral instability, and urban lizards already exhibited ecological adjustments that permitted a more rapid recovery (i.e. the ‘urban resilience’ hypothesis). Testing if urban animals are more resilient to natural disasters can inform conservationists interested in understanding their role in facilitating invasive species expansion and what their increasing presence may indicate for animal populations.
Accuracy of the Tuning Fork Test for Determination of Presence and Location of Tibial Stress Fractures in a Military Training Population
Authors: May Todd , Marra Janelle , Leu Amy , Torbert Denise , VanWagner Tricia , Alexander Zachary , Rainie-Lobacz Robin , Ryan Margaret
Published: February 2021

Introduction

Stress fractures or bone stress injuries arise from trauma or overuse, often as a result of rapid increase in training. This rapid increase in training occurs frequently as military recruits begin their entry-level training, as many individuals are not accustomed to the level of activity required during boot camp. Tibial stress fractures are the most common bone stress injuries in the military setting. MRI is the gold standard test for identification of stress fractures, but MRI may not be available in field settings. Although limited evidence has suggested that a vibrating tuning fork may be beneficial in determining the presence of a stress fracture, the tuning fork has become a frequent tool used to detect or diagnose stress fractures.

Materials and Methods

Military personnel with suspected unilateral tibial stress fractures were asked to participate in evaluation of tuning forks as a diagnostic tool, in addition to receiving standard diagnostics and treatment. Points of maximal shin tenderness to palpation and vibration, followed by the application of a tuning fork, were evaluated. Each service member also underwent an abbreviated MRI evaluation with a 1.5T magnet consisting of coronal and sagittal STIR (Short Tau Inversion Recovery) and T1 (weighted longitudinal relaxation time) sequences. The results of tuning fork testing were compared to the MRI findings, considering grade 1 changes on MRI to represent a true stress fracture. A two-by-two table was used to determine the performance of tuning fork testing, relative to MRI findings, applying conventional definitions of sensitivity, specificity, positive predictive value, and negative predictive value.

Results

Among 63 male active duty members with suspected tibial stress fractures, 39 had MRI-confirmed stress fractures. Tuning fork testing, relative to MRI, demonstrated overall sensitivity of 61.5%, specificity of 25.0%, positive predictive value of 57.1%, and negative predictive value of 28.6%. A sub-analysis restricting to grade 3 and grade 4 MRI findings did not improve the diagnostic performance of tuning forks.

Conclusions

The tuning fork is an ineffective tool for diagnosing tibial stress fractures.
Type 2 diabetes mellitus, glycaemic control, associated therapies and risk of rheumatoid arthritis: a retrospective cohort study
Authors: Zemedikun Dawit T , Gokhale Krishna , Chandan Joht Singh , Cooper Jennifer , Lord Janet M , Filer Andrew , Falahee Marie , Nirantharakumar Krishnarajah , Raza Karim
Published: February 2021

Objective

To compare the incident risk of RA in patients with type 2 diabetes mellitus (T2DM) and to explore the role of glycaemic control and associated therapeutic use in the onset of RA.

Methods

This study was a retrospective cohort study using patients derived from the IQVIA Medical Research Data (IMRD-UK) database between 1995 and 2019. A total of 224 551 newly diagnosed patients with T2DM were matched to 449 101 patients without T2DM and followed up to assess their risk of RA. Further analyses investigated the effect of glycaemic control, statin use and anti-diabetic drugs on the relationship between T2DM and RA using a time-dependent Cox regression model.

Results

During the study period, the incidence of RA was 8.1 and 10.6 per 10 000 person-years in the exposed and unexposed groups, respectively. The adjusted hazard ratio (aHR) was 0.73 (95% CI 0.67, 0.79). In patients who had not used statins in their lifetime, the aHR was 0.89 (95% CI 0.69, 1.14). When quantifying the effects of glycaemic control, anti-diabetic drugs and statins using time-varying analyses, there was no association with glycaemic control [aHR 1.00 (95% CI 0.99, 1.00)], use of metformin [aHR 1.00 (95% CI 0.82, 1.22)], dipeptidyl peptidase-4 inhibitors [DPP4is; aHR 0.94 (95% CI 0.71, 1.24)] and the development of RA. However, statins demonstrated a protective effect for progression of RA in those with T2DM [aHR 0.76 (95% CI 0.66, 0.88)], with evidence of a duration–response relationship.

Conclusion

There is a reduced risk of RA in patients with T2DM that may be attributable to the use of statins.
Upadacitinib improves patient-reported outcomes vs placebo or adalimumab in patients with rheumatoid arthritis: results from SELECT-COMPARE
Authors: Strand Vibeke , Tundia Namita , Bergman Martin , Ostor Andrew , Durez Patrick , Song In-Ho , Enejosa Jeffrey , Schlacher Casey , Song Yan , Fleischmann Roy
Published: February 2021

Objective

To evaluate the impact of upadacitinib vs placebo and adalimumab treatment, on patient-reported outcomes (PROs) in SELECT-COMPARE in an active RA population with inadequate responses to MTX (MTX-IR).

Methods

PROs in patients receiving upadacitinib (15 mg QD), placebo, or adalimumab (40 mg EOW) while on background MTX were evaluated over 48 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA) and pain by visual analogue scale (VAS), the HAQ Disability Index (HAQ-DI), the 36-Item Short Form Survey (SF-36), morning (AM) stiffness duration and severity, the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), and work instability. Least squares mean (LSM) changes and proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and scores ≥ normative values were evaluated.

Results

Upadacitinib and adalimumab resulted in greater LSM changes from baseline vs placebo across all PROs (P < 0.05) at week 12, and pain and AM stiffness severity (P < 0.05) at week 2. More upadacitinib- vs placebo-treated (P < 0.05) and similar percentages of upadacitinib- vs adalimumab-treated patients reported improvements ≥ MCID across all PROs at week 12. Upadacitinib vs adalimumab resulted in greater LSM changes from baseline in PtGA, pain, HAQ-DI, stiffness severity, FACIT-F, and the SF-36 Physical Component Summary (PCS) (all P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients reported scores ≥ normative values in HAQ-DI and SF-36 PCS (P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients maintained clinically meaningful improvements in PtGA, pain, HAQ-DI, FACIT-F, and AM stiffness through 48 weeks.

Conclusion

In MTX-IR patients with RA, treatment with upadacitinib resulted in statistically significant and clinically meaningful improvements in PROs equivalent to or greater than with adalimumab.

Trial registration

ClinicalTrials.gov, http://clinicaltrials.gov, NCT02629159.
Xiamen Xinjingdi Group Co Ltd v Eton Properties Limited: clarifying the steps and issues to consider when lodging a trust claim in cross-border disputes
Authors: Chung Benny , Yeon Thomas
Published: February 2021

Xiamen Xinjingdi Group Co Ltd v Eton Properties Limited is a recent Hong Kong Court of Final Appeal judgment which concerns a very complex commercial dispute and covers multiple areas of law. In this article, we will focus on Lord Sumption NPJ’s analysis of the trust claims and evaluate the judgment as well as its potential implications. We argue that while this judgment has helpfully clarified the law in relation to trust claims with a cross-border context, the legal reasoning and conclusions reached therein cannot be said to be free of errors.
Preparedness and response of a tertiary hospital to the COVID-19 pandemic in Nigeria: challenges, opportunities and lessons
Authors: Obaseki Darlington E , Osaigbovo Iriagbonse I , Ogboghodo Esohe O , Adeleye Omokhoa , Akoria Obehi A , Oko-oboh Gregrey A , Okwara Benson U , Omuemu Casmir E , Okugbo Stanley
Published: February 2021

Africa was the last continent to be affected by the COVID-19 pandemic. Much of the discourse on Africa's response captured in scientific journals revolves around nations, public health agencies and organizations, but little is documented about how individual healthcare facilities have fared. This article reports the challenges faced in a tertiary hospital in Nigeria, including space constraints, diagnostic challenges, shortages in personal protective equipment and health worker infections. The opportunities and strengths that aided the response are also highlighted. The lessons learned will be useful to similar facilities. More information about health facility response at various levels is needed to comprehensively assess Africa's response to the pandemic.
A possible role for ticks in the transmission of Madurella mycetomatis in a mycetoma-endemic village in Sudan
Authors: Azrag Rasha S , Bakhiet Sahar M , Mhmoud Najwa A , Almalik A M , Mohamed A H , Fahal Ahmed H
Published: February 2021

Background

Currently there is a wide knowledge gap in our understanding of mycetoma epidemiological characteristics, including the infection route.

Methods

A cross-sectional descriptive epidemiological study was carried out to determine the role of exposure to animals and insects such as ticks in the transmission of eumycetoma in two adjacent villages at eastern Sudan.

Results

Significant differences were found between the two villages in the level of contact and exposure to animals and ticks, the percentages of people bitten by ticks, participation in cleaning animal pens and knowledge of the medical importance of ticks. In the village with a high mycetoma prevalence rate, there were high infestation rates of ticks in domestic animals. Hyalomma and Rhipicephalus species were the most prevalent species in houses with mycetoma patients and together they constituted 83% of the total collection. Pool screening of vectors for the detection of Madurella mycetomatis recombinant RNA genes showed one positive pool from Rhipicephalus evertsi following amplification of the universal fungal primer and one positive sample from Hyalomma rufipes following the use of a specific primer.

Conclusion

The findings indicate a possible role of ticks in the transmission of eumycetoma causative agents. However, further in-depth studies are needed to verify this.
Association between psychosocial factors and mental health symptoms to cervical spine pain with or without radiculopathy on health outcomes: systematic review protocol
Authors: Mansfield Michael , Spahr Nicolas , Smith Toby , Stubbs Brendon , Haig Lesley , Thacker Mick
Published: February 2021

Introduction:

Cervical spine pain with or without radiculopathy (CSp ± R) has significant negative impacts to a person's quality of life. Psychosocial factors and/or mental health symptoms are associated with spinal pain with or without radiculopathy and negatively impact health outcomes. This area of research is not yet established for CSp ± R. Our objective is to conduct a systematic review assessing the association between psychosocial factors and/or mental health symptoms and health outcomes in adults with CSp ± R.

Methods:

A systematic electronic search of 3 online databases will retrieve studies in which adults (older than 18 years) with CSp ± R, assessing how psychosocial factors or mental health symptoms impact outcomes related to disability, pain, and/or healthcare utilisation. Data extracted will include study design, CSp ± R definition, psychosocial and/or mental health symptoms, and health outcomes. Reporting study quality through the Newcastle–Ottawa Quality Scale Assessment and certainty through Grading of Recommendations, Assessment, Development and Evaluations will be completed. Studies will be assessed from a clinical perspective, methodology design, and statistical testing to determine whether studies can be pooled for meta-analysis. If there is significant clinical heterogeneity, narrative description will be undertaken.

Perspective:

This will be a comprehensive synthesis review to enhance understanding of the association of psychosocial factors and/or mental health symptoms and CSp ± R on health outcomes. The findings will support the formulation of prognosis, collaborative management decisions, and guide healthcare resources to improve outcomes for this patient group. The review will identify gaps in research, thereby informing future experimental and observational study design.
Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation
Authors: Thorne Adam M. , Lantinga Veerle , Bodewes Silke , de Kleine Ruben H. J. , Nijkamp Maarten W. , Sprakel Joost , Hartog Hermien , Polak Wojciech G. , Porte Robert J. , de Meijer Vincent E.
Published: February 2021

Background.

Liver splitting allows the opportunity to share a deceased graft between 2 recipients but remains underutilized. We hypothesized that liver splitting during continuous dual hypothermic oxygenated machine perfusion (DHOPE) is feasible, with shortened total cold ischemia times and improved logistics. Here, we describe a left lateral segment (LLS) and extended right lobe (ERL) liver split procedure during continuous DHOPE preservation with subsequent transplantation at 2 different centers.

Methods.

After transport using static cold storage, a 51-year-old brain death donor liver underwent end-ischemic DHOPE. During DHOPE, the donor liver was maintained <10 °C and oxygenated with a Po
2 of >106 kPa. An ex situ ERL/LLS split was performed with continuing DHOPE throughout the procedure to avoid additional ischemia time.

Results.

Total cold ischemia times for the LLS and ERL were 205 minutes and 468 minutes, respectively. Both partial grafts were successfully transplanted at 2 different transplant centers. Peak aspartate aminotransferase and alanine aminotransferase were 172 IU/L and 107 IU/L for the LLS graft, and 839 IU/L and 502 IU/L for the ERL graft, respectively. The recipient of the LLS experienced an episode of acute cellular rejection. The ERL transplantation was complicated by severe acute pancreatitis with jejunum perforation requiring percutaneous drainage and acute cellular rejection. No device-related adverse events were observed.

Conclusions.

Liver splitting during continuous DHOPE preservation is feasible, has the potential to substantially shorten cold ischemia time and may optimize transplant logistics. Therefore liver splitting with DHOPE can potentially improve utilization of split liver transplantation.
Methane-derived carbon flow through host-virus trophic networks in soil
Authors: Lee Sungeun , Sieradzki Ella T. , Nicolas Alexa M. , Walker Robin L. , Firestone Mary K. , Hazard Christina , Nicol Graeme W.
Published: February 2021

The concentration of atmospheric methane continues to increase with microbial communities controlling soil-atmosphere fluxes. While there is substantial knowledge of the diversity and function of organisms regulating methane production and consumption, the frequency and impact of interactions with viruses on their activity in soil is unknown. Metagenomic sequencing of soil microbial communities has enabled identification of linkages between viruses and hosts. However, determining host-virus linkages through sequencing does not determine whether a virus or a host are active. In this study, we identified active individual interactionsin situby following the transfer of assimilated carbon from active hosts to viruses. Using DNA stable-isotope probing combined with metagenomic analyses, we characterized methane-fueled microbial networks in acidic and neutral pH soils, specifically primary and secondary utilisers of carbon, together with the recent transfer of methane-derived carbon to viruses. Sixty-three percent of viral contigs from replicated soil incubations contained genes associated with known methanotrophic bacteria. Genomic sequences from13C-enriched viruses were present in clustered regularly interspaced short palindromic repeats (CRISPR) arrays of multiple, closely-relatedMethylocystispopulations, revealing differences in their history of viral interaction. Viruses infecting non-methanotrophic methylotrophs and heterotrophic predatory bacteria were also identified through the analysis of shared homologous genes, demonstrating that carbon is transferred to a diverse range of viruses associated with methane-fueled microbial food networks.
Targeted enzyme assisted chemotherapy (TEAC) – a novel microRNA-guided and selenium-based regimen to specifically eradicate hepatocellular carcinoma
Authors: Selvam Arun Kumar , Jawad Rim , Gramignoli Roberto , Achour Adnane , Salter Hugh , Björnstedt Mikael
Published: February 2021

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. Here we introduce a novel therapeutic regimen by treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity as compared to MSC alone. Furthermore, microRNA antisense targeted sites for miR122, known to be widely expressed in normal hepatocytes whilst downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.
Understanding conformational dynamics from macromolecular crystal diffuse scattering
Authors: Mazumder Parichita , Ayyer Kartik
Published: February 2021

All macromolecular crystals contain some extent of disorder. The diffraction from such crystals contains diffuse scattering in addition to Bragg peaks and this scattering contains information about correlated displacements in the constituent molecules. While much work has been performed recently in decoding the dynamics of the crystalline ordering, the goal of understanding the internal dynamics of the molecules within a unit cell has been out-of-reach. In this article, we propose a general framework to extract the internal conformational modes of a macromolecule from diffuse scattering data. We combine insights on the distribution of diffuse scattering from short- and long-range disorder with a Bayesian global optimization algorithm to obtain the best fitting internal motion modes to the data. To illustrate the efficacy of the method, we apply it to a publicly available dataset from triclinic lysozyme. Our mostly parameter-free approach can enable the recovery of a much richer, dynamic structure from macromolecular crystallography.
Unexpected organellar locations of ESCRT machinery in Giardia intestinalis and complex evolutionary dynamics spanning the transition to parasitism in the lineage Fornicata
Authors: Pipaliya Shweta V. , Santos Rui , Salas-Leiva Dayana , Balmer Erina A. , Wirdnam Corina D. , Roger Andrew J. , Hehl Adrian B. , Faso Carmen , Dacks Joel B.
Published: February 2021

Comparing a parasitic lineage to its free-living relatives is a powerful way to understand how the evolutionary transition to parasitism occurred.Giardia intestinalis(Fornicata) is a leading cause of gastrointestinal disease world-wide and is famous for its unusual complement of cellular compartments, such as having peripheral vacuoles instead of typical endosomal compartments. Endocytosis plays an important role inGiardia’s pathogenesis. Endosomal sorting complexes required for transport (ESCRT) are membrane-deforming proteins associated with the late endosome/multivesicular body (MVB). MVBs are ill-defined inG. intestinalisand roles for identified ESCRT-related proteins are not fully understood in the context of its unique endocytic system. Furthermore, components thought to be required for full ESCRT functionality have not yet been documented in this species.

We used genomic and transcriptomic data from several Fornicata species to clarify the evolutionary genome streamlining observed inGiardia, as well as to detect any divergent orthologs of the Fornicata ESCRT subunits. We observed differences in the ESCRT machinery complement betweenGiardiastrains. Microscopy-based investigations of key components of ESCRT machinery such asGiVPS36andGiVPS25 link them to peripheral vacuoles, highlighting these organelles as simplified MVB equivalents. Unexpectedly, we show ESCRT components associated with the Endoplasmic Reticulum, and for the first time, mitosomes. Finally, we identified the rare ESCRT component CHMP7 in several fornicate representatives, includingGiardia, and show that contrary to current understanding, CHMP7 evolved from a gene fusion of VPS25 and SNF7 domains, prior to the last eukaryotic common ancestor, over 1.5 billion years ago. Our findings show that ESCRT machinery inG. intestinalisis far more varied and complete than previously thought, and associating to multiple cellular locations and presenting changes in ESCRT complement which pre-date adoption of a parasitic lifestyle.
IN VITROANTI-VIRAL ACTIVITY OF HEXETIDINE (BACTIDOL®) ORAL MOUTHWASH AGAINST HUMAN CORONAVIRUS OC43 AND INFLUENZA A (H1N1) VIRUS
Authors: Tobias -Altura Marohren C , Ngelangel Corazon A
Published: February 2021

Mouthwashes are used to decrease oral cavity microbial load due to their antiseptic properties. Hexetidine is a broad-spectrum antiseptic used for minor infections of mucous membranes, and in particular as a 0.1% mouthwash for local infections and oral hygiene.

This study determined the anti-viral activity of the mouthwash hexetidine (Bactidol®), specifically in reducing viral concentration of Human Coronavirus OC43 (HCoV OC43; ATCC®VR-1558™) and Influenza A virus (IAV H1N1; clinical strain) in Vero 6 and MDCK cell cultures respectively, using in-vitro suspension assay (ASTM E-1052-11) designed to evaluate virucidal property of microbicides like hexetidine.

Study results indicated that hexetidine was able to reduce infectivity of HCoV OC43 and IAV H1N1 at 25%, 50% and 100% concentrations by more than 80% at 15- and 30-seconds exposure times. One hundred percent (100%) concentration of hexetidine was found to be cytotoxic to MDCK cell line used for IAV H1N1 propagation. Hexetidine-treated cell lines achieved >80% survival rate for MDCK and Vero E6 at a contact time of 15 seconds and 30 seconds (which are the approximate times of gargling with hexetidine mouthwash).

The anti-viral activity of hexetidine mouthwash against other more virulent or pathogenic coronaviruses like SARS-CoV-2 can be explored further.