bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial
Authors: Alexeeva Ekaterina , Horneff Gerd , Dvoryakovskaya Tatyana , Denisova Rina , Nikishina Irina , Zholobova Elena , Malievskiy Viktor , Santalova Galina , Stadler Elena , Balykova Larisa , Spivakovskiy Yuriy , Kriulin Ivan , Alshevskaya Alina , Moskalev Andrey 
Published: January 2021

Abstract
Background
Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease.

Methods
A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit.

Results
By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients.

Conclusions
Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.
mGlu3 receptor regulates microglial cell reactivity in neonatal rats
Authors: Zinni Manuela , Mairesse Jérôme , Pansiot Julien , Fazio Francesco , Iacovelli Luisa , Antenucci Nico , Orlando Rosamaria , Nicoletti Ferdinando , Vaiman Daniel , Baud Olivier 
Published: January 2021

Abstract
Background
Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence supports a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia.

Methods
We used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular and genetic approaches.

Results
Exposure to LPD/IL-1β significantly downregulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central role in the control of inflammation in resting and activated microglia. Microglia reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade, siRNA knock-down, and genetic knock-out of mGlu3 receptors mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β.

Conclusions
Overall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.
Environmental noise stress disturbs commensal microbiota homeostasis and induces oxi-inflammmation and AD-like neuropathology through epithelial barrier disruption in the EOAD mouse model
Authors: Chi Huimin , Cao Wa , Zhang Ming , Su Donghong , Yang Honglian , Li Zhe , Li Chao , She Xiaojun , Wang Kun , Gao Xiujie , Ma Kefeng , Zheng Pengfang , Li Xiaofang , Cui Bo 
Published: January 2021

AbstractBackgroundBoth genetic factors and environmental hazards, including environmental noise stress, have been associated with gut microbiome that exacerbates Alzheimer’s disease (AD) pathology. However, the role and mechanism of environmental risk factors in early-onset AD (EOAD) pathogenesis remain unclear.MethodsThe molecular pathways underlying EOAD pathophysiology following environmental noise exposure were evaluated using C57BL/6 wild-type (WT) and APP/PS1 Tg mouse models. The composition differences in intestinal microbiota were analyzed by 16S rRNA sequencing and Tax4Fun to predict the metagenome content from sequencing results. An assessment of the flora dysbiosis-triggered dyshomeostasis of oxi-inflamm-barrier and the effects of the CNS end of the gut–brain axis was conducted to explore the underlying pathological mechanisms.ResultsBoth WT and APP/PS1 mice showed a statistically significant relationship between environmental noise and the taxonomic composition of the corresponding gut microbiome. Bacterial-encoded functional categories in noise-exposed WT and APP/PS1 mice included phospholipid and galactose metabolism, oxidative stress, and cell senescence. These alterations corresponded with imbalanced intestinal oxidation and anti-oxidation systems and low-grade systemic inflammation following noise exposure. Mechanistically, axis-series experiments demonstrated that following noise exposure, intestinal and hippocampal tight junction protein levels reduced, whereas serum levels of inflammatory mediator were elevated. Regarding APP/PS1 overexpression, noise-induced abnormalities in the gut–brain axis may contribute to aggravation of neuropathology in the presymptomatic stage of EOAD mice model.ConclusionOur results demonstrate that noise exposure has deleterious effects on the homeostasis of oxi-inflamm-barrier in the microbiome–gut–brain axis. Therefore, at least in a genetic context, chronic noise may aggravate the progression of EOAD.
Differential neurovirulence of Usutu virus lineages in mice and neuronal cells
Authors: Clé Marion , Constant Orianne , Barthelemy Jonathan , Desmetz Caroline , Martin Marie France , Lapeyre Lina , Cadar Daniel , Savini Giovanni , Teodori Liana , Monaco Federica , Schmidt-Chanasit Jonas , Saiz Juan-Carlos , Gonzales Gaëlle , Lecollinet Sylvie , Beck Cécile , Gosselet Fabien , Van de Perre Philippe , Foulongne Vincent , Salinas Sara , Simonin Yannick 
Published: January 2021

Abstract
Background
Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location.

Methods
The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model).

Results
Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage.

Conclusions
Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.
A systematic review on clinical effectiveness, side-effect profile and meta-analysis on continuation rate of etonogestrel contraceptive implant
Authors: Moray Kusum V. , Chaurasia Himanshu , Sachin Oshima , Joshi Beena 
Published: January 2021

AbstractBackgroundUnintended pregnancies (UIP) have a significant impact on health of women and the health budget of countries. Contraception is an effective way to prevent UIPs. The study objective was to collate evidence on clinical effectiveness of etonogestrel subdermal implant (ESI), continuation rate and side effect profile among eligible women of reproductive age group, as compared to levonorgestrel intrauterine system (LNG-IUS), copper intrauterine device (Cu-IUD) and depot medroxy progesterone acetate injections; other types of contraceptive implants were excluded as comparators.MethodsThe protocol of the systematic review was registered in Prospero (registration number: CRD42018116580). MEDLINE via PubMed, Cochrane library and web of science were the electronic databases searched. A search strategy was formulated and studies from 1998 to 2019 were included. Clinical trial registries and grey literature search was done. Critical assessment of included studies was done using appropriate tools. A qualitative synthesis of included studies was done and a meta-analysis was conducted in RevMan software for continuation rates of ESI as compared to other long acting reversible contraceptives (LARC) e.g. LNG IUS and Cu-IUD.ResultsThe search yielded 23,545 studies. After excluding 467 duplicates, 23,078 titles were screened and 51 studies were included for the review. Eight of the 15 studies reporting clinical effectiveness reported 100% effectiveness and overall pearl index ranged from 0 to 1.4. One-year continuation rates ranged from 57–97%; 44–95% at the end of second year and 25–78% by 3 years of use. Abnormal menstruation was the most commonly reported side effect. There was no significant difference in bone mineral density at 1 year follow-up. The meta-analyses showed that odds ratio (OR) of 1-year continuation rate was 1.55 (1.36, 1.76) for LNG-IUS vs. ESI and 1.34 (1.13, 1.58) for copper-IUD vs. ESI; showing that continuation rates at the end of one-year were higher in LNG-IUS and copper-IUD as compared to ESI.ConclusionESI is clinically effective and safe contraceptive method to use, yet 1-year continuation rates are lower as compared to LNG-IUS and copper-IUD, mostly attributed to the disturbances in the menstruation.
User-centred assistive SystEm for arm Functions in neUromuscuLar subjects (USEFUL): a randomized controlled study
Authors: Longatelli Valeria , Antonietti Alberto , Biffi Emilia , Diella Eleonora , D’Angelo Maria Grazia , Rossini Mauro , Molteni Franco , Bocciolone Marco , Pedrocchi Alessandra , Gandolla Marta 
Published: January 2021

Abstract
Background
Upper limb assistive devices can compensate for muscular weakness and empower the user in the execution of daily activities. Multiple devices have been recently proposed but there is still a lack in the scientific comparison of their efficacy.

Methods
We conducted a cross-over multi-centric randomized controlled trial to assess the functional improvement at the upper limb level of two arms supports on 36 patients with muscular dystrophy. Participants tested a passive device (i.e., Wrex by Jaeco) and a semi-active solution for gravity compensation (i.e., Armon Ayura). We evaluated devices’ effectiveness with an externally-assessed scale (i.e., Performance of the Upper Limb-PUL-module), a self-perceived scale (i.e., Abilhand questionnaire), and a usability scale (i.e., System Usability Scale). Friedman’s test was used to assess significant functional gain for PUL module and Abilhand questionnaire. Moreover, PUL changes were compared by means of the Friedman’s test.

Results
Most of the patients improved upper limb function with the use of arm supports (median PUL scores increase of 1–3 points). However, the effectiveness of each device was related to the level of residual ability of the end-user. Slightly impaired patients maintained the same independence without and with assistive devices, even if they reported reduced muscular fatigue for both devices. Moderately impaired patients enhanced their arm functionality with both devices, and they obtained higher improvements with the semi-active one (median PUL scores increase of 9 points). Finally, severely impaired subjects benefited only from the semi-active device (median PUL scores increase of 12 points). Inadequate strength was recognized as a barrier to passive devices. The usability, measured by the System Usability Scale, was evaluated by end-users “good” (70/100 points) for the passive, and “excellent” (80/100 points) for the semi-active device.

Conclusions
This study demonstrated that assistive devices can improve the quality of life of people suffering from muscular dystrophy. The use of passive devices, despite being low cost and easy to use, shows limitations in the efficacy of the assistance to daily tasks, limiting the assistance to a predefined horizontal plane. The addition of one active degree of freedom improves efficacy and usability especially for medium to severe patients. Further investigations are needed to increase the evidence on the effect of arm supports on quality of life and diseases’ progression in subjects with degenerative disorders.
Trial registration clinicaltrials.gov, NCT03127241, Registered 25th April 2017. The clinical trial was also registered as a post-market study at the Italian Ministry of Health.
Characterization of four virulent Klebsiella pneumoniae bacteriophages, and evaluation of their potential use in complex phage preparation
Authors: Zurabov Fedor , Zhilenkov Evgeniy 
Published: January 2021

AbstractBackgroundNowadays, hundreds of thousands of deaths per year are caused by antibiotic resistant nosocomial infections and the prognosis for future years is much worse, as evidenced by modern research. Bacteria of theKlebsiellagenus are one of the main pathogens that cause nosocomial infections. Among the many antimicrobials offered to replace or supplement traditional antibiotics, bacteriophages are promising candidates.MethodsThis article presents microbiological, physicochemical and genomic characterization of 4 virulent bacteriophages belonging toSiphoviridae,MyoviridaeandPodoviridaefamilies. Phages were studied by electron microscopy; their host range, lytic activity, adsorption rate, burst size, latent period, frequency of phage-resistant forms generation, lysis dynamics and sensitivity of phage particles to temperature and pH were identified; genomes of all 4 bacteriophages were studied by restriction digestion and complete genome sequence.ResultsStudied phages showed wide host range and high stability at different temperature and pH values. In contrast with single phages, a cocktail of bacteriophages lysed all studied bacterial strains, moreover, no cases of the emergence of phage-resistant bacterial colonies were detected. Genomic data proved that isolated viruses do not carry antibiotic resistance, virulence or lysogenic genes. Three out of four bacteriophages encode polysaccharide depolymerases, which are involved in the degradation of biofilms and capsules.ConclusionsThe bacteriophages studied in this work are promising for further in vivo studies and might be used in phage therapy as part of a complex therapeutic and prophylactic phage preparation. The conducted studies showed that the complex preparation is more effective than individual phages. The use of the complex phage cocktail allows to extend the lytic spectrum, and significantly reduces the possibility of phage-resistant forms generation.
Understanding factors affecting breastfeeding practices in one city in the Kingdom of Saudi Arabia: an interpretative phenomenological study
Authors: Murad Amal , Renfrew Mary J. , Symon Andrew , Whitford Heather 
Published: January 2021

Abstract
Background
Breastfeeding duration has declined in the Kingdom of Saudi Arabia (KSA) in recent decades, although accurate national data about different breastfeeding indicators by infant age are lacking. This qualitative study, the first in KSA, aimed to understand the factors affecting mothers’ decisions and experiences regarding any breastfeeding practices.

Methods
A qualitative phenomenological approach was used to investigate mothers’ experiences of breastfeeding. Non-probability convenience sampling and snowballing strategies were designed to recruit participants. Semi-structured interviews were conducted with 16 mothers, from two hospitals and three primary health clinics in Al-Madinah city, from December 2017 to March 2018. Interpretative phenomenological analysis was the analysis framework.

Results
Three themes were identified: 1) ‘Up against the system’: policies, staff and systems were the main barriers to exclusive breastfeeding; 2) ‘Social support and negativity’: family support in the first 40 postpartum days protected breastfeeding continuation and was highly appreciated, but negative comments limited breastfeeding practices thereafter; and 3) ‘Managing tensions’: mothers’ religious beliefs about breastfeeding boosted their decisions; however, the challenge of managing tensions influenced mothers to stop breastfeeding earlier than they wished. The study revealed that mothers had no doubts about wanting to breastfeed their babies; but continuation was adversely affected by unhelpful hospital policies and staff actions, the lack of ongoing social support, and by others people’s negativity, rather than by the mothers’ own views. Stopping breastfeeding earlier than planned was a complex decision for most mothers. However, mothers said that they intended to breastfeed their next baby successfully.

Conclusions
Healthcare professionals (maternity staff, paediatricians and pharmacists) need education and training to support exclusive breastfeeding effectively. Increasing the number of hospitals with Baby Friendly Hospital Initiative accreditation, which includes staff practice changes, is needed to protect and support exclusive breastfeeding. Ongoing professional and peer support, and improving conditions at workplaces and universities, are needed to help mothers to continue breastfeeding successfully. Effective, coordinated national policies can support mothers’ decisions in relation to breastfeeding. Such changes will reduce the tensions experienced by women and help them to achieve their breastfeeding goals and to breastfeed for longer.
Duration of breastfeeding, age at introduction of complementary foods and allergy-related diseases: a prospective cohort study
Authors: Ekelund Louise , Gloppen Inga , Øien Torbjørn , Simpson Melanie Rae 
Published: January 2021

Abstract
Background
The influences of breastfeeding and infant diet in the prevention of allergy-related diseases are uncertain and many of the studies conducted on the topic are limited by methodological challenges. Our aim was to assess whether the duration of breastfeeding and age at complementary food introduction affected the prevalence of asthma, wheeze, allergic rhinoconjunctivitis (ARC) and eczema at two and six years of age.

Methods
We used information gathered between 2000 and 2014 through questionnaires in the Prevention of Allergy among Children in Trondheim (PACT) study, a prospective cohort study in Trondheim, Norway. The current study includes 6802 children who submitted questionnaires detailing breastfeeding duration and or age at introduction to complementary foods, as well as at least one of the child health questionnaires completed at two and six years of age. Adjusted odds ratios (aORs) were calculated for each combination of exposure and outcomes and sensitivity analyses were performed to assess the possible influence of recall bias and reverse causality.

Results
The mean duration of breastfeeding was 11 months (SD 5.6) in this study population and 5695 of 6796 (84%) infants had been breastfed for at least 6 months. We did not find any conclusive preventative effect of longer breastfeeding on parental reported doctor-diagnosed asthma, aOR 0.79 (95% CI 0.51, 1.21). However, at 6 years of age we observed a reduction in the less strictly defined outcome wheeze, aOR 0.71 (95% CI 0.53, 0.95). Longer breastfeeding was associated with a reduced risk of ARC at 2 years, aOR 0.65 (95% CI 0.49, 0.86), with a continued protective trend at 6 years, aOR 0.77 (95% CI 0.58, 1.04).

Conclusions
Longer breastfeeding resulted in a reduced risk of wheeze and a trend towards a protective effect on ARC up until school age. No conclusive associations were seen between the duration of breastfeeding or age at introduction to complementary foods and prevention of asthma, wheeze, ARC and eczema.

Trial registration
The trial is registered in Current Controlled Trials as ISRCTN28090297.