bluuebunny/crossref_metadata_2025 huggingface dataset:
Cumulative live birth rates according to the number of oocytes retrieved following the “freeze-all” strategy
Authors: Zhao Zhonghua , Shi Hao , Li Jing , Zhang Yile , Chen Caihong , Guo Yihong
Published: February 2020

Background

In recent years, some studies have shown that there is a positive association between the number of oocytes retrieved and the cumulative live birth rate (CLBR) after fresh and frozen cycles of one oocyte retrieval. However, almost no studies have examined the association between the number of oocytes retrieved and the CLBR when using the “freeze-all” strategy. We performed this study to investigate the effects of an extreme oocyte yield during the first “freeze-all” cycle on the cumulative live birth rate among patients younger than 35 years old.

Methods

This was a retrospective cohort study performed in a university-affiliated reproductive medicine centre. Data obtained from 3276 women aged younger than 35 years who underwent their first “freeze-all” cycle (IVF/ICSI) were collected between January 2009 and December 2016. In all, 5025 frozen cycles took place during the follow-up period from January 2009 to December 2018. Patients were divided into five groups according to oocytes retrieved (group 1: 4–10 oocytes; group 2: 11–20 oocytes; group 3: 21–30 oocytes; group 4: 31–40 oocytes; group 5: > 40 oocytes). The primary outcome was the cumulative live birth rate.

Results

Unadjusted results showed that the cumulative live birth rate significantly increased as the number of oocytes retrieved increased and reached up to 93.82% in cases with yields of 21–30 oocytes (P < 0.05), after which it did not have a significant increase (P > 0.05). After adjusting for confounders, our results showed that the number of oocytes retrieved is an independent positive predictor of cumulative live birth rate when using a “freeze-all” strategy. (P < 0.001). In addition, the fertilization rate and the gonadotropin dose also influenced the cumulative live birth rate (P<0.05).

Conclusions

Among women younger than 35 years old who underwent the “freeze-all” strategy, the number of oocytes retrieved positively correlated with the cumulative live birth rate. Taking both efficacy and safety into account, ovarian stimulation should be rational, and the upper limit of the oocyte yield should be no more than 30.
Developing a framework for performance assessment of the public long-term care system in Korea: methodological and policy lessons
Authors: Kim Hongsoo , Jeon Boyoung
Published: February 2020

Background

Limited evidence exists on how to assess long-term care system performance. This study aims to report on the process and results of developing a performance assessment framework to evaluate the long-term care system financed by the public long-term care insurance in South Korea.

Methods

The framework was developed through a six-step approach, including setting the goals and scope of performance assessment in the given policy context, reviewing existing performance frameworks, developing a framework with a wide range of potential indicators, refining the framework through a series of Delphi surveys and expert meetings, examining the feasibility of generated indicators through a pilot test, receiving the comments of stakeholders, and finalising the performance framework.

Results

The finalised framework has 4 domains – coverage, quality of care, quality of life and system sustainability – and 28 indicators, including 10 core indicators to monitor long-term care system performance. Usability and feasibility along with policy relevance were important criteria in selecting these indicators. The proposed framework can be used to assess the performance of the long-term care system in Korea, and the framework and its methodological approach can be benchmarks for other countries developing their own framework.

Conclusions

It is critical to reconcile and prioritise various stakeholders’ views and information needs as well as to balance methodological rigor with practical usefulness and feasibility in the development and implementation of a long-term care performance monitoring system.
Maintenance of antibody response to diphtheria/tetanus vaccine in patients aged 2–5 years with polyarticular-course juvenile idiopathic arthritis receiving subcutaneous abatacept
Authors:   for the Pediatric Rheumatology Collaborative Study Group and the Paediatric Rheumatology International Trials Organisation, Brunner Hermine I. , Tzaribachev Nikolay , Cornejo Gabriel Vega , Joos Rik , Gervais Elisabeth , Cimaz Rolando , Calvo Penadés Inmaculada , Cuttica Rubén , Lutz Thomas , Quartier Pierre , Gandhi Yash , Nys Marleen , Wong Robert , Martini Alberto , Lovell Daniel J. , Ruperto Nicolino
Published: February 2020

Background

Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA.

Findings

This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2–5 years, with ≥2 continuous months of weekly weight-tiered (10–< 25 kg [50 mg], 25–< 50 kg [87.5 mg]) subcutaneous abatacept treatment (with/without methotrexate and/or low-dose corticosteroids), who received diphtheria/tetanus vaccine prior to enrolment, were eligible. Protective antibody levels to diphtheria/tetanus (> 0.1 IU/mL), and safety, were assessed.

Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6–12 and 2–< 6 months of abatacept exposure, respectively. All patients had protective antibody levels to tetanus and 26 (89.7%) patients had protective antibody levels to diphtheria. Of the 3 patients without protective antibody levels to diphtheria, each had an antibody level of 0.1 IU/mL, bordering the lower threshold of protection. Concomitant use of methotrexate and/or low-dose corticosteroids had no evident effect on antibody levels. No unexpected adverse events, including cases of diphtheria or tetanus, were reported during the 24-month period.

Conclusions

Patients aged 2–5 years with pJIA who received 2–24 months of weekly subcutaneous abatacept, with or without concomitant methotrexate and/or low-dose corticosteroids, maintained effective diphtheria and tetanus vaccination protection without new safety signals.

Trial registration

ClinicalTrials.gov (NCT01844518); registered May 1, 2013; https://clinicaltrials.gov/ct2/show/NCT01844518?term=NCT01844518&rank=1
Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway
Authors: Balzano Tiziano , Arenas Yaiza M. , Dadsetan Sherry , Forteza Jerónimo , Gil-Perotin Sara , Cubas-Nuñez Laura , Casanova Bonaventura , Gracià Francisco , Varela-Andrés Natalia , Montoliu Carmina , Llansola Marta , Felipo Vicente
Published: February 2020

Background

Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum.

The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis.

Methods

We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices.

Results

Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction.

Conclusion

Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.
Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons
Authors: Janach Gabriel M. S. , Reetz Olivia , Döhne Noah , Stadler Konstantin , Grosser Sabine , Byvaltcev Egor , Bräuer Anja U. , Strauss Ulf
Published: February 2020

Background

Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ.

Methods

We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-γ.

Results

We show that IFN-γ receptors are present in the membrane of rat’s neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-γ diminishedIh, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-γ, whereas their frequency remained unchanged.

Conclusions

The expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.
Adapting rapid assessment procedures for implementation research using a team-based approach to analysis: a case example of patient quality and safety interventions in the ICU
Authors: Holdsworth Laura M. , Safaeinili Nadia , Winget Marcy , Lorenz Karl A. , Lough Mary , Asch Steve , Malcolm Elizabeth
Published: February 2020

Background

Innovations to improve quality and safety in healthcare are increasingly complex, targeting multiple disciplines and organizational levels, and often requiring significant behavior change by those delivering care. Learning health systems must tackle the crucial task of understanding the implementation and effectiveness of complex interventions, but may be hampered in their efforts by limitations in study design imposed by business-cycle timelines and implementation into fast-paced clinical environments. Rapid assessment procedures are a pragmatic option for producing timely, contextually rich evaluative information about complex interventions implemented into dynamic clinical settings.

Methods

We describe our adaptation of rapid assessment procedures and introduce a rapid team-based analysis process using an example of an evaluation of an intensive care unit (ICU) redesign initiative aimed at improving patient safety in four academic medical centers across the USA. Steps in our approach included (1) iteratively working with stakeholders to develop evaluation questions; (2) integration of implementation science frameworks into field guides and analytic tools; (3) selecting and training a multidisciplinary site visit team; (4) preparation and trust building for 2-day site visits; (5) engaging sites in a participatory approach to data collection; (6) rapid team analysis and triangulation of data sources and methods using a priori charts derived from implementation frameworks; and (7) validation of findings with sites.

Results

We used the rapid assessment approach at each of the four ICU sites to evaluate the implementation of the sites’ innovations. Though the ICU projects all included three common components, they were individually developed to suit the local context and had mixed implementation outcomes. We generated in-depth case summaries describing the overall implementation process for each site; implementation barriers and facilitators for all four sites are presented. One of the site case summaries is presented as an example of findings generated using the method.

Conclusions

A rapid team-based approach to qualitative analysis using charts and team discussion using validation techniques, such as member-checking, can be included as part of rapid assessment procedures. Our work demonstrates the value of including rapid assessment procedures for implementation research when time and resources are limited.
The application of the single branch-first combined with the mid-arch clamping technique and the embedded anastomosis technique for DeBakey type II aortic dissection
Authors: Li Quan , Qu Hong , Liu Tianqi , Li Min , Chen Shanliang , Li Peijie , Xu Li , Wang Hengbao
Published: February 2020

Background

Patients with DeBakey type II aortic dissection or ascending aortic aneurysms involving the right innominate artery require hemiarch replacement and placement of a right innominate artery graft. Traditional aortic hemiarch replacement surgery must be performed under right axillary artery cannulation perfusion and moderate or deep hypothermia circulatory arrest. However, the axillary artery perfusion is always associated with left subclavian artery “steal blood”, and it cannot guarantee blood supply to the left cerebral hemisphere in patients with an incomplete circle of Willis, and hypothermia and hypoperfusion cause damage to the brain and spinal cord; therefore, postoperative complications of the nervous system are common. Herein, we present a hemiarch replacement procedure with the use of the single branch-first combined with the mid-arch clamping technique. This procedure can not only reduce the axillary artery incision but also eliminate the need for mid-deep hypothermia and circulatory arrest.

Case presentation

A 41-year-old male patient underwent surgery with this technique. Computed tomography angiography performed upon admission showed calcified plaques scattered throughout the aorta and showed DeBakey type II aortic dissection involving the right innominate artery, accompanied by cardiac tamponade. The patient underwent aortic root repair, ascending aorta replacement, and hemiarch replacement as well as the placement of a right innominate artery graft. Aortic root anastomosis was performed with the embedded anastomosis technique. There were no postoperative complications. The patient was discharged 11 days after the operation. During more than 3 months of follow-up, there were no cases of aortic valve regurgitation or anastomotic fistula.

Conclusions

The single branch-first combined with the mid-arch clamping technique for the right innominate artery can reduce the axillary artery incision and avoid damage to the body under mid-deep hypothermia and circulatory arrest. The embedded anastomosis technique is easy to perform, results in a limited amount of bleeding and requires almost no extra needling. We believe that these techniques can serve as good alternative strategies for patients with DeBakey type II aortic dissection or ascending aortic aneurysms involving the right innominate artery.
Two decades on - cardiothoracic surgical care practitioners in the UK: a narrative review
Authors: Shegafi Mohammed Bahran , Nashef Samer , Starodub Roksolana , Lee Gerry
Published: February 2020

Background

The role of Surgical Care Practitioner (SCP) was first introduced by the NHS in the field of cardiothoracic surgery more than two decades ago to overcome the chronic shortage of junior doctors, and subsequently evolved into other surgical specialties. This review aims to provide evidence on the current situation of SCPs’ clinical outcomes within their surgical extended role, with an emphasis on the cardiothoracic surgical field.

Method

A systematic search of PubMed, Scopus, Embase via Ovid, Web of Science and TRIP was conducted with no time restriction to explore the evidence on SCPs. All included articles were reviewed by three researchers using the selection criteria, and a narrative synthesis was undertaken.

Findings

Ten out of the 38 studies identified were selected for inclusion. Only one study specifically investigated cardiothoracic SCPs. Three themes were identified: (1) clinical outcomes (six studies), (2) workforce impact (two studies) and (3) colleagues’ opinions (two studies). All studies demonstrated that SCPs provided safe practice, added value and were of benefit to workforce environments and surgical teams.

Conclusion

Although the current literature provides assurances that the presence of SCPs within surgical teams is beneficial in terms of their clinical outcomes, their impact on the workforce and colleagues’ opinions, a significant gap was identified around the SCPs’ role within their surgical extended role, specifically in cardiac surgery. Thus, prospective clinical research is required to evaluate SCPs’ clinical impact.
Taste and smell function in Wolfram syndrome
Authors: Alfaro Raul , Doty Tasha , Narayanan Anagha , Lugar Heather , Hershey Tamara , Pepino M. Yanina
Published: February 2020

Background

Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although olfactory dysfunction, a classical clinical marker of neurodegenerative processes, has been reported in Wolfram syndrome, its use as a clinical marker in Wolfram is limited due to data scarcity. In addition, it is unknown whether Wolfram syndrome affects the sense of taste.

Methods

Smell and taste perception were assessed in participants with Wolfram syndrome (n = 40) who were 15.1 ± 6.0 years of age (range: 5.1–28.7 years) and two sex- and age-matched control groups: one group with type 1 diabetes mellitus (T1D;n = 25) and a healthy control group (HC;n = 29). Smell sensitivity was assessed by measuring n-butanol detection thresholds and smell identification by using the University of Pennsylvania Smell Identification Test (UPSIT). Taste function was assessed using NIH Toolbox, which includes the assessment of sucrose (sweet) taste preference, and perceived intensity of sucrose, sodium chloride (salty), and quinine hydrochloride (bitter) both in the tip of the tongue (regional test) and the whole mouth.

Results

Smell sensitivity was not significantly different among groups; however, smell identification was impaired in Wolfram syndrome, as reflected by significantly lower UPSIT scores in Wolfram syndrome compared to HC and T1D (P < 0.001). Compared to participants in the control groups, participants with Wolfram syndrome had a blunted perception of sweetness and saltiness when taste stimuli were applied regionally (P < 0.05), but differences in perceived intensity were no longer significant among groups when taste stimuli were tasted with the whole mouth. Groups preferred similar sucrose concentrations.

Conclusion

Wolfram syndrome was associated with olfactory dysfunction. However, the olfactory dysfunction was qualitative (related to smell identification) and not secondary to olfactory insensitivity or diabetes, suggesting is arising from dysfunction in central olfactory brain regions. In contrast to olfaction, and despite decreased perception of taste intensity in the anterior tongue, the sense of taste was overall well-conserved in individuals with Wolfram syndrome. Future longitudinal studies of taste and smell perception in Wolfram syndrome will be important to determine the use of the chemical senses as clinical markers of disease progression.
Encephalitozoon cuniculi infection in farmed rabbits in Egypt
Authors: Morsy Eman Anter , Salem Heba Mohammed , Khattab Marwa Salah , Hamza Dalia Anwar , Abuowarda Mai Mohammed
Published: February 2020

Background

Encephalitozoon cuniculi is an important microsporidian parasite with zoonotic potential. The present study highlights the impact of encephalitozoonosis on rabbit health in Egypt. Three rabbit farms in Giza, with a total of 16,400 rabbits were investigated due to occurrence of rabbits displaying clinical signs consistent with encephalitozoonosis.

Results

Clinical signs observed during a 4 months observation period in 2018 included vestibular disease, paresis, limb paralysis, cataracts, phacoclastic uveitis, frequent urination, marked decrease in body weight and in some pregnant females, also repeated abortions. The total morbidity rates in adult and young rabbits were 76.7% and 81.5%, respectively. The highest mortality rate was recorded in offspring (12.3%), followed by dams (5.6%), and the lowest recorded mortality rate was in males (0.04%). Post-mortem findings included enteritis, pale enlarged kidneys, congested leptomeninges, focal brain necrosis, and endometrial congestion. Histopathological examination revealed nonsuppurative meningoencephalitis and glial nodules with central necrosis in the brain, vacuolation and necrosis of renal tubular epithelium, and corneal ulceration and ruptured lens capsule with fragmentation of lenticular fibres. E. cuniculi were observed in the brain, retinal ganglion cells, kidneys, and liver. Transmission electron microscopy examination revealed the presence of different developmental stages of E. cuniculi in the brain and kidney. Presence of E. cuniculi was confirmed by conventional polymerase chain reaction using a universal 16S gene for Encephalitozoon spp. followed by sequencing and sequence analysis.

Conclusions

The presence of E. cuniculi in rabbits was confirmed at three farms in Egypt. Nervous signs and ocular lesions were the most predominant findings in these farms.
Estrogen enhances the proliferation and migration of ovarian cancer cells by activating transient receptor potential channel C3
Authors: Li Shengnan , Jiang Kuo , Li Jia , Hao Xiaohua , Chu Wenguang , Luo Ceng , Zhu Yuanyuan , Xie Rougang , Chen Biliang
Published: February 2020

Background

Recent studies have suggested that estrogen (E2) plays an important role in epithelial ovarian cancer (EOC). However, the mechanism of E2 in ovarian cancers is unclear. The purpose of this study was to investigate the effect of E2 on ovarian cancers and illuminate the mechanism of E2 in promote ovarian cancers proliferation.

Results

We demonstrated that E2 stimulated the proliferation and invasion of ovarian cancer cells. In this study, ovarian cancer specimens were also analyzed for transient receptor potential channel C3 (TRPC3) expression; TRPC3 expression levels were higher in ovarian cancer samples than in normal ovarian tissue samples. Previous studies have shown that TRPC3 contributes to the progression of human ovarian cancer. In this study, we further investigated the interaction between E2 and TRPC3. We found that E2 stimulation enhanced the expression of TRPC3 at both the mRNA and protein levels. E2 stimulation enhanced the influx of Ca2+. Moreover, siRNA-mediated silencing of TRPC3 expression inhibited the ability of E2 to stimulate the influx of Ca2+.

Conclusions

In conclusion, TRPC3 plays a significant role in the stimulatory activity of E2 and could be a therapeutic target for the treatment of EOC. Furthermore, this study elucidates the molecular mechanism by which E2 promotes the proliferation and migration of EOC cells.
Neuroprem: the Neuro-developmental outcome of very low birth weight infants in an Italian region
Authors:   Neuroprem Working Group, Lugli Licia , Pugliese Marisa , Plessi Carlotta , Berardi Alberto , Guidotti Isotta , Ancora Gina , Grandi Sara , Gargano Giancarlo , Braibanti Silvia , Sandri Fabrizio , Soffritti Silvia , Ballardini Elisa , Arena Vittoria , Stella Marcello , Perrone Serafina , Moretti Sabrina , Rizzo Vittoria , Ferrari Fabrizio , Picciolini Odoardo , Bellù Roberto , Turoli Daniela , Corvaglia Luigi Tommaso , Garani Gianpaolo , Paoletti Vittoria , Biasucci Giacomo , Biasini Augusto , Benenati Belinda , Stagi Paolo , Magnani Cristina , Dallaglio Sara , DellaCasa Muttini Elisa , Roversi Maria Federica , Bedetti Luca , Lucaccioni Laura , Bertoncelli Natascia , Boncompagni Alessandra
Published: February 2020

Introduction

The survival of preterm babies has increased worldwide, but the risk of neuro-developmental disabilities remains high, which is of concern to both the public and professionals. The early identification of children at risk of neuro-developmental disabilities may increase access to intervention, potentially influencing the outcome.

Aims

Neuroprem is an area-based prospective cohort study on the neuro-developmental outcome of very low birth weight (VLBW) infants that aims to define severe functional disability at 2 years of age.

Methods

Surviving VLBW infants from an Italian network of 7 neonatal intensive care units (NICUs) were assessed for 24 months through the Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and neuro-functional evaluation according to the International Classification of Disability and Health (ICF-CY). The primary outcome measure was severe functional disability at 2 years of age, defined as cerebral palsy, a BSDI III cognitive composite score < 2 standard deviation (SD) or a GMDS-R global quotients score < 2 SD, bilateral blindness or deafness.

Results

Among 211 surviving VLBW infants, 153 completed follow-up at 24 months (72.5%). Thirteen patients (8.5%) developed a severe functional disability, of whom 7 presented with cerebral palsy (overall rate of 4.5%). Patients with cerebral palsy were all classified with ICF-CY scores of 3 or 4. BSDI III composite scores and GMDS-R subscales were significantly correlated with ICF-CY scores (p < 0.01).

Conclusion

Neuroprem represents an Italian network of NICUs aiming to work together to ensure preterm neuro-developmental assessment. This study updates information on VLBW outcomes in an Italian region, showing a rate of cerebral palsy and major developmental disabilities in line with or even lower than those of similar international studies. Therefore, Neuroprem provides encouraging data on VLBW neurological outcomes and supports the implementation of a preterm follow-up programme from a national network perspective.
Randomized trial comparing low-pressure versus standard-pressure pneumoperitoneum in laparoscopic colectomy: PAROS trial
Authors: Celarier S. , Monziols S. , Francois M. O. , Assenat V. , Carles P. , Capdepont M. , Fleming C. , Rullier E. , Napolitano G. , Denost Q.
Published: February 2020

Background

Laparoscopy, by its minimally invasive nature, has revolutionized digestive and particularly colorectal surgery by decreasing post-operative pain, morbidity, and length of hospital stay. In this trial, we aim to assess whether low pressure in laparoscopic colonic surgery (7 mm Hg instead of 12 mm Hg) could further reduce pain, analgesic consumption, and morbidity, resulting in a shorter hospital stay.

Methods and analysis

The PAROS trial is a phase III, double-blind, randomized controlled trial. We aim to recruit 138 patients undergoing laparoscopic colectomy. Participants will be randomly assigned to either a low-pressure group (7 mm Hg) or a standard-pressure group (12 mm Hg). The primary outcome will be a comparison of length of hospital stay between the two groups. Secondary outcomes will compare post-operative pain, consumption of analgesics, morbidity within 30 days, technical and oncological quality of the surgical procedure, time to passage of flatus and stool, and ambulation. All adverse events will be recorded. Analysis will be performed on an intention-to-treat basis.

Trial registration

This research received the approval from the Committee for the Protection of Persons and was the subject of information to the ANSM. This search is saved in the ID-RCB database under registration number 2018-A03028–47. This research is retrospectively registered January 23, 2019, at http://clinicaltrials.gov/ed under the name “LaPAroscopic Low pRessure cOlorectal Surgery (PAROS)”. This trial is ongoing.
GERiatric Screening in the treatment of elderly patients with Ovarian Carcinoma (GERSOC): study protocol for a pragmatic, cluster randomised controlled trial
Authors: van Soolingen Neeltje J. , Smorenburg Carolina H. , Hamaker Marije E. , Groen Wim G. , Retèl Valesca P. , Lok Christianne A. R. , van de Poll-Franse Lonneke V. , Trum Johannes W.
Published: February 2020

Background

Approximately 40% of the newly diagnosed patients with advanced ovarian cancer are aged 70 years or older. Standard treatment for advanced disease consists of cytoreductive surgery and combination chemotherapy. In older patients, standard treatment is often withheld or prematurely stopped due to suspected frailty. It remains challenging to distinguish fit elderly patients who can endure standard therapy from frail patients who may benefit from an adapted treatment strategy. As a comprehensive geriatric assessment (CGA) can contribute to the identification of frail patients and improve tailored therapy in this population, screening tests were developed to select those who may benefit from a CGA. However, the use of these geriatric screening tests has rarely been compared with usual clinical care. The GERSOC-trial will evaluate whether geriatric screening in elderly patients with advanced-stage ovarian cancer improves treatment completion and quality of life.

Methods

This pragmatic, cluster randomised controlled trial will be conducted at a minimum of 20 hospitals in the Netherlands. Hospitals are randomly assigned to geriatric screening care (in which a geriatric screening comprised of the G8 questionnaire and the Timed Up and Go test is performed), or care as usual (in which current usual care is continued). A total of 320 patients aged ≥ 70 years with primary, advanced-stage ovarian carcinoma will be included. Patients considered fit on geriatric screening will receive standard treatment; patients who are considered unfit will be referred to a geriatrician for analysis and treatment advice. The primary outcome is the percentage difference in completed standard and adapted therapies between the two study arms. Secondary outcomes include quality of life, cost-effectiveness and survival.

Discussion

This trial aims to gather evidence for the use of geriatric screening in treatment decision-making in elderly patients with advanced ovarian cancer. If proven feasible, beneficial and cost-effective, geriatric screening may be implemented in routine clinical practice.

Trial registration

Netherlands Trial Registry, ID:NL6745. Registered on 2 August 2017.
Rodents as intermediate hosts of cestode parasites of mammalian carnivores and birds of prey in Poland, with the first data on the life-cycle of Mesocestoides melesi
Authors: Bajer Anna , Alsarraf Mohammed , Dwużnik Dorota , Mierzejewska Ewa J. , Kołodziej-Sobocińska Marta , Behnke-Borowczyk Jolanta , Banasiak Łukasz , Grzybek Maciej , Tołkacz Katarzyna , Kartawik Natalia , Stańczak Łukasz , Opalińska Patrycja , Krokowska-Paluszak Małgorzata , Górecki Grzegorz , Alsarraf Mustafa , Behnke Jerzy M.
Published: February 2020

Background

Rodents constitute an important part of the diet of many carnivore species. This predator-prey food chain is exploited by helminth parasites, such as cestodes, whose larval stages develop in rodents and then mature to the adult stage in predators. The main aim of our study was to use molecular techniques for identification of cestode species recovered from both intermediate and definitive hosts, with a particular focus on the genus Mesocestoides.

Methods

Larval cestodes were obtained during our long-term studies on rodent helminth communities in the Mazury Lake District in the north-east Poland in 2000–2018. Cestode larvae/cysts were collected from body cavities or internal organs (e.g. liver) during autopsies. Adult tapeworms were derived from nine red foxes, three Eurasian badgers and one Eurasian lynx. PCR amplification, sequencing and phylogenetic analyses were conducted employing three genetic markers: 18S rDNA, mitochondrial (mt) 12S rDNA and the mt cytochrome c oxydase subunit 1 (cox1) gene fragment.

Results

Altogether 19 Mesocestoides samples were analyzed, including 13 adult tapeworms from definitive hosts and six larval samples from 4 bank voles and 2 yellow-necked mice. Phylogenetic analyses revealed three well-supported trees of similar topology. In each case the Mesocestoides samples formed two separate clades. All isolates from foxes, the lynx isolate and two isolates from rodents grouped with Mesocestoides litteratus. Four isolates from rodents and all three isolates from Eurasian badgers were resolved in a separate clade, most similar to North American M. vogae (syn. M. corti). Examination of fixed, stained adult specimens from Eurasian badgers revealed consistency with the morphology of Mesocestoides melesi. Therefore, this clade is likely to represent M. melesi, a species first described in 1985 from the Eurasian badger Meles meles. Molecular analysis allowed also the identification of Taenia crassiceps, Hydatigera kamiyai and Cladotaenia globifera among larvae derived from rodents.

Conclusions

Molecular and phylogenetic analyses support the recognition of M. melesi as a valid species. Our data represent the first record of the larvae of this species in rodents. This is the first report on the occurrence of H. kamiyai in rodents from Poland.
Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection
Authors: Hendrickx Sarah , Van Bockstal Lieselotte , Bulté Dimitri , Mondelaers Annelies , Aslan Hamide , Rivas Luis , Maes Louis , Caljon Guy
Published: February 2020

Background

Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure.

Methods

Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis.

Results

Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector.

Conclusions

Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.
Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer
Authors: Zhou Qing , Perakis Samantha O. , Ulz Peter , Mohan Sumitra , Riedl Jakob M. , Talakic Emina , Lax Sigurd , Tötsch Martin , Hoefler Gerald , Bauernhofer Thomas , Pichler Martin , Gerger Armin , Geigl Jochen B. , Heitzer Ellen , Speicher Michael R.
Published: February 2020

Background

Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance.

Methods

Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset.

Results

We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance.

Conclusions

Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.
Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior
Authors: Li Hui , Ding Xiang , Terkeltaub Robert , Lin Hang , Zhang Yuqing , Zhou Bin , He Ke , Li Kun , Liu Zhichen , Wei Jie , Yang Yuanheng , Xie Hui , Zeng Chao , Lei Guanghua
Published: February 2020

Background

Metformin could activate adenosine monophosphate-activated protein kinase (AMPK) which was postulated as a potential therapeutic target for osteoarthritis. This study aimed to examine the effects of metformin on cartilage and pain in osteoarthritis mouse model.

Methods

Eighty 10-week-old male C57BL/6 mice were randomized to 6 groups: non-operation, sham-operation, destabilization of the medial meniscus (DMM)-operation with intragastric saline/metformin, and DMM-operation with intraarticular saline/metformin. Articular cartilage degeneration was examined by scanning electron microscopy (SEM) and graded using the scoring system recommended by Osteoarthritis Research Society International (OARSI). Mechanical withdrawal threshold and hind paw weight distribution were measured to assess the pain-related behavior. Cell Counting Kit-8 assay, quantificational real-time polymerase chain reaction, and western blot analysis were conducted to examine the anabolic and anti-catabolic effect of metformin and the role of AMPK in mediating its effects on interleukin-1β stimulated primary mice chondrocytes.

Results

Compared with mice receiving intragastric and intraarticular saline, mice in both intragastric and intraarticular metformin displayed attenuated articular cartilage degeneration, indicated by less cartilage damage under SEM and significantly lower OARSI scores. A higher paw withdrawal threshold and a decreased weight-bearing asymmetry were observed in the intragastric and intraarticular metformin mice compared with their corresponding saline groups in DMM model of osteoarthritis. In vitro experiments showed that metformin not only decreased the level of matrix metalloproteinase 13, but also elevated type II collagen production through activating AMPK pathway.

Conclusions

Metformin attenuates osteoarthritis structural worsening and modulates pain, suggesting its potential for osteoarthritis prevention or treatment.
Integrated Mobile Element Scanning (ME-Scan) method for identifying multiple types of polymorphic mobile element insertions
Authors: Loh Jui Wan , Ha Hongseok , Lin Timothy , Sun Nawei , Burns Kathleen H. , Xing Jinchuan
Published: February 2020

Background

Mobile elements are ubiquitous components of mammalian genomes and constitute more than half of the human genome. Polymorphic mobile element insertions (pMEIs) are a major source of human genomic variation and are gaining research interest because of their involvement in gene expression regulation, genome integrity, and disease.

Results

Building on our previous Mobile Element Scanning (ME-Scan) protocols, we developed an integrated ME-Scan protocol to identify three major active families of human mobile elements, AluYb, L1HS, and SVA. This approach selectively amplifies insertion sites of currently active retrotransposons for Illumina sequencing. By pooling the libraries together, we can identify pMEIs from all three mobile element families in one sequencing run. To demonstrate the utility of the new ME-Scan protocol, we sequenced 12 human parent-offspring trios. Our results showed high sensitivity (> 90%) and accuracy (> 95%) of the protocol for identifying pMEIs in the human genome. In addition, we also tested the feasibility of identifying somatic insertions using the protocol.

Conclusions

The integrated ME-Scan protocol is a cost-effective way to identify novel pMEIs in the human genome. In addition, by developing the protocol to detect three mobile element families, we demonstrate the flexibility of the ME-Scan protocol. We present instructions for the library design, a sequencing protocol, and a computational pipeline for downstream analyses as a complete framework that will allow researchers to easily adapt the ME-Scan protocol to their own projects in other genomes.
Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project
Authors:   the EU-AIMS LEAP group, Moessnang Carolin , Baumeister Sarah , Tillmann Julian , Goyard David , Charman Tony , Ambrosino Sara , Baron-Cohen Simon , Beckmann Christian , Bölte Sven , Bours Carsten , Crawley Daisy , Dell’Acqua Flavio , Durston Sarah , Ecker Christine , Frouin Vincent , Hayward Hannah , Holt Rosemary , Johnson Mark , Jones Emily , Lai Meng-Chuan , Lombardo Michael V. , Mason Luke , Oldenhinkel Marianne , Persico Antonio , Cáceres Antonia San José , Spooren Will , Loth Eva , Murphy Declan G. M. , Buitelaar Jan K. , Banaschewski Tobias , Brandeis Daniel , Tost Heike , Meyer-Lindenberg Andreas
Published: February 2020

Background

Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the “social brain,” a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD.

Methods

As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N= 205) and typically developing (TD) individuals (N= 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits.

Results

We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders.

Conclusions

Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition.