bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of insomnia on development of Alzheimer’s disease
Authors: Sadeghmousavi Shaghayegh , Eskian Mahsa , Rahmani Farzaneh , Rezaei Nima
Published: October 2020

Alzheimer’s disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer’s disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.
Age-associated changes in the circulating human antibody repertoire are upregulated in autoimmunity
Authors: Arvey Aaron , Rowe Michael , Legutki Joseph Barten , An Gang , Gollapudi Anantha , Lei Anna , Colston Bill , Putterman Chaim , Smith David , Stiles Janelle , Tarasow Theodore , Ramamoorthy Preveen
Published: October 2020

Background

The immune system undergoes a myriad of changes with age. While it is known that antibody-secreting plasma and long-lived memory B cells change with age, it remains unclear how the binding profile of the circulating antibody repertoire is impacted.

Results

To understand humoral immunity changes with respect to age, we characterized serum antibody binding to high density peptide microarrays in a diverse cohort of 1675 donors. We discovered thousands of peptides that bind antibodies in age-dependent fashion, many of which contain di-serine motifs. Peptide binding profiles were aggregated into an “immune age” by a machine learning regression model that was highly correlated with chronological age. Applying this regression model to previously-unobserved donors, we found that a donor’s predicted immune age is longitudinally consistent over years, suggesting it could be a robust long-term biomarker of humoral immune ageing. Finally, we assayed serum from donors with autoimmune disease and found a significant association between “accelerated immune ageing” and autoimmune disease activity.

Conclusions

The circulating antibody repertoire has increased binding to thousands of di-serine peptide containing peptides in older donors, which can be represented as an immune age. Increased immune age is associated with autoimmune disease, acute inflammatory disease severity, and may be a broadly relevant biomarker of immune function in health, disease, and therapeutic intervention.
Basal Ti level in the human placenta and meconium and evidence of a materno-foetal transfer of food-grade TiO2 nanoparticles in an ex vivo placental perfusion model
Authors: Guillard A. , Gaultier E. , Cartier C. , Devoille L. , Noireaux J. , Chevalier L. , Morin M. , Grandin F. , Lacroix M. Z. , Coméra C. , Cazanave A. , de Place A. , Gayrard V. , Bach V. , Chardon K. , Bekhti N. , Adel-Patient K. , Vayssière C. , Fisicaro P. , Feltin N. , de la Farge F. , Picard-Hagen N. , Lamas B. , Houdeau E.
Published: October 2020

Background

Titanium dioxide (TiO2) is broadly used in common consumer goods, including as a food additive (E171 in Europe) for colouring and opacifying properties. The E171 additive contains TiO2 nanoparticles (NPs), part of them being absorbed in the intestine and accumulated in several systemic organs. Exposure to TiO2-NPs in rodents during pregnancy resulted in alteration of placental functions and a materno-foetal transfer of NPs, both with toxic effects on the foetus. However, no human data are available for pregnant women exposed to food-grade TiO2-NPs and their potential transfer to the foetus. In this study, human placentae collected at term from normal pregnancies and meconium (the first stool of newborns) from unpaired mothers/children were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and scanning transmission electron microscopy (STEM) coupled to energy-dispersive X-ray (EDX) spectroscopy for their titanium (Ti) contents and for analysis of TiO2 particle deposition, respectively. Using an ex vivo placenta perfusion model, we also assessed the transplacental passage of food-grade TiO2 particles.

Results

By ICP-MS analysis, we evidenced the presence of Ti in all placentae (basal level ranging from 0.01 to 0.48 mg/kg of tissue) and in 50% of the meconium samples (0.02–1.50 mg/kg), suggesting a materno-foetal passage of Ti. STEM-EDX observation of the placental tissues confirmed the presence of TiO2-NPs in addition to iron (Fe), tin (Sn), aluminium (Al) and silicon (Si) as mixed or isolated particle deposits. TiO2 particles, as well as Si, Al, Fe and zinc (Zn) particles were also recovered in the meconium. In placenta perfusion experiments, confocal imaging and SEM-EDX analysis of foetal exudate confirmed a low transfer of food-grade TiO2 particles to the foetal side, which was barely quantifiable by ICP-MS. Diameter measurements showed that 70 to 100% of the TiO2 particles recovered in the foetal exudate were nanosized.

Conclusions

Altogether, these results show a materno-foetal transfer of TiO2 particles during pregnancy, with food-grade TiO2 as a potential source for foetal exposure to NPs. These data emphasize the need for risk assessment of chronic exposure to TiO2-NPs during pregnancy.
Is there a relationship between Eustachian tube dysfunction and nasal septal deviation in a sample of the Lebanese population?
Authors: Al Karaki Victoria , Hallit Souheil , Nacouzi Mansour , Rohayem Ziad
Published: October 2020

Background

The Eustachian tube (ET) is considered an organ by itself due to its specific functions. An ET Dysfunction (ETD) is discussed when this tube is unable to ventilate the middle ear properly. Clinically, the patient reports usually some aural fullness, “popping”, “under water” sensation as if the ear is clogged. This condition is common affecting at least 5% of the adult population. It can impair quality of life and become disabling. On the other side, the prevalence of nasal septal deviation (NSD) is believed to be around 22.83% in the adult population. Nasal septal deviation is thought to cause a decline in the middle ear ventilation according to certain authors. The primary outcome is to define the predictive value of the side of Eustachian Tube Dysfunction (ETD) symptoms vis-à-vis the side of nasal septal deviation (NSD) in patients having the two conditions concomitantly.

Methods

A cross-sectional study was conducted between July 2018 and September 2019. Overall, 60 consecutive subjects (total of 120 ears), randomly seen at the Otorhinolaryngology Outpatient Clinics at the Eye and Ear International Hospital, Lebanon, all year-round were enrolled and tested without any geographic preferences. The Eustachian Tube Dysfunction Questionnaire (ETDQ) -7 questionnaire was used to evaluate ETD.

Results

A significantly higher ETD score was found in males compared to females, in those with left septal deviation compared to right and in those who have symptoms on the left compared to right side. Frequent exposure to higher changes in altitude (commute from home to workplace) was also significantly associated with higher ETD scores (r = 0.265), whereas higher Left Tympanometric peak pressure (TPP in daPa) on tympanometry was significantly associated with lower ETD score (r = − 0.467). Furthermore, 25 patients who had symptoms on the left side had also a septal deviation to the left side (86.2%), whereas 29 (93.5%) patients who had the symptoms on the right side had septal deviation to the right side (p < 0.001).

Conclusion

Our data highlighted the importance of altitude and geographic distribution of patients especially in a population exposed to barotrauma on a daily basis like the Lebanese population. Tympanometry, on the other hand, failed to correlate with patient reported symptoms and thus needs further evaluation. The reported ETD symptoms of the patient correlates to the side of NSD.
BM-MSCs differentiated to chondrocytes for treatment of full-thickness cartilage defect of the knee
Authors: Mardones Rodrigo , Giai Via Alessio , Pipino Gennaro , Jofre Claudio M. , Muñoz Sara , Narvaez Edgar , Maffulli Nicola
Published: October 2020

Background

Full-thickness articular cartilage injury of the knee is a major cause of disability. The aim of this study is to assess the outcome of patients treated with differentiated to chondrocytes bone marrow mesenchymal stem cells (BM-MSCs) cultured on a collagen type I/III (Chondro-Gide®) scaffold. The secondary aim was to confirm the absence of adverse events.

Methods

Fifteen patients (19 knees) with symptomatic full-thickness cartilage defects of the knee were enrolled. Bone marrow was harvested from the iliac crest, BM-MSCs were prepared, and expanded cells were grown in a standard medium or in a standard culture medium containing TGF-β. BM-MSCs differentiated to chondrocytes were seeded in a porcine collagen type I/III scaffold (Chondro-Gide®) and cultured in TGF-β containing media. After 4 weeks, the membrane was sutured on the cartilage defect. All patients underwent plain radiographs (antero-posterior, lateral, and axial view of the patella) and MRI of the affected knee. The Oxford knee score, the Lyhsolm scale, and the VAS score were administered to all patients. At final follow-up a MRI for the study of articular cartilage was undertaken.

Results

The mean size of the cartilage lesions was 20 × 17 mm (range, 15 × 10 mm–30 × 30 mm). At final follow-up, the median Oxford knee score and Lyhsolm scale scores significantly improved from 29 (range 12–39; SD 7.39) to 45 (range 24–48; SD 5.6) and from 55.5 (range 25–81; SD 17.7) to 94.5 (58–100; SD 10.8), respectively. Pain, according to the VAS score, significantly improved. Sixty percent of patients reported their satisfaction as excellent, 20% as good, 14% as fair, and 1 patient as poor.

Conclusion

The treatment of full-thickness chondral injuries of the knee with differentiated to chondrocytes BM-MSCs and Chondro-Gide® scaffold showed encouraging outcomes. Further studies involving more patients, and with longer follow-up, are required to evaluate the effectiveness of the treatment and the long-term results.
Donor nerve graft assessment for covering thumb nerve defects: a cadaveric study
Authors: Namazi Hamid , Sobhani Ahmad , Gholamzadeh Saeed , Dehghanian Amirreza , Dehghani Nazhvani Fatemeh
Published: October 2020

Background

Even though several studies reported donor autologous nerve grafts for digital nerve defects, there is no report in the literature regarding acceptable graft for thumb nerves. The purpose of this study is to provide guidelines for autologous nerve graft selection by detecting similarities between thumb nerve zones and donor nerve with regard to the number of fascicles and cross-sectional area.

Materials and methods

Five cadavers were used in this study. An anatomical zoning system was defined for thumb nerves (zones 1, 2, 3). Sural nerve (SN), medial antebrachial cutaneous nerve (MABCN), lateral antebrachial cutaneous nerve (LABCN), posterior interosseous nerve (PIN), and anterior interosseous nerve (AIN) were selected as donor nerve grafts. The number of fascicles and surface area (mm2) was defined.

Results

The mean of the fascicle number in zone 1, zone 2, zone 3, AIN, PIN, LABCN, MABCN, and SN were 3.8, 4.7, 6.1, 2.2, 1.8, 4.5, 3.1, and 6.4, respectively. The mean of the surface area in zone 1, zone 2, zone 3, AIN, PIN, LABCN, MABCN, and SN were 2.19, 6.26, 4.04, 1.58, 0.71, 5.00, 3.01, and 8.06, respectively.

Conclusions

LABCN is the best choice for all zones that has fascicular matching with all three zones of thumb nerves and caliber matching with zones 2 and 3. In zone 1, the best nerve graft is MABCN which has both suitable caliber and fascicle count.
Cosmetic and functional results of a newly reconstructed thumb by combining the phalanx of second toe and the great toenail flap transplantation
Authors: Yin Yefeng , Tao Xiaomei , Li Yanzhao , Bao Buhe , Ying Ying , Bao Tuya , Wang Jiangning
Published: October 2020

Background

Microsurgical toe-to-hand transfer is a gold standard when it comes to repairing a thumb defect. Great toenail flap, thumbnail valva flap, free great toe, and second toe transplantation are the common methods in thumb reconstruction. Second toe transplantation achieves good function, but poor esthetics. Great toe transplantation achieves better esthetics, but hindered walking, due to the foot’s loss of the great toe and moreover suboptimal thumb function. It is difficult to maintain both functional and esthetic satisfaction in thumb reconstruction.

Methods

We experimented with three different methods of toe to hand transfer. From October 2009 to July 2019, 30 patients with traumatic thumb defects received one of 3 different kinds of thumb reconstruction in our clinic according to their level of amputation. Divided evenly into three groups of ten, group one received a great toe transplantation, group two received a second toe transplantation, and group three received a combined great toenail flap and second toe phalanx transplantation. Each of the patients’ thumbs had different levels of amputation at the metatarsophalangeal joint (MPJ) or distal interphalangeal joint (DIPJ).

Results

One patient suffered from a partial flap necrosis and received a groin flap to cover the defect. No other thumbs had any complications. The functional and esthetic results of both the donor and the recipient sites were satisfactory. Results show that, for patients with traumatic thumb defects, the combined transfer of flap and second toe phalanx was the best option.

Conclusions

Compared to the great toe or second toe transfer, combined free transfer of the great toenail flap and second toe phalanx achieved a substantially better functional and esthetic result in the thumb reconstruction.
Sequential ruptures of penetrating atherosclerotic ulcers of ascending aorta, aortic arch and descending thoracic aorta
Authors: Kaul Pankaj , Paniagua Rodolfo , Petsa Afroditi , Singh Raj
Published: October 2020

Background

Penetrating ulcers of aorta, aortic dissections and intramural hematomas all come under acute aortic syndromes and have important similarities and differences.

Case report

We report a 67 year old man with rupture of a large penetrating ulcer of the distal ascending aorta with hemopericardium and left hemothorax. He underwent interposition graft replacement of ascending aorta and hemi-arch with a 30 mm Gelweave Vascutek graft but represented 6 months later with development of a penetrating ulcer which ruptured into a huge 14 cm pseudoaneurysm. This was repaired with a 28 mm Vascutek Gelseal graft replacement of arch and interposition graft reconstruction of innominate and left common carotid arteries. 6 weeks later, however, he ruptured his proximal descending aorta and underwent TEVAR satisfactorily. Unfortunately, 2 days later, he developed a pathological fracture of left proximal tibia with metastasis from a primary renal cell carcinoma. He died 3 weeks later from respiratory failure.

We shall briefly outline the similarities and differences in presentation and management of penetrating aortic ulcers, aortic dissections and intramural haematomas. We shall discuss, in greater detail, penetrating ulcers of thoracic aorta, their natural history, location, complications and management.

Conclusion

This case report is unique on account of initial successful surgical redressal following rupture of penetrating ulcer of distal ascending aorta into left pleural and pericardial cavities, normally associated with instant death. The haemodynamic effects of the rupture were staggered due to initial contained rupture into a smaller pseudoaneurysm, followed by a further rupture into a false aneurysmal sac followed eventually by generalised rupture into the pleural and pericardial cavities - a unique way of aortic rupture. Further development of another penetrating ulcer and a small pseudoaneurysm in the distal arch 6 months later which further ruptured into a larger 14 cm false aneurysmal sac, which again did not result in exsanguination, is again extraordinarily rare. Thereafter he underwent emergency thoracic endovascular aortic repair (TEVAR) for a further rupture of descending thoracic aorta. All three ruptures were managed successfully and would usually be associated with near-certain death, only for the patient to succumb eventually to the complications of metastatic renal cell carcinoma.
Loop electrosurgical excision procedure combined with cold coagulation for cervical intraepithelial neoplasia and adenocarcinoma in-situ: a feasible treatment with a low risk of residual/recurrent disease
Authors: Yang Eun Jung , Kim Nae Ry , Choi Ji Yeon , Kim Wook Youn , Lee Sun Joo
Published: October 2020

Objective

This study was performed to evaluate the significance of positive resection margins (RMs) with the loop electrosurgical excision procedure combined with cold coagulation (LEEP with CC) as a definitive treatment for patients with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in-situ.

Methods

We retrospectively reviewed 467 patients who underwent LEEP with CC. A right-angled triangular loop in a single pass followed by a CC (120 °C) to the cone bed for 10 to 20 s was used. Pathology reports and clinical data were obtained and evaluated.

Results

Histopathology evaluation of LEEP tissue samples revealed the presence of CIN 1 in 69, CIN 2/3 in 366, AIS in 5 and invasive carcinoma in 16 (microinvasive squamous cell carcinoma (SCC) and invasive SCC, 13 and 3) patients. Margins were positive in 66 (14.5%) cases: 0 in CIN 1, 54 in CIN 2/3 (12.4%), 1 in AIS (20.0%) and 11 in microinvasive/invasive SCC (68.8%). Although 54 CIN2/3 patients with positive RMs did not undergo additional treatment, 1 of these (1.9%) was confirmed to have residual CIN3 at the first follow-up. Two of 8 (25.0%) microinvasive SCC patients with positive RMs were confirmed to have residual diseases (1 microinvasive SCC and 1 invasive SCC) after hysterectomy. Four out of 360 (1 positive RM, 3 negative RM) CIN cases recurred during the study period.

Conclusions

These results suggest that CIN patients with positive RMs after LEEP with CC may be followed up without additional treatment.
Artificial intelligence algorithm for predicting cardiac arrest using electrocardiography
Authors: Kwon Joon-myoung , Kim Kyung-Hee , Jeon Ki-Hyun , Lee Soo Youn , Park Jinsik , Oh Byung-Hee
Published: October 2020

Background

In-hospital cardiac arrest is a major burden in health care. Although several track-and-trigger systems are used to predict cardiac arrest, they often have unsatisfactory performances. We hypothesized that a deep-learning-based artificial intelligence algorithm (DLA) could effectively predict cardiac arrest using electrocardiography (ECG). We developed and validated a DLA for predicting cardiac arrest using ECG.

Methods

We conducted a retrospective study that included 47,505 ECGs of 25,672 adult patients admitted to two hospitals, who underwent at least one ECG from October 2016 to September 2019. The endpoint was occurrence of cardiac arrest within 24 h from ECG. Using subgroup analyses in patients who were initially classified as non-event, we confirmed the delayed occurrence of cardiac arrest and unexpected intensive care unit transfer over 14 days.

Results

We used 32,294 ECGs of 10,461 patients and 4483 ECGs of 4483 patients from a hospital were used as development and internal validation data, respectively. Additionally, 10,728 ECGs of 10,728 patients from another hospital were used as external validation data, which confirmed the robustness of the developed DLA. During internal and external validation, the areas under the receiver operating characteristic curves of the DLA in predicting cardiac arrest within 24 h were 0.913 and 0.948, respectively. The high risk group of the DLA showed a significantly higher hazard for delayed cardiac arrest (5.74% vs. 0.33%, P < 0.001) and unexpected intensive care unit transfer (4.23% vs. 0.82%, P < 0.001). A sensitivity map of the DLA displayed the ECG regions used to predict cardiac arrest, with the DLA focused most on the QRS complex.

Conclusions

Our DLA successfully predicted cardiac arrest using diverse formats of ECG. The results indicate that cardiac arrest could be screened and predicted not only with a conventional 12-lead ECG, but also with a single-lead ECG using a wearable device that employs our DLA.
Does cystic fibrosis constitute an advantage in COVID-19 infection?
Authors: Bezzerri Valentino , Lucca Francesca , Volpi Sonia , Cipolli Marco
Published: October 2020

The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.
Candida thrombophlebitis in children: a systematic review of the literature
Authors: Colomba Claudia , Campa Luigi , Siracusa Lucia , Giordano Salvatore , Vella Maria C. , Corsello Giovanni , Giuffrè Mario , Cascio Antonio
Published: October 2020

Objective

To describe a case of thrombophlebitis associated with Candida infection and to analyze other published reports to define clinical characteristics, prognostic data, diagnostic and therapeutic strategies.

Study design

A computerized search was performed without language restriction using PubMed and Scopus databases. An article was considered eligible for inclusion if it reported cases with Candida thrombophlebitis. Our case was also included in the analysis.

Results

A total of 16 articles reporting 27 cases of Candida thrombophlebitis were included in our review. The median age of patients was 4 years. In 10 cases there was a thrombophlebitis of peripheral veins; in the remaining cases the deep venous circle was interested. Candida albicans was the most frequently involved fungal species. The most recurrent risk factors were central venous catheter (19/28), broad spectrum antibiotics (17/28), intensive care unit (8/28), surgery (3/28), mechanical assisted ventilation (5/28), total parenteral nutrition (8/28), cancer (2/28), premature birth (6/28), cystic fibrosis (2/28). Fever was the most frequent clinical feature. All children with peripheral and deep thrombophlebitis were given antifungal therapy: amphotericin B was the most used, alone or in combination with other antifungal drugs. Heparin was most frequently used as anticoagulant therapy. Illness was fatal in two cases.

Conclusion

Candida thrombophlebitis is a rare but likely underdiagnosed infectious complication in pediatric critically ill patients. It is closely connected to risk factors such as central venous catheter, hospitalization in intensive care unit, prematurity, assisted ventilation, chronic inflammatory diseases. Antifungal therapy and anticoagulant drugs should be optimized for each patient and surgical resection is considered in the persistence of illness.
Chlorhexidine bathing of the exposed circuits in extracorporeal membrane oxygenation: an uncontrolled before-and-after study
Authors: Yeo Hye Ju , Kim Dohyung , Ha Mihyang , Je Hyung Gon , Kim Jeong Soo , Cho Woo Hyun
Published: October 2020

Background

Although the prevention of extracorporeal membrane oxygenation (ECMO) catheter-related infection is crucial, scientific evidence regarding best practices are still lacking.

Methods

We conducted an uncontrolled before-and-after study to test whether the introduction of disinfection with 2% chlorhexidine gluconate (CHG) and 70% isopropyl alcohol (IPA) of the exposed circuits and hub in patients treated with ECMO would affect the rate of blood stream infection (BSI) and microbial colonization of the ECMO catheter. We compared the microbiological and clinical data before and after the intervention.

Results

A total of 1740 ECMO catheter days in 192 patients were studied. These were divided into 855 ECMO catheter days in 96 patients before and 885 ECMO catheter days in 96 patients during the intervention. The rates of BSI were significantly decreased during the intervention period at 11.7/1000 ECMO catheter days before vs. 2.3/1000 ECMO catheter days during (difference 9.4, 95% confidence interval (CI) 1.5–17.3, p = 0.019). Furthermore, the colonization of the ECMO catheter was similarly significantly reduced during the intervention period at 10.5/1000 ECMO catheter days before vs. 2.3/1000 ECMO catheter days during intervention (difference 8.3, 95% CI 0.7–15.8, p = 0.032). Hospital mortality (41.7% vs. 24%, p = 0.009) and sepsis-related death (17.7% vs. 6.3%, p = 0.014) were also significantly decreased during intervention.

Conclusion

Extensive disinfection of exposed ECMO circuits and hub with 2% CHG/IPA was associated with a reduction in both BSI and microbial colonization of ECMO catheters. A further randomized controlled study is required to verify these results.

Trial registration

KCT 0004431
Trastuzumab-induced upregulation of a protein set in extracellular vesicles emitted by ErbB2-positive breast cancer cells correlates with their trastuzumab sensitivity
Authors: Drucker Arik , Yoo Byong Hoon , Khan Iman Aftab , Choi Dongsic , Montermini Laura , Liu Xiaoyang , Jovanovic Sanja , Younis Tallal , Rosen Kirill V.
Published: October 2020

Background

ErbB2/HER2 oncoprotein often drives breast cancers (BCs) which are treated with the anti-ErbB2 antibody trastuzumab. The efficacy of trastuzumab-based metastatic BC therapies is routinely assessed by imaging studies. Trastuzumab typically becomes ineffective in the case of this disease and is then replaced by other drugs. Biomarkers of BC trastuzumab response could allow imaging studies and the switch to other drugs to occur earlier than is now possible. Moreover, bone-only BC metastases can be hard to measure, and biomarkers of their trastuzumab response could facilitate further treatment decisions. Such biomarkers are presently unavailable. In this study, we searched for proteins whose levels in BC cell-emitted extracellular vesicles (EVs) potentially correlate with BC trastuzumab sensitivity.

Methods

We isolated EVs from cultured trastuzumab-sensitive and trastuzumab-resistant human BC cells before and after trastuzumab treatment and characterized these EVs by nanoparticle tracking analysis and electron microscopy. We found previously that ErbB2 drives BC by downregulating a pro-apoptotic protein PERP. We now tested whether trastuzumab-induced PERP upregulation in EVs emitted by cultured human BC cells correlates with their trastuzumab sensitivity. We also used mass spectrometry to search for additional proteins whose levels in such EVs reflect BC cell trastuzumab sensitivity. Once we identified proteins whose EV levels correlate with this sensitivity in culture, we explored the feasibility of testing whether their levels in the blood EVs of trastuzumab-treated metastatic BC patients correlate with patients’ response to trastuzumab-based treatments.

Results

We found that neither trastuzumab nor acquisition of trastuzumab resistance by BC cells affects the size or morphology of EVs emitted by cultured BC cells. We established that EV levels of proteins PERP, GNAS2, GNA13, ITB1, and RAB10 correlate with BC cell trastuzumab response. Moreover, these proteins were upregulated during trastuzumab-based therapies in the blood EVs of a pilot cohort of metastatic BC patients that benefited from these therapies but not in those derived from patients that failed such treatments.

Conclusions

Upregulation of a protein set in EVs derived from cultured breast tumor cells correlates with tumor cell trastuzumab sensitivity. It is feasible to further evaluate these proteins as biomarkers of metastatic BC trastuzumab response.
A genome assembly and the somatic genetic and epigenetic mutation rate in a wild long-lived perennial Populus trichocarpa
Authors: Hofmeister Brigitte T. , Denkena Johanna , Colomé-Tatché Maria , Shahryary Yadollah , Hazarika Rashmi , Grimwood Jane , Mamidi Sujan , Jenkins Jerry , Grabowski Paul P. , Sreedasyam Avinash , Shu Shengqiang , Barry Kerrie , Lail Kathleen , Adam Catherine , Lipzen Anna , Sorek Rotem , Kudrna Dave , Talag Jayson , Wing Rod , Hall David W. , Jacobsen Daniel , Tuskan Gerald A. , Schmutz Jeremy , Johannes Frank , Schmitz Robert J.
Published: October 2020

Background

Plants can transmit somatic mutations and epimutations to offspring, which in turn can affect fitness. Knowledge of the rate at which these variations arise is necessary to understand how plant development contributes to local adaption in an ecoevolutionary context, particularly in long-lived perennials.

Results

Here, we generate a new high-quality reference genome from the oldest branch of a wildPopulus trichocarpatree with two dominant stems which have been evolving independently for 330 years. By sampling multiple, age-estimated branches of this tree, we use a multi-omics approach to quantify age-related somatic changes at the genetic, epigenetic, and transcriptional level. We show that the per-year somatic mutation and epimutation rates are lower than in annuals and that transcriptional variation is mainly independent of age divergence and cytosine methylation. Furthermore, a detailed analysis of the somatic epimutation spectrum indicates that transgenerationally heritable epimutations originate mainly from DNA methylation maintenance errors during mitotic rather than during meiotic cell divisions.

Conclusion

Taken together, our study provides unprecedented insights into the origin of nucleotide and functional variation in a long-lived perennial plant.
On the definition of a self-sustaining chemical reaction system and its role in heredity
Authors: Liu Yu
Published: October 2020

Background

The ability to self-sustain is one of the essential properties of life. However, a consistent and satisfying definition of self-sustainability is still missing. Currently, self-sustainability refers to either “no-intervention by a higher entity” or “regeneration of all the system’s components”. How to connect self-sustainability with heredity, another essential of life, is another problem, as they are often considered to be independent of each other. Last but not least, current definitions of self-sustainability failed to provide a practical method to empirically discern whether a chemical system is self-sustaining or not.

Results

Here I propose a definition of self-sustainability. It takes into account the chemical reaction network itself and the external environment which is simplified as a continuous-flow stirred tank reactor. One distinct property of self-sustaining systems is that the system can only proceed if molecular triggers (or called, seeds) are present initially. The molecular triggers are able to establish the whole system, indicating that they carry the preliminary heredity of the system. Consequently, life and a large group of fires (and other dissipative systems) can be distinguished. Besides, the general properties and various real-life examples of self-sustaining systems discussed here together indicate that self-sustaining systems are not uncommon.

Conclusions

The definition I proposed here naturally connects self-sustainability with heredity. As this definition involves the continuous-flow stirred tank reactor, it gives a simple way to empirically test whether a system is self-sustaining or not. Moreover, the general properties and various real-life examples of self-sustaining systems discussed here provide practical guidance on how to construct and detect such systems in real biology and chemistry.

Reviewers

This article was reviewed by Wentao Ma and David Baum.
The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression
Authors: Petitprez Florent , Levy Sacha , Sun Cheng-Ming , Meylan Maxime , Linhard Christophe , Becht Etienne , Elarouci Nabila , Tavel David , Roumenina Lubka T. , Ayadi Mira , Sautès-Fridman Catherine , Fridman Wolf H. , de Reyniès Aurélien
Published: October 2020

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer’s disease.
Radiographic remission in rheumatoid arthritis quantified by computer-aided joint space analysis (CASJA): a post hoc analysis of the RAPID 1 trial
Authors: Pfeil Alexander , Nussbaum Anica , Renz Diane M. , Hoffmann Tobias , Malich Ansgar , Franz Marcus , Oelzner Peter , Wolf Gunter , Böttcher Joachim
Published: October 2020

Background

The reduction of finger joint space width (JSW) in patients with rheumatoid arthritis (RA) is strongly associated with joint destruction. Treatment with certolizumab pegol (CZP), a PEGylated anti-TNF, has been proven to be effective in RA patients. The computer-aided joint space analysis (CAJSA) provides the semiautomated measurement of joint space width at the metacarpal-phalangeal joints (MCP) based on hand radiographs. The aim of this post hoc analysis of the RAPID 1 trial was to quantify MCP joint space distance (JSD-MCP) measured by CAJSA between baseline and week 52 in RA patients treated with certolizumab pegol (CZP) plus methotrexate (MTX) compared with MTX/placebo.

Methods

Three hundred twenty-eight patients were included in the post hoc analysis and received placebo plus MTX, CZP 200 mg plus MTX and CZP 400 mg plus MTX. All patients underwent X-rays of the hand at baseline and week 52 as well as assessment of finger joint space narrowing of the MCP using CAJSA (Version 1.3.6; Sectra; Sweden). The joint space width (JSW) was expressed as mean joint space distance of the MCP joints I to V (JSD-MCPtotal).

Results

The MTX group showed a significant reduction of joint space of − 4.8% (JSD-MCPtotal), whereas in patients treated with CZP 200 mg/MTX and CZP 400 mg/MTX a non-significant change (JSD-MCPtotal + 0.6%) was observed. Over 52 weeks, participants with DAS28 remission (DAS28 ≤ 2.6) exhibited a significant joint space increase of + 3.3% (CZP 200 mg plus MTX) and + 3.9% (CZP pegol 400 mg plus MTX).

Conclusion

CZP plus MTX did not reduce JSD-MCPtotal estimated by CAJSA compared with MTX/placebo. Furthermore, clinical remission (DAS28 ≤ 2.6) in patients treated with CZP plus MTX was associated with an increasing JSD, indicating radiographic remission in RA.
Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation—a prospective, observational study
Authors: Andréasson Kristofer , Neringer Karl , Wuttge Dirk M. , Henrohn Dan , Marsal Jan , Hesselstrand Roger
Published: October 2020

Objective

Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs.

Methods

This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5 g twice daily since at least 3 months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3 g MMF (MPA_AUC3g) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI).

Results

Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1 g. Drug exposure expressed as MPA_AUC3gvaried up to 8-fold between patients (median 115, range 27–226 mg h/L).

MPA_AUC3gwas inversely related to body weight (rs = − 0.58,p < 0.001) and renal function (rs = − 0.34,p = 0.054). Anti-topoisomerase-1 antibodies and male sex were associated with lower MPA_AUC3g(87 vs 123 and 71 vs 141;p = 0.008 andp = 0.015, respectively). MPA_AUC3gwas inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (rs = − 0.54,p = 0.004;rs = − 0.36,p = 0.034), but not to gastrointestinal symptoms. MPA_AUC3gwas inversely related to PPI usage (rs = − 0.45,p = 0.007). We found no association between MPA_AUC3gand disease subtype, disease duration or disease activity.

Conclusion

MMF-treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.
Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis
Authors: Christodoulou-Vafeiadou Eleni , Geka Christina , Ntari Lydia , Kranidioti Ksanthi , Argyropoulou Eleni , Meier Florian , Armaka Marietta , Mourouzis Iordanis , Pantos Constantinos , Rouchota Maritina , Loudos George , Denis Maria C. , Karagianni Niki , Kollias George
Published: October 2020

Background

The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model.

Methods

TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis.

Results

TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.

Conclusions

The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.
Effects of electromagnetic fields treatment on rat critical-sized calvarial defects with a 3D-printed composite scaffold
Authors: Tu Chang , Chen Jingyuan , Huang Chunwei , Xiao Yifan , Tang Xiangyu , Li Hao , Ma Yongzhuang , Yan Jiyuan , Li Weigang , Wu Hua , Liu Chaoxu
Published: October 2020

Background

Current strategies for craniofacial defect are faced with unmet outcome. Combining 3D-printing with safe, noninvasive magnetic therapy could be a promising breakthrough.

Methods

In this study, polylactic acid/hydroxyapatite (PLA/HA) composite scaffold was fabricated. After seeding rat bone marrow mesenchymal stem cells (BMSCs) on scaffolds, the effects of electromagnetic fields (EMF) on the proliferation and osteogenic differentiation capacity of BMSCs were investigated. Additionally, 6-mm critical-sized calvarial defect was created in rats. BMSC-laden scaffolds were implanted into the defects with or without EMF treatment.

Results

Our results showed that PLA/HA composite scaffolds exhibited uniform porous structure, high porosity (~ 70%), suitable compression strength (31.18 ± 4.86 MPa), modulus of elasticity (10.12 ± 1.24 GPa), and excellent cyto-compatibility. The proliferation and osteogenic differentiation capacity of BMSCs cultured on the scaffolds were enhanced with EMF treatment. Mechanistically, EMF exposure functioned partly by activating mitogen-activated protein kinase (MAPK) or MAPK-associated ERK and JNK pathways. In vivo, significantly higher new bone formation and vascularization were observed in groups involving scaffold, BMSCs, and EMF treatment, compared to scaffold alone. Furthermore, after 12 weeks of implanting, craniums in groups including scaffold, BMSCs, and EMF exposure showed the greatest biomechanical properties.

Conclusion

In conclusion, EMF treatment combined with 3D-printed scaffold has great potential applications in craniofacial regeneration.
A systematic review of patient prioritization tools in non-emergency healthcare services
Authors: Déry Julien , Ruiz Angel , Routhier François , Bélanger Valérie , Côté André , Ait-Kadi Daoud , Gagnon Marie-Pierre , Deslauriers Simon , Lopes Pecora Ana Tereza , Redondo Eduardo , Allaire Anne-Sophie , Lamontagne Marie-Eve
Published: October 2020

Background

Patient prioritization is a strategy used to manage access to healthcare services. Patient prioritization tools (PPT) contribute to supporting the prioritization decision process, and to its transparency and fairness. Patient prioritization tools can take various forms and are highly dependent on the particular context of application. Consequently, the sets of criteria change from one context to another, especially when used in non-emergency settings. This paper systematically synthesizes and analyzes the published evidence concerning the development and challenges related to the validation and implementation of PPTs in non-emergency settings.

Methods

We conducted a systematic mixed studies review. We searched evidence in five databases to select articles based on eligibility criteria, and information of included articles was extracted using an extraction grid. The methodological quality of the studies was assessed by using the Mixed Methods Appraisal Tool. The article selection process, data extraction, and quality appraisal were performed by at least two reviewers independently.

Results

We included 48 studies listing 34 different patient prioritization tools. Most of them are designed for managing access to elective surgeries in hospital settings. Two-thirds of the tools were investigated based on reliability or validity. Inconclusive results were found regarding the impact of PPTs on patient waiting times. Advantages associated with PPT use were found mostly in relationship to acceptability of the tools by clinicians and increased transparency and equity for patients.

Conclusions

This review describes the development and validation processes of PPTs used in non-urgent healthcare settings. Despite the large number of PPTs studied, implementation into clinical practice seems to be an open challenge. Based on the findings of this review, recommendations are proposed to develop, validate, and implement such tools in clinical settings.

Systematic review registration

PROSPERO CRD42018107205
Systematic review of economic evaluations investigating education, exercise, and dietary weight management to manage hip and knee osteoarthritis: protocol
Authors: Mazzei Darren R. , Ademola Ayoola , Abbott J. Haxby , Sajobi Tolulpe , Hildebrand Kevin , Marshall Deborah A.
Published: October 2020

Background

International guidelines recommend education, exercise, and dietary weight management as core treatments to manage osteoarthritis (OA) regardless of disease severity or co-morbidity. Evidence supports the clinical effectiveness of OA management programs, but the cost-effectiveness of core treatments remains unclear. We will systematically review, synthesize, and assess the literature in economic evaluations of core treatments (education, exercise, and dietary weight management) for the management of hip and/or knee OA.

Methods

We will search the following elecftronic databases (from inception onwards): MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), National Health Services Economic Evaluation Database, and EconLit. Economic evaluations alongside randomized or nonrandomized clinical trials investigating OA education, exercise, and dietary weight management interventions will be included. Title, abstract, and full text of relevant publications will be screened independently by two reviewers. A content matter expert will resolve any conflicts between two reviewers. Key information from relevant papers will be extracted and tabulated to provide an overview of the published literature. Methodological quality will be evaluated using the Consensus on Health Economic Criteria list. A narrative synthesis without meta-analysis will be conducted. Subgroup analysis will attempt to find trends between research methods, intervention characteristics, and results.

Discussion

The findings of this review will evaluate the breadth and quality of economic evaluations conducted alongside clinical trials for core treatments in OA management.

Systematic review registration

PROSPERO CRD42020155964
General conformable estimators with finite-time stability
Authors: Meléndez-Vázquez Fidel , Fernández-Anaya Guillermo , Hernández-Martínez Eduardo G.
Published: October 2020

In this paper, some estimators are proposed for nonlinear dynamical systems with the general conformable derivative. In order to analyze the stability of these estimators, some Lyapunov-like theorems are presented, taking into account finite-time stability. Thus, to prove these theorems, a stability function is defined based on the general conformable operator, which implies exponential stability. The performance of the estimators is assessed by means of numerical simulations. Furthermore, a comparison is made between the results obtained with the integer, fractional, and general conformable derivatives.