bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a roadmap for mainstreaming nutrition-sensitive interventions at state level in Nigeria
Authors: Ezekannagha Oluchi , Drimie Scott , von Fintel Dieter , Maziya-Dixon Busie , Mbhenyane Xikombiso
Published: September 2020

Background

National programs are often developed with little consideration to the sub-national local factors that might affect program success. These factors include political support, capacity for implementation of program and variation in malnutrition indices being tackled. State context factors are evident in the distribution of malnutrition (e.g. high prevalence or gap among Local Government Areas), in the implementation of nutrition-sensitive interventions (e.g. access to early childhood education) and in the political economic context (e.g. presence of external funding agencies). Context is shaped by the economy, population, religion, and poverty, which impact everyday lives. Considering these contexts, a roadmap was developed and validated. The aim of this paper is to report expert review and stakeholder validation to determine feasibility of the developed contextualised roadmap for two Nigerian states.

Methods

A validation tool was developed and reviewed using three experts. The content review occurred in two rounds to obtain recommendation and revisions of the developed roadmap and the validation tool. A pilot test of the roadmap and validation tool was done using two stakeholders in South Africa. The roadmap and the validation tool were then sent to the stakeholders and potential end-users in Nigeria using electronic media. Two research assistants were also engaged to deliver and collect hard copies to those who preferred it.

Results

Of the ten stakeholders invited, nine responded. All participants showed an adequate understanding of the roadmap as evidenced by the scores given. Responses regarding the translation of the roadmap to implementation varied. The majority (86,6%) either strongly agreed or agreed that the actions were translatable (43.0 and 43.6% respectively).

Conclusions

The final roadmap comprises of actions that are appropriate for the state’s context. It is recommended that stakeholders or end-users of any programme must be involved in the validation of such contextual programmes to improve chances of success.
A scoping review of policies promoting and supporting sustainable food systems in the university setting
Authors: Grech Amanda , Howse Eloise , Boylan Sinead
Published: September 2020

Background

Transitioning towards sustainable food systems for the health of the population and planet will require governments and institutions to develop effective governance to support the adoption of sustainable food practices. The aim of the paper is to describe current governance within Australian and New Zealand universities designed to support sustainable food systems.

Methods

A systematic search of governance documents to support sustainable food systems within Australian and New Zealand universities was conducted. Data were obtained from 1) targeted websites 2) internet search engines and 3) expert consultations. Inclusion criteria consisted of university governance documents including by-laws, policies, guidelines, frameworks, and procedures that support sustainable food systems.

Results

Twenty-nine governance documents across nineteen Australian and New Zealand universities were included for synthesis, including waste management policies (n = 3), fair-trade/procurement policies (n = 6), catering and or event guidelines (n = 7) and catering policies (n = 2), and environmental management plans (n = 11). The main strategies adopted by universities were sustainable waste management and prevention (e.g. reducing landfill, reducing wasted food, (27%)), ethical procurement practices (i.e. fair-trade (27%)) and environmentally sustainable food consumption (e.g. local, seasonal, organic, vegetarian food supply (14.5%)). Only 12.5% of universities addressed all three of the main strategies identified.

Conclusions

This study indicates that while sustainable food systems are considered in some university governance documents, efforts are predominantly focused on aspects such as waste management or procurement of fair-trade items which as stand-alone practices are likely to have minimal impact. This review highlights the scope of universities to provide strong leadership in promoting and supporting sustainable food systems through holistic institutional policies and governance mechanisms.
Coping with the COVID-19 pandemic – the role of leadership in the Arab ethnic minority in Israel
Authors: Saban Mor , Myers Vicki , Wilf-Miron Rachel
Published: September 2020

Background

The Arab ethnic minority makes up 21% of Israel’s population, yet comprised just 8.8% of confirmed cases and 3.6% of deaths from COVID-19, despite their higher risk profile and greater burden of underlying illness. This paper presents differences in patterns of morbidity and mortality from COVID-19 in the Arab, ultra-Orthodox and overall populations in Israel, and suggests possible reasons for the low rates of infection in the Arab population.

Methods

Data were obtained from the Israeli Ministry of Health’s (MOH) open COVID-19 database, which includes information on 1270 localities and is updated daily. The database contains the number of COVID-19 diagnostic tests performed, the number of confirmed cases and deaths in Israel.

Results

In the first 4 months of Israel’s COVID-19 outbreak, just 2060 cases were confirmed in the Arab population, comprising 8.8% of the 23,345 confirmed cases, or 2.38 times less than would be expected relative to the population size. In contrast, the ultra-Orthodox made up 30.1% of confirmed cases yet just 10.1% of the population. Confirmed case rate per 100,000 was twice as high in the general Jewish population compared to the Arab population. The Arab mortality rate was 0.57 per 100,000, compared to 3.37 in the overall population, and to 7.26 in the ultra-Orthodox community. We discuss possible reasons for this low morbidity and mortality including less use of nursing homes, and effective leadership which led to early closure of mosques and high adherence to social distancing measures, even during the month of Ramadan.

Conclusions

Despite a disproportionate burden of underlying illness, the Arab population did not fulfil initial predictions during the first wave of the COVID-19 outbreak and maintained low numbers of infections and deaths. This contrasts with reports of increased mortality in ethnic minorities and economically disadvantaged populations in other countries, and with high rates of infection in the ultra-Orthodox sector in Israel. Effective leadership and cooperation between individuals and institutions, particularly engagement of community and religious leaders, can reduce a group’s vulnerability and build resilience in an emergency situation such as the current pandemic.
Loss of FBXW7-mediated degradation of BRAF elicits resistance to BET inhibitors in adult T cell leukemia cells
Authors: Yeh Chien-Hung , Bellon Marcia , Wang Fang , Zhang Hong , Fu Liwu , Nicot Christophe
Published: September 2020

Background

Human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia (ATL) has a very poor prognosis with a median survival of 8 months and a 4-year overall survival of 11% for acute ATL. Present treatment options are limited and there is no curative therapy for ATL. Ubiquitin ligase FBXW7 is commonly mutated or functionally inactivated in human cancers. Consistent with the notion that FBXW7 controls the degradation of many oncoproteins, loss of FBXW7 has been linked to increased drug resistance or sensitivity in cancer cells.

Method

In this study, we have characterized FBXW7 mutants previously identified in HTLV-I-infected ATL patient samples. TET-inducible ATL cells carrying wild type or mutated FBXW7 were analyzed for target degradation and for drug sensitivity.

Results

Our results demonstrate that mutations in FBXW7 can selectively disrupt ubiquitination and proteasome degradation of target proteins: c-MYC, cyclin E and MCL1. Both c-MYC and MYCN were highly expressed in uncultured ATL patient’s samples and ATL-derived cell lines; and ATL cells demonstrated sensitivity to BET inhibitors in vitro and in vivo. High-throughput reverse phase protein array revealed BRAF as a novel target of FBXW7 and further experiments showed that mutations in FBXW7 preventing degradation of BRAF provided resistance to BET inhibitors. In contrast to R465, hot spot FBXW7 mutations at R505C retained degradation of BRAF but not NOTCH1, c-MYC, cyclin E, or MCL1. Finally, a combination therapy using BET inhibitors along with a BRAF or an ERK inhibitor prevented tumor cell resistance and growth.

Conclusion

Our results suggest that FBXW7 status may play an important role in drug therapy resistance of cancer cells. Genetic characterization of FBXW7 may be one factor included in future personalized cancer treatment identification.
Multiparametric investigation of non functionalized-AGuIX nanoparticles in 3D human airway epithelium models demonstrates preferential targeting of tumor cells
Authors: Sancey Lucie , Sabido Odile , He Zhiguo , Rossetti Fabien , Guignandon Alain , Bin Valérie , Coll Jean-Luc , Cottier Michèle , Lux François , Tillement Olivier , Constant Samuel , Mas Christophe , Boudard Delphine
Published: September 2020

Liquid deposit mimicking surface aerosolization in the airway is a promising strategy for targeting bronchopulmonary tumors with reduced doses of nanoparticle (NPs). In mimicking and studying such delivery approaches, the use of human in vitro 3D culture models can bridge the gap between 2D cell culture and small animal investigations. Here, we exposed airway epithelia to liquid-apical gadolinium-based AGuIX® NPs in order to determine their safety profile. We used a multiparametric methodology to investigate the NP’s distribution over time in both healthy and tumor-bearing 3D models. AGuIX® NPs were able to target tumor cells in the absence of specific surface functionalization, without evidence of toxicity. Finally, we validated the therapeutic potential of this hybrid theranostic AGuIX® NPs upon radiation exposure in this model. In conclusion, 3D cell cultures can efficiently mimic the normal and tumor-bearing airway epitheliums, providing an ethical and accessible model for the investigation of nebulized NPs.
LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP
Authors: Hu Lin , Wang Jing , Wang Yunliang , Wu Linpeng , Wu Chao , Mao Bo , Maruthi Prasad E. , Wang Yuhong , Chin Y. Eugene
Published: September 2020

Background

LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated.

Methods

LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro, colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo, metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway.

Results

LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2.

Conclusions

LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity.

Graphical abstract
Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair
Authors: Israelov Hila , Ravid Orly , Atrakchi Dana , Rand Daniel , Elhaik Shirin , Bresler Yael , Twitto-Greenberg Rachel , Omesi Liora , Liraz-Zaltsman Sigal , Gosselet Fabien , Schnaider Beeri Michal , Cooper Itzik
Published: September 2020

Background

Excessive inflammation might activate and injure the blood-brain barrier (BBB), a common feature of many central nervous system (CNS) disorders. We previously developed an in vitro BBB injury model in which the organophosphate paraoxon (PX) affects the BBB endothelium by attenuating junctional protein expression leading to weakened barrier integrity. The objective of this study was to investigate the inflammatory cellular response at the BBB to elucidate critical pathways that might lead to effective treatment in CNS pathologies in which the BBB is compromised. We hypothesized that caspase-1, a core component of the inflammasome complex, might have important role in BBB function since accumulating evidence indicates its involvement in brain inflammation and pathophysiology.

Methods

An in vitro human BBB model was employed to investigate BBB functions related to inflammation, primarily adhesion and transmigration of peripheral blood mononuclear cells (PBMCs). Caspase-1 pathway was studied by measurements of its activation state and its role in PBMCs adhesion, transmigration, and BBB permeability were investigated using the specific caspase-1 inhibitor, VX-765. Expression level of adhesion and junctional molecules and the secretion of pro-inflammatory cytokines were measured in vitro and in vivo at the BBB endothelium after exposure to PX. The potential repair effect of blocking caspase-1 and downstream molecules was evaluated by immunocytochemistry, ELISA, and Nanostring technology.

Results

PX affected the BBB in vitro by elevating the expression of the adhesion molecules E-selectin and ICAM-1 leading to increased adhesion of PBMCs to endothelial monolayer, followed by elevated transendothelial-migration which was ICAM-1 and LFA-1 dependent. Blocking caspase-8 and 9 rescued the viability of the endothelial cells but not the elevated transmigration of PBMCs. Inhibition of caspase-1, on the other hand, robustly restored all of barrier insults tested including PBMCs adhesion and transmigration, permeability, and VE-cadherin protein levels. The in vitro inflammatory response induced by PX and the role of caspase-1 in BBB injury were corroborated in vivo in isolated blood vessels from hippocampi of mice exposed to PX and treated with VX-765.

Conclusions

These results shed light on the important role of caspase-1 in BBB insult in general and specifically in the inflamed endothelium, and suggest therapeutic potential for various CNS disorders, by targeting caspase-1 in the injured BBB.
Returning of antiretroviral medication dispensed over a period of 8 months suggests non-adherence despite full adherence according to real time medication monitoring
Authors: Ngowi Kennedy Michael , Masika Lydia , Lyamuya Furaha , Muro Eva , Mmbaga Blandina T. , Sprangers Mirjam A. G. , Nieuwkerk Pythia T. , Aarnoutse Rob E. , Reiss Peter , Sumari-de Boer I. Marion
Published: September 2020

Real-time medication monitoring (RTMM) may potentially enhance adherence to antiretroviral treatment (ART). We describe a participant in an ongoing trial who, shortly after completing trial participation, died of cryptococcal meningitis despite high levels of adherence according to self-report, pill-counts and RTMM (> 99%). However, she evidenced consistently high HIV viral load throughout the 48-week study follow-up. Subsequently, her relatives unsolicitedly returned eight months’ dispensed ART medication that she was supposed to have taken. This brief report illustrates the challenges of adherence measurements including RTMM, and reinforces the need to combine adherence assessments with viral load monitoring in HIV care.
In vitro virucidal activity of Echinaforce®, an Echinacea purpurea preparation, against coronaviruses, including common cold coronavirus 229E and SARS-CoV-2
Authors: Signer Johanna , Jonsdottir Hulda R. , Albrich Werner C. , Strasser Marc , Züst Roland , Ryter Sarah , Ackermann-Gäumann Rahel , Lenz Nicole , Siegrist Denise , Suter Andreas , Schoop Roland , Engler Olivier B.
Published: September 2020

Background

Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro.

Methods

To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium.

Results

In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 μg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 μg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50μg/ml Echinaforce®.

Conclusions

These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.
Radiation-induced lung toxicity – cellular and molecular mechanisms of pathogenesis, management, and literature review
Authors: Käsmann Lukas , Dietrich Alexander , Staab-Weijnitz Claudia A. , Manapov Farkhad , Behr Jürgen , Rimner Andreas , Jeremic Branislav , Senan Suresh , De Ruysscher Dirk , Lauber Kirsten , Belka Claus
Published: September 2020

Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.
Minimum 3.5-year outcomes of operative treatment for Achilles tendon partial tears in the midportion and retrocalcaneal area
Authors: Lohrer Heinz
Published: September 2020

Background

Achilles tendon partial tears are not easy to diagnose and to manage. Most frequently, they are located in the midportion and insertional area. These entities result from different pathologic pathways, and different treatment strategies are applied. The outcome is rarely investigated.

Methods

This study includes patients who underwent surgery for partial tears in the midportion or retrocalcaneal Achilles tendon area between the years 2009 and 2015 by a single surgeon. Patients were prospectively assessed preoperatively and 3, 6, and 12 months postoperatively, using the VISA-A-G questionnaire. The final retrospective follow-up was performed after a minimum of 3.5 years postoperatively. Forty-eight Achilles tendon partial tears at the level of the retrocalcaneal bursa (impingement lesions) and 27 midportion Achilles tendon partial tears were identified. After applying rigorous exclusion criteria, 21 and 16 cases, respectively, remained for the final follow-up. Results were analysed by inferential and descriptive statistics.

Results

The VISA-A-G outcome scores improved significantly from preoperative to 6 months, 12 months, and final postoperative assessment. Preoperatively, the average VISA-A-G score was 42.1 (range, 18–73) for patients operated for Achilles tendon partial tears at the level of the retrocalcaneal bursa and 44.6 (range, 10–73) for the midportion Achilles tendon partial tear group, respectively. At final follow-up 88.8 (range, 15 to 100) and 96.9 (range, 71 to 100) were scored in the respective treatment groups. A repeated measures ANOVA determined that mean performance levels showed a statistically significant difference between measurements (p< 0.001). There was no systematic effect found between groups (p= 0.836).

Conclusions

In Achilles tendon partial tears recalcitrant to conservative treatment, operative intervention is highly successful in most cases, irrespective of the level of the injury. Results were statistically equal when comparing the midportion and retrocalcaneal Achilles tendon partial tear groups.

Trial registration

DRKS, DRKS00014266. Registered 06 April 2018. ‘Retrospectively registered’,https://www.drks.de/drks_web/navigate.do?navigationId=results.
In cervical arthroplasty, only prosthesis with flexible biomechanical properties should be used for achieving a near-physiological motion pattern
Authors: Muhlbauer Manfred , Tomasch Ernst , Sinz Wolfgang , Trattnig Siegfried , Steffan Hermann
Published: September 2020

Background

In cervical arthroplasty, qualitative motion analysis generally investigates the position of the center of rotation (COR) before and after surgery. But is the pre-op COR suitable as reference? We believe that only a comparison against healthy individuals can answer whether a physiological motion pattern has been achieved. The aim of our study was to examine how the COR for flexion/extension after insertion of 3 biomechanically completely different types of disc prostheses compares to healthy volunteers, and whether and how prosthesis design contributes to a more natural or maybe even worse motion pattern.

Methods

In 15 healthy volunteers, MRI in flexion and in extension was taken, and the coordinates for the CORs (COR-HV) from C3 to C7 were determined. Then pre- and post-op flexion/extension x-rays from 30 patients with a one-level disc prosthesis underwent analysis for determination of COR from C3 to C7; 10 patients who received a Bryan, a Prestige STLP, or a Discover prosthesis were chosen, respectively. Change of post-op COR position was investigated in relation to the COR-HV.

Results

The pre-operative COR is not congruent with the COR found in healthy subjects and therefore cannot be used as reference for investigation whether a disc prosthesis resembles natural motion. However, the comparison with healthy individuals shows that prosthesis insertion can change the coordinates of the COR to any direction in all levels from C3/4 to C6/7 regardless of the operated segment. Prostheses with flexible biomechanical properties can contribute to shift the COR toward normal, but devices with unphysiological biomechanical design, like fixed ball socket designs, for instance, can make the motion pattern even worse.

Conclusions

Even if the small cohorts in our study do not allow strong conclusions, it seems that in cervical arthroplasty, the biomechanical concept of the prosthesis has a significant impact whether a near-physiological motion pattern can be achieved or not. As it is a rumor but not scientifically proven that prosthesis design has no influence on clinical outcome, surgeons should only choose devices with flexible biomechanical properties for disc replacement.
Modified hybrid cementing technique reduces stem tip pain and improves patient’s satisfaction after revision total knee arthroplasty
Authors: Kim Man Soo , Koh In Jun , Sohn Sueen , Park Hyung Chul , In Yong
Published: September 2020

Background

There have been no studies comparing patient-reported outcome measures including end-of-stem tip pain and patient satisfaction based on the use of cementing techniques in revision total knee arthroplasty (TKA). The purpose of this study was to compare end-of-stem tip pain and PROMs with hybrid and modified hybrid cementing techniques in revision TKAs.

Method

Sixty-two cases of revision TKA performed by a single surgeon were divided into two groups based on the cementing technique with a minimum follow-up of 2 years. Two types of cementing technique for femoral and tibial stems were used as follows: (1) a hybrid cementing technique (33 cases), in which cement was applied immediately distal to the modular junction of the stem and the component while the distal stem was press-fitted into the diaphysis without using cement; and (2) a modified hybrid cementing technique (29 cases), in which cement was applied to the tip of femoral and tibial stems. The thigh and shin were assessed for the end-of-stem tip pain. Patient satisfaction was evaluated based on the satisfaction items of New Knee Society Score.

Results

Modified hybrid cementing significantly lowered the percentage of patients manifesting shin pain (3.4% vs. 24.2%, p = 0.029). Patients treated with the modified hybrid cementing technique showed a higher satisfaction rate (p = 0.003). Multivariate logistic regression analysis showed an increase in the odds of satisfaction 32.686-fold (p = 0.004) in patients without pain at the end-of-stem tip in the shin and 9.261-fold (p = 0.027) in patients treated with the modified hybrid cementing technique.

Conclusion

The modified hybrid cementing technique for fixation of long-stem in revision TKAs reduced the end-of-stem tip pain in the shin, leading to significantly higher satisfaction compared with the hybrid cementing technique after revision TKA.

Level of evidence

Level III
Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations
Authors: Konopka Anna , Whelan Donna R. , Jamali Md Shafi , Perri Emma , Shahheydari Hamideh , Toth Reka P. , Parakh Sonam , Robinson Tina , Cheong Alison , Mehta Prachi , Vidal Marta , Ragagnin Audrey M. G. , Khizhnyak Ivan , Jagaraj Cyril J. , Galper Jasmin , Grima Natalie , Deva Anand , Shadfar Sina , Nicholson Garth A. , Yang Shu , Cutts Suzanne M. , Horejsi Zuzana , Bell Toby D. M. , Walker Adam K. , Blair Ian P. , Atkin Julie D.
Published: September 2020

Background

Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in motor neurons of almost all amyotrophic lateral sclerosis (ALS) patients, and mutations in TDP-43 are also present in ALS. Loss and gain of TDP-43 functions are implicated in pathogenesis, but the mechanisms are unclear. While the RNA functions of TDP-43 have been widely investigated, its DNA binding roles remain unclear. However, recent studies have implicated a role for TDP-43 in the DNA damage response.

Methods

We used NSC-34 motor neuron-like cells and primary cortical neurons expressing wildtype TDP-43 or TDP-43 ALS associated mutants (A315T, Q331K), in which DNA damage was induced by etoposide or H2O2 treatment. We investigated the consequences of depletion of TDP-43 on DNA repair using small interfering RNAs. Specific non homologous end joining (NHEJ) reporters (EJ5GFP and EJ2GFP) and cells lacking DNA-dependent serine/threonine protein kinase (DNA-PK) were used to investigate the role of TDP-43 in DNA repair. To investigate the recruitment of TDP-43 to sites of DNA damage we used single molecule super-resolution microscopy and a co-immunoprecipitation assay. We also investigated DNA damage in an ALS transgenic mouse model, in which TDP-43 accumulates pathologically in the cytoplasm. We also examined fibroblasts derived from ALS patients bearing the TDP-43 M337V mutation for evidence of DNA damage.

Results

We demonstrate that wildtype TDP-43 is recruited to sites of DNA damage where it participates in classical NHEJ DNA repair. However, ALS-associated TDP-43 mutants lose this activity, which induces DNA damage. Furthermore, DNA damage is present in mice displaying TDP-43 pathology, implying an active role in neurodegeneration. Additionally, DNA damage triggers features typical of TDP-43 pathology; cytoplasmic mis-localisation and stress granule formation. Similarly, inhibition of NHEJ induces TDP-43 mis-localisation to the cytoplasm.

Conclusions

This study reveals that TDP-43 functions in DNA repair, but loss of this function triggers DNA damage and is associated with key pathological features of ALS.
STARR-seq identifies active, chromatin-masked, and dormant enhancers in pluripotent mouse embryonic stem cells
Authors: Peng Tianran , Zhai Yanan , Atlasi Yaser , ter Huurne Menno , Marks Hendrik , Stunnenberg Hendrik G. , Megchelenbrink Wout
Published: September 2020

Background

Enhancers are distal regulators of gene expression that shape cell identity and control cell fate transitions. In mouse embryonic stem cells (mESCs), the pluripotency network is maintained by the function of a complex network of enhancers, that are drastically altered upon differentiation. Genome-wide chromatin accessibility and histone modification assays are commonly used as a proxy for identifying putative enhancers and for describing their activity levels and dynamics.

Results

Here, we applied STARR-seq, a genome-wide plasmid-based assay, as a read-out for the enhancer landscape in “ground-state” (2i+LIF; 2iL) and “metastable” (serum+LIF; SL) mESCs. This analysis reveals that active STARR-seq loci show modest overlap with enhancer locations derived from peak calling of ChIP-seq libraries for common enhancer marks. We unveil ZIC3-bound loci with significant STARR-seq activity in SL-ESCs. Knock-out of Zic3 removes STARR-seq activity only in SL-ESCs and increases their propensity to differentiate towards the endodermal fate. STARR-seq also reveals enhancers that are not accessible, masked by a repressive chromatin signature. We describe a class of dormant, p53 bound enhancers that gain H3K27ac under specific conditions, such as after treatment with Nocodazol, or transiently during reprogramming from fibroblasts to pluripotency.

Conclusions

In conclusion, loci identified as active by STARR-seq often overlap with those identified by chromatin accessibility and active epigenetic marking, yet a significant fraction is epigenetically repressed or display condition-specific enhancer activity.
Developing consensus on core outcome domains and measurement instruments for assessing effectiveness in perioperative pain management after sternotomy, breast cancer surgery, total knee arthroplasty, and surgery related to endometriosis
Authors: Kaiser Ulrike , Liedgens Hiltrud , Meissner Winfried , Weinmann Claudia , Zahn Peter , Pogatzki-Zahn Esther
Published: September 2020

Introduction

Evidence synthesis of clinical trials requires consistent outcome assessment. For pain management after surgery, inconsistency of effectiveness assessment is still observed. A subproject of IMI-PainCare (Innovative Medicine Initiatives, www.imi-paincare.eu) aims for identifying core outcome domains and measurement instruments for postoperative pain in four surgical fields (sternotomy, breast cancer surgery, total knee arthroplasty, and surgery related to endometriosis) in order to harmonize outcome assessment for perioperative pain management.

Methods

A multifaceted process will be performed according to existing guidelines (Core Outcome Measures in Effectiveness Trials (COMET), COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)). In a first step, outcome domains will be identified via systematic literature review and consented on during a 1-day consensus meeting by 10 stakeholder groups, including patient representatives, forming an IMI PROMPT consensus panel. In a second step, outcome measurement instruments regarding the beforehand consented core outcome domains and their psychometric properties will be searched for via systematic literature review and approved by COSMIN checklist for study quality and scale quality separately. In a three-step online survey, the IMI PROMPT consensus panel will vote for most suitable measurement instruments. The process is planned to be conducted between 11/2017 (systematic literature review on common outcome domains) and 3/2022 (final voting on core outcome measurement).
Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials
Authors: Genovese Mark C. , Burmester Gerd R. , Hagino Owen , Thangavelu Karthinathan , Iglesias-Rodriguez Melitza , John Gregory St , González-Gay Miguel A. , Mandrup-Poulsen Thomas , Fleischmann Roy
Published: September 2020

Background

Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes.

Methods

Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes.

Results

Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominalp <  0.0001) and − 0.42 (− 0.54, − 0.31; nominalp <  0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was − 0.13 (− 0.22, − 0.04; nominalp = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA.

Conclusions

In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings.

Trial registration

ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.
Existence of a mountain pass solution for a nonlocal fractional $(p, q)$-Laplacian problem
Authors: Behboudi F. , Razani A. , Oveisiha M.
Published: September 2020

Here, a nonlocal nonlinear operator known as the fractional $(p,q)$
(
p
,
q
)
-Laplacian is considered. The existence of a mountain pass solution is proved via critical point theory and variational methods. To this aim, the well-known theorem on the construction of the critical set of functionals with a weak compactness condition is applied.
An extension of Darbo’s fixed point theorem for a class of system of nonlinear integral equations
Authors: Deep Amar , Deepmala  , Rezaei Roshan Jamal , Nisar Kottakkaran Sooppy , Abdeljawad Thabet
Published: September 2020

We introduce an extension of Darbo’s fixed point theorem via a measure of noncompactness in a Banach space. By using our extension we study the existence of a solution for a system of nonlinear integral equations, which is an extended result of (Aghajani and Haghighi in Novi Sad J. Math. 44(1):59–73, 2014). We give an example to show the specified existence results.
Screening, identification, and colonization of fungal root endophytes against Dematophora necatrix: a ubiquitous pathogen of fruit trees
Authors: Pal Joginder , Sharma Satish K. , Devi Sunita , Sharma Ranjna , Raj Hans , Karn Monika , Verma Shalini , Vedukola Pulla Reddy , Sharma Anju
Published: September 2020

The goal of the present research was to ascertain the potential root endophytic fungi against Dematophora necatrix, Hartig, the causal pathogen of white root rot in apples; however, it has an expanded range of hosts across different fruit trees. Out of 36 endophytic fungi segregated from symptomless roots of apple, wheat, maize, marigold, cherry, and garlic plants, only 9 isolates showed inhibitory effect during preliminary screening and were further assayed under in vitro, pot, and field conditions against the white root rot pathogen/disease. Under in vitro conditions, maximum mycelial inhibition of 81.48% was obtained with the isolate Aspergillus aculeatus strain C2. Microscopic studies on interaction between fungal endophyte with hyphal tips of D. necatrix revealed various morphological abnormalities in the hyphae. In glasshouse conditions, seed treatment pursued by soil application with Crinipellis tabtim strain M8 isolate was highly effective and exhibited 93.55% disease control. Similarly, under field conditions, the overall maximum disease control was exhibited by Crinipellis tabtim strain M8 (84.95%). The most promising root endophytes that were identified rely on morphological and ITS sequence analysis. Root colonization assay was performed which revealed maximum endosphere and rhizosphere colonization with Crinipellis tabtim strain M8. Additionally, confocal microscopic illustrations of transverse sections of root cells tenanted by fungal endophytes as compared to untreated control suggested the persistence and establishment of endophytes in the endosphere of apple seedlings. These findings present the first report on colonization of apple roots by fungal root endophytes suggesting an alternative and sustainable approach for management of white root rot disease.
Efficacy of cinnamon oil and its active ingredient (cinnamaldehyde) on the cotton mealy bug Phenacoccus solenopsis Tinsley and the predator Chrysoperla carnea
Authors: Ghada Abd-Allah E. , Naglaa Youssef M.
Published: September 2020

Background

The importance of Chrysoperla carnea (Steph.) (Neuroptera: Chrysopidae) as a predator is due to nourishing this predator on some dangerous pests as the cotton mealybug, Phenacoccus solenopsis Tinsley, belongs to Hemiptera: Pseudococcidae. So the predator C. carnea was used in the management of various pests. The basic aim of this study was the indirect effect of some natural materials against some stages of C. carnea through feeding of the predator on the treated prey, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae).

Results

The results showed the comparison between the effectiveness of cinnamaldehyde and cinnamic oil in controlling the pest as soon as ineffectiveness on the predator. Cinnamaldehyde was very save against C. carnea which did not effect on the biology of it and the predator completed its life cycle as control (water + tween 80). Thus, the results suggested that cinnamaldehyde could be included in the Integrated Pest Management (IPM) Program without any adverse effect on bio-control agents used in an IPM.

Conclusion

This study may be a great alternative to chemical pesticides in controlling cotton mealybug, P. solenopsis, and at the same time, this material is saving to the predator C. carnea. This alternative is cinnamaldehyde (the active ingredient of cinnamon oil).
To reperfuse or not to reperfuse: a case report of Wellens’ syndrome with suspected COVID-19 infection
Authors: Suryawan I Gde Rurus , Bakhriansyah Jordan , Puspitasari Mia , Gandi Parama , Intan Ryan Enast , Alkaff Firas Farisi
Published: September 2020

Background

Wellens’ syndrome is known to be associated with left anterior descending artery occlusion that could lead to an extensive anterior wall myocardial infarction. Thus, emergency cardiac catheterization is needed. However, during coronavirus disease 2019 (COVID-19) pandemic, it is recommended for hemodynamically stable acute coronary syndrome patients with COVID-19 infection to be treated conservatively in an isolated hospital ward.

Case presentation

We report an 85-year-old patient with chief complaints of typical, squeezing chest pain in the past 4 h. The patient had a high fever, dyspnea, sore throat, and fatigue for 3 days. He had previously come into contact with COVID-19 positive relatives. The patient was hemodynamically stable and pulmonary auscultation revealed coarse rales in the entire lung. Electrocardiography (ECG) evaluation during the pain episode showed non-specific ST-T changes in lead V2-V5. After sublingual nitrate was administered, ECG evaluation during the pain-free period revealed a biphasic T wave inversion in lead V2 and V3. Laboratory workup showed elevated cardiac marker and leucopenia with neutrophilia and lymphopenia. Rapid immunochromatographic test and initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) evaluation from nasopharyngeal swab showed negative results. However, radiographic evaluations suggest the diagnosis of COVID-19 infection. While waiting for the second RT-PCR evaluation, the patient was diagnosed with Wellens’ syndrome with suspected COVID-19 infection. The patient was treated conservatively according to national guidelines and scheduled for elective cardiac catheterization. On the third day, the patient felt better and insisted on being discharged home. Ten days after discharged, the patient died of myocardial infarction.

Conclusion

Emergency cardiac catheterization should be done for patient with Wellens’ syndrome, regardless of the COVID-19 infection status.
A fast-marching eikonal solver for tilted transversely isotropic media
Authors: Waheed Umair bin
Published: September 2020

Fast and accurate traveltime computation for quasi-P waves in anisotropic media is an essential ingredient of many seismic processing and interpretation applications such as Kirchhoff modeling and migration, microseismic source localization, and traveltime tomography. Fast-sweeping methods are widely used for solving the anisotropic eikonal equation due to their flexibility in solving general equations compared to the fast-marching method. However, it has been observed that fast sweeping can be much less efficient than fast marching for models with curved characteristics and practical grid sizes. By representing a tilted transversely isotropic (TTI) equation as a sequence of elliptically isotropic (EI) eikonal equations, we determine that the fast-marching algorithm can be used to compute fast and accurate traveltimes for TTI media. The tilt angle is absorbed into the description of the effective EI model; therefore, the adopted approach does not compromise on the solution accuracy. Through tests on benchmark synthetic models, we test our fast-marching algorithm and discover considerable improvement in accuracy by using factorization and a second-order finite-difference stencil. The adopted methodology opens the door to the possibility of using the fast-marching algorithm for a wider class of anisotropic eikonal equations.
Emergency Embolization of Pelvic Vessels in Patients With Locally Advanced Cervical Cancer and Massive Vaginal Bleeding: A Case Series in a Latin American Oncological Center
Authors: Alméciga Adriana , Rodriguez Juliana , Beltrán Julián , Sáenz James , Merchán Abel , Egurrola Jorge , Burbano Javier , Trujillo Lina , Heredia Fernando , Pareja René
Published: September 2020

PURPOSE

Locally advanced cervical cancer may present with uncontrollable vaginal bleeding in up to 70% of cases. Pelvic vessel embolization has been used as an urgent maneuver for achieving fast hemostatic control. This report describes outcomes of selective pelvic vessel embolization in patients with severe bleeding due to a locally advanced cervical cancer.

METHODS

In this retrospective study, technical aspects, clinical variables, and bleeding-related morbidity were described. The frequency of recurrent disease and the vital status at 1 year of follow-up were determined. Analysis was performed with statistical software R, version 3.6.2. The setting was Instituto Nacional de Cancerología- Bogotá, Colombia, between January 2009 and July 2017.

RESULTS

A total of 47 patients were included. Median age was 44 years (range, 26-70 years). The pre-embolization median hemoglobin level was 7.9 g/dL (range, 5.0-11.3 g/dL). Blood transfusions were administered to 41 women (87.2%). Bleeding control was achieved in 95.7% of cases in the first 24 hours after the embolization. There were no major complications. In 17 cases (36.2%), minor complications were reported; the most common was pelvic pain. In 17.1% of cases, a second embolization was required. After 12 months of follow-up, 27.7% of patients were alive without disease, 44.7% were alive with disease, and 25.5% of them have died of cervical cancer progression.

CONCLUSION

Selective pelvic vessel embolization is a useful alternative in patients with locally advanced cervical cancer and life-threatening bleeding. Its impact on recurrent disease and death due to oncologic cause is not clear.