bluuebunny/crossref_metadata_2025 huggingface dataset:
Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure
Authors: Chao Yung-Mei , Wu Kay L. H. , Tsai Pei-Chia , Tain You-Lin , Leu Steve , Lee Wei-Chia , Chan Julie Y. H.
Published: May 2020

Background

Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring.

Methods

Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction.

Results

Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phoxsubunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension.

Conclusion

Dysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.
Correction to: The ‘can do, do do’ concept in COPD; quadrant interpretation, affiliation and tracking longitudinal changes
Authors: van ’t Hul Alex J. , Koolen Noortje H. , van Hees Jeroen W. , van den Borst Bram , Spruit Martijn A.
Published: May 2020

An amendment to this paper has been published and can be accessed via the original article.
Anticipating the impact of the COVID-19 pandemic on TB patients and TB control programmes
Authors: Togun Toyin , Kampmann Beate , Stoker Neil Graham , Lipman Marc
Published: May 2020

The COVID-19 pandemic has currently overtaken every other health issue throughout the world. There are numerous ways in which this will impact existing public health issues. Here we reflect on the interactions between COVID-19 and tuberculosis (TB), which still ranks as the leading cause of death from a single infectious disease globally. There may be grave consequences for existing and undiagnosed TB patients globally, particularly in low and middle income countries (LMICs) where TB is endemic and health services poorly equipped. TB control programmes will be strained due to diversion of resources, and an inevitable loss of health system focus, such that some activities cannot or will not be prioritised. This is likely to lead to a reduction in quality of TB care and worse outcomes. Further, TB patients often have underlying co-morbidities and lung damage that may make them prone to more severe COVID-19. The symptoms of TB and COVID-19 can be similar, with for example cough and fever. Not only can this create diagnostic confusion, but it could worsen the stigmatization of TB patients especially in LMICs, given the fear of COVID-19. Children with TB are a vulnerable group especially likely to suffer as part of the “collateral damage”. There will be a confounding of symptoms and epidemiological data through co-infection, as happens already with TB–HIV, and this will require unpicking. Lessons for COVID-19 could be learned from the vast experience of running global TB control programmes, while the astonishingly rapid and relatively well co-ordinated response to COVID-19 demonstrates how existing programmes could be significantly improved.
ApoE and apoC-III-defined HDL subtypes: a descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity
Authors: Amaya-Montoya Mateo , Pinzón-Cortés Jairo A. , Silva-Bermúdez Lina S. , Ruiz-Manco Daniel , Pérez-Matos Maria C. , Jiménez-Mora Mario A. , Mendivil Carlos O.
Published: May 2020

Background

The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans.

Methods

Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting.

Results

HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = − 0.55, P = 0.017) and E-C- alpha 1 HDL (r = − 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025).

Conclusions

The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.
The lack of selection criteria for surgery in patients with non-colorectal non-neuroendocrine liver metastases
Authors: Bohlok Ali , Lucidi Valerio , Bouazza Fikri , Daher Ali , Germanova Desislava , Van Laethem Jean Luc , Hendlisz Alain , Donckier Vincent
Published: May 2020

Background

The benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM.

Methods

Data for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence < 1 year postoperatively who did not benefit from surgery (N= 28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥ 5 years postoperatively and benefited from surgery (N= 20). Clinicopathologic parameters, the Association Française de Chirurgie (AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups.

Results

The majority of patients were female and a majority had an ASA score ≤ 2 at the time of liver surgery. The median age was 55 years. Almost half of the patients (46%) presented with a single-liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and 10-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were the size of liver metastases > 50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (scores 3–4) was predictive for the poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor, and the size of liver metastases was significantly higher in the ER group.

Conclusion

In patients with resectable NCRNNELM, no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit.
Using an equity-based framework for evaluating publicly funded health insurance programmes as an instrument of UHC in Chhattisgarh State, India
Authors: Nandi Sulakshana , Schneider Helen
Published: May 2020

Background

Universal health coverage (UHC) has provided the impetus for the introduction of publicly funded health insurance (PFHI) schemes in the mixed health systems of India and many other low- and middle-income countries. There is a need for a holistic understanding of the pathways of impact of PFHI schemes, including their role in promoting equity of access.

Methods

This paper applies an equity-oriented evaluation framework to assess the impacts of PFHI schemes in Chhattisgarh State by synthesising literature from various sources and highlighting knowledge gaps. Data were collected from an extensive review of publications on PFHI schemes in Chhattisgarh since 2009, including empirical studies from the first author’s PhD and grey literature such as programme evaluation reports, media articles and civil society campaign documents. The framework was constructed using concepts and frameworks from the health policy and systems research literature on UHC, access and health system building blocks, and is underpinned by the values of equity, human rights and the right to health.

Results

The analysis finds that evidence of equitable enrolment in Chhattisgarh’s PFHI scheme may mask many other inequities. Firstly, equitable enrolment does not automatically lead to the acceptability of the scheme for the poor or to equity in utilisation. Utilisation, especially in the private sector, is skewed towards the areas that have the least health and social need. Secondly, related to this, resource allocation patterns under PFHI deepen the ‘infrastructure inequality trap’, with resources being effectively transferred from tribal and vulnerable to ‘better-off’ areas and from the public to the private sector. Thirdly, PFHI fails in its fundamental objective of effective financial protection. Technological innovations, such as the biometric smart card and billing systems, have not provided the necessary safeguards nor led to greater accountability.

Conclusion

The study shows that development of PFHI schemes, within the context of wider neoliberal policies promoting private sector provisioning, has negative consequences for health equity and access. More research is needed on key knowledge gaps related to the impact of PFHI schemes on health systems. An over-reliance on and rapid expansion of PFHI schemes in India is unlikely to achieve UHC.
Farnesoid X receptor knockout protects brain against ischemic injury through reducing neuronal apoptosis in mice
Authors: Shan Hui-Min , Zang Minhua , Zhang Qi , Shi Ru-Bing , Shi Xiao-Jing , Mamtilahun Muyassar , Liu Chang , Luo Long-long , Tian Xiaoying , Zhang Zhijun , Yang Guo-Yuan , Tang Yaohui , Pu Jun , Wang Yongting
Published: May 2020

Background

Farnesoid X receptor (FXR) is a nuclear receptor that plays a critical role in controlling cell apoptosis in diverse diseases. Previous studies have shown that knocking out FXR improved cardiac function by reducing cardiomyocyte apoptosis in myocardial ischemic mice. However, the role of FXR after cerebral ischemia remains unknown. In this study, we explored the effects and mechanisms of FXR knockout (KO) on the functional recovery of mice post cerebral ischemia-reperfusion.

Methods

Adult male C57BL/6 wild type and FXR KO mice were subjected to 90-min transient middle cerebral artery occlusion (tMCAO). The mice were divided into five groups: sham, wild-type tMCAO, FXR KO tMCAO, wild-type tMCAO treated with calcium agonist Bayk8644, and FXR KO tMCAO treated with Bayk8644. FXR expression was examined using immunohistochemistry and Western blot. Brain infarct and brain atrophy volume were examined at 3 and 14 days after stroke respectively. Neurobehavioral tests were conducted up to 14 days after stroke. The protein levels of apoptotic factors (Bcl-2, Bax, and Cleaved caspase-3) and mRNA levels of pro-inflammatory factors (TNF-α, IL-6, IL-1β, IL-17, and IL-18) were examined using Western blot and RT-PCR. TUNEL staining and calcium imaging were obtained using confocal and two-photon microscopy.

Results

The expression of FXR was upregulated after ischemic stroke, which is located in the nucleus of the neurons. FXR KO was found to reduce infarct volume and promote neurobehavioral recovery following tMCAO compared to the vehicle. The expression of apoptotic and pro-inflammatory factors decreased in FXR KO mice compared to the control. The number of NeuN+/TUNEL+ cells declined in the peri-infarct area of FXR KO mice compared to the vehicle. We further demonstrated that inhibition of FXR reduced calcium overload and addition of ionomycin could reverse this neuroprotective effect in vitro. What is more, in vivo results showed that enhancement of intracellular calcium concentrations could aggravate ischemic injury and reverse the neuroprotective effect of FXR KO in mice.

Conclusions

FXR KO can promote neurobehavioral recovery and attenuate ischemic brain injury, inflammatory release, and neuronal apoptosis via reducing calcium influx, suggesting its role as a therapeutic target for stroke treatments.
Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale
Authors: Halappanavar Sabina , van den Brule Sybille , Nymark Penny , Gaté Laurent , Seidel Carole , Valentino Sarah , Zhernovkov Vadim , Høgh Danielsen Pernille , De Vizcaya Andrea , Wolff Henrik , Stöger Tobias , Boyadziev Andrey , Poulsen Sarah Søs , Sørli Jorid Birkelund , Vogel Ulla
Published: May 2020

Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test methods for hazard and risk assessment of nanomaterials.
EZH2-inhibitor DZNep enhances apoptosis of renal tubular epithelial cells in presence and absence of cisplatin
Authors: Chen Si-qi , Li Jia-qi , Wang Xiao-qiao , Lei Wen-jing , Li Hao , Wan Jiao , Hu Zheng , Zou Yao-wei , Wu Xiao-yu , Niu Hong-xin
Published: May 2020

Background

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers. However, the role of EZH2 in nonneoplastic diseases, such as kidney diseases, is unknown and has been investigated.

Materials and method

NRK-52E cells were treated with DZNep, a potent inhibitor of EZH2, with different concentrations and for different times to evaluate the apoptosis level of NRK-52E cells by Western blot and Flow cytometry analysis. The binding of EZH2 to the Deptor promoter was determined by ChIP assay.

Results

The inhibition of EZH2 with 3-deazaneplanocin A (DZNep), a specific inhibitor of EZH2, led to the apoptosis of NRK-52E cells and the inhibition of mTORC1 and mTORC2 activity. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region. Further experiments were performed to examine the effects of EZH2 inhibition on cisplatin-induced injured cells. Cisplatin induced the activation of mTORC1 and mTORC2 and apoptosis in NRK-52E cells, and DZNep inhibited mTORC1 and mTORC2 activity and aggravated cell apoptosis.

Conclusions

These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells. The inhibition of EZH2 aggravated the cisplatin-induced injury in renal tubular cells by inactivating the mTOR complexes. The present study provides new insight into renal protection and suggests that EZH2 might be a target.
Management of anal cancer patients – a pattern of care analysis in German-speaking countries
Authors: Martin Daniel , von der Grün Jens , Rödel Claus , Fokas Emmanouil
Published: May 2020

Background

Radiotherapy dose and target volume prescriptions for anal squamous cell carcinoma (ASCC) vary considerably in daily practice and guidelines, including those from NCCN, UK, Australasian, and ESMO. We conducted a pattern-of-care survey to assess the patient management in German speaking countries.

Methods

We developed an anonymous questionnaire comprising 18 questions on diagnosis and treatment of ASCC. The survey was sent to 361 DEGRO-associated institutions, including 41 university hospitals, 118 non-university institutions, and 202 private practices.

Results

We received a total of 101 (28%) surveys, including 20 (19.8%) from university, 36 (35.6%) from non-university clinics, and 45 (44.6%) from private practices. A total of 28 (27.8%) institutions reported to treat more than 5 patients with early-stage ASCC and 42 (41.6%) institutions treat more than 5 patients with locoregionally-advanced ASCC per year.

Biopsy of suspicious inguinal nodes was advocated in only 12 (11.8%) centers. Screening for human immunodeficiency virus (HIV) is done in 28 (27.7%). Intensity modulated radiotherapy or similar techniques are used in 97%. The elective lymph node dose ranged from 30.6 Gy to 52.8 Gy, whereas 87% prescribed 50.4–55. 8 Gy (range: 30.6 to 59.4 Gy) to the involved lymph nodes. The dose to gross disease of cT1 or cT2 ASCC ranged from 50 to ≥60 Gy. For cT3 or cT4 tumors the target dose ranged from 54 Gy to more than 60 Gy, with 76 (75.2%) institutions prescribing 59.4 Gy. The preferred concurrent chemotherapy regimen was 5-FU/Mitomycin C, whereas 6 (6%) prescribed Capecitabine/Mitomycin C. HIV-positive patients are treated with full-dose CRT in 87 (86.1%) institutions. First assessment for clinical response is reported to be performed at 4–6 weeks after completion of CRT in 2 (2%) institutions, at 6–8 weeks in 20 (19.8%), and 79 (78%) institutions wait up to 5 months.

Conclusions

We observed marked differences in radiotherapy doses and treatment technique in patients with ASCC, and also variable approaches for patients with HIV. These data underline the need for an consensus treatment guideline for ASCC.
Madelung’s disease and pulmonary aspergillosis: a case report and literature review
Authors: Ma Weijiang , Zhao Xilong , Li Xu , Zang Chenxi , Yang Limin , Wang Yan , Liu Xin
Published: May 2020

Background

Madelung’s disease (MD) is a rare disorder of fat metabolism, which is usually associated with diabetes, hyperuricemia, liver disease, nevertheless there is no report of a patient with MD and pulmonary aspergillosis (PA). This article aimed to enhance the awareness of this two diseases and discuss the possible mechanism of the combination of them preliminarily.

Case presentation

In this case, we described a 56-year-old male patient with cough, expectoration and dyspnea. His neck has a very peculiar appearance. Chest enhanced CT scan showed there were multiple nodules in both lungs, some of which had cavities and the mediastinal lymph nodes were swollen. Ultrasound scan of the neck showed diffuse hyperplasia of subcutaneous fat in neck and bilateral supraclavicular fossa. Fortunately, after performing pulmonary wedge resection aimed at pathological examination and giving relevant treatments, this patient was finally diagnosed as MD with PA, and his symptoms were significantly relieved.

Conclusions

MD is rare, the phenomenon that MD combined with PA is rarer. Immune disorder may be the possible mechanism.
Equine saliva components during mastication, and in vivo pH changes in the oral biofilm of sound and carious tooth surfaces after sucrose exposure
Authors: Lundström Torbjörn , Lingström Peter , Wattle Ove , Carlén Anette , Birkhed Dowen
Published: May 2020

Background

The role of saliva composition and dietary sugar in development of infundibular caries in equine cheek teeth is not fully understood. This study analysed electrolyte and urea concentrations in saliva in relation to different forage and measured pH changes after sucrose application in vivo in sound and carious cheek teeth.

Results

Forage type had no effect on the equine saliva electrolyte concentrations, which varied considerably both intra- and inter-individually. Chewing resulted in increased values for all electrolytes except bicarbonate. Compared with stimulated human saliva, horse saliva after mastication, contained higher amounts of potassium, calcium and bicarbonate, and less phosphate. The in vivo pH measurements showed a lower resting pH and a more pronounced pH drop after sucrose application in carious teeth compared to sound teeth.

Conclusions

No large differences were found between the composition of equine saliva and human saliva. A more pronounced acidogenicity was found for the carious than sound teeth. Thus, the caries process in equine cheek teeth seems to follow the same pattern as in human teeth, caused by acid production by oral microorganisms after sugar consumption.
Child marriage practices among the Rohingya in Bangladesh
Authors: Melnikas Andrea J. , Ainul Sigma , Ehsan Iqbal , Haque Eashita , Amin Sajeda
Published: May 2020

Background

Previous research suggests that child marriage may be accelerated during times of crisis and insecurity as resources are scarce and child marriage may be a survival strategy for girls and their families. In 2017, the Rohingya experienced a mass displacement to Bangladesh in response to escalating violence in Myanmar. This displacement has resulted in an estimated population of nearly 1 million Rohingya living in Cox’s Bazar.

Methods

We conducted in-depth interviews (n = 48) and focus group discussions (n = 12) with Rohingya male and female adolescents and young adults (14–24 years), and program managers and service providers (n = 24) working in Cox’s Bazar to understand their experience of living or working in the camps, preferences for timing of marriage, and marriage practices in Myanmar and in the camps. We also interviewed Bangladeshis in the host community to complement our understanding of marriage in the camps and its influence in the broader community. Our primary objective was to describe how displacement influenced marriage timing and practices.

Results

We found that child marriage is a strong cultural phenomenon among the Rohingya, primarily rooted in socio-cultural and religious beliefs around readiness for marriage. Although child marriage was practiced by the Rohingya in Myanmar, specific state law and oppression by military forces prevented many from marrying before age 18. Now this preference is more easily practiced in the camps in Bangladesh where the displaced Rohingya experience less marriage regulation. Host community participants perceive the presence of the Rohingya as encouraging both polygamy and child marriage in their communities, leading to tension among the host community.

Conclusions

Our findings support evidence that conflict and displacement increase child marriage in populations already vulnerable to child marriage by exacerbating gender inequities. However, our findings also suggest group norms around religious and cultural preferences for age at marriage play a significant role in post-displacement behaviors surrounding marriage.
Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice
Authors: Tribble James R. , Harder Jeffrey M. , Williams Pete A. , John Simon W. M.
Published: May 2020

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia following ocular hypertensive insults is unknown. To elucidate the molecular identity of microglia after long-term exposure to ocular hypertension, we used a mouse model of glaucoma (DBA/2 J). We performed RNA-sequencing of microglia mRNA from the optic nerve head at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD45lo/CD11b+/CD11c−). Furthermore, RNA-sequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults. Transcriptomic profiling of optic nerve head microglia mRNA identifies metabolic priming with marked changes in mitochondrial gene expression, and changes to phagocytosis, inflammatory, and sensome pathways. The data predict that many functions of microglia that help maintain tissue homeostasis are affected. Comparative analysis of these data with data from previously published whole optic nerve head tissue or monocyte-only samples from DBA/2 J mice demonstrate that many of the neuroinflammatory signatures in these data sets arise from infiltrating monocytes and not reactive microglia. Finally, our data demonstrate that prophylactic radiation therapy of DBA/2 J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. Together, our data provide a unique resource for the community to help drive further hypothesis generation and testing in glaucoma.
Constrained characteristic functions, multivariable interpolation, and invariant subspaces
Authors: Hu Jian , Wang Maofa , Wang Wei
Published: May 2020

In this paper, we present a functional model theorem for completely non-coisometric n-tuples of operators in the noncommutative variety $\mathcal{V}_{f,\varphi,\mathcal{I}}(\mathcal{H})$Vf,φ,I(H) in terms of constrained characteristic functions. As an application, we prove that the constrained characteristic function is a complete unitary invariant for this class of elements, which can be viewed as the noncommutative analogue of the classical Sz.-Nagy–Foiaş functional model for completely nonunitary contractions. On the other hand, we provide a Sarason-type commutant lifting theorem. Applying this result, we solve the Nevanlinna–Pick-type interpolation problem in our setting. Moreover, we also obtain a Beurling-type characterization of the joint invariant subspaces under the operators $B_{1},\ldots,B_{n}$B1,…,Bn, where the n-tuple $(B_{1},\ldots,B_{n})$(B1,…,Bn) is the universal model associated with the abstract noncommutative variety $\mathcal{V}_{f,\varphi,\mathcal{I}}$Vf,φ,I.
First detection of autochthonous extensively drug-resistant NDM-1 Pseudomonas aeruginosa ST235 from a patient with bloodstream infection in Italy, October 2019
Authors: Loconsole Daniela , Accogli Marisa , Monaco Monica , Del Grosso Maria , De Robertis Anna Lisa , Morea Anna , Capozzi Loredana , Del Sambro Laura , Simone Annarosa , De Letteriis Vincenzo , Quarto Michele , Parisi Antonio , Chironna Maria
Published: May 2020

Background

Pseudomonas aeruginosa (PA) is one of the most common and serious causes of healthcare-associated bacteremia. The emergence and dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) PA strains pose a major clinical concern. ST235-PA is a high-risk clone which shows a high capacity to acquire antibiotic resistance. Here we describe the first autochthonous New Delhi metallo-β-lactamase (NDM)-producing Pseudomonas aeruginosa ST235 identified in Italy.

Case presentation

In October 2019, a patient residing in an elderly health care and rehabilitation facility, was hospitalized and died from sepsis caused by an XDR-PA. The strain belonged to the high-risk clone sequence type ST235. Whole genome sequencing (WGS) revealed the presence of genes encoding NDM-1 and multiple β-lactamases, many clinically significant multidrug efflux pump complexes and also the virulence gene ExoU, which is associated with a high cytotoxic phenotype.

Conclusions

Few strains of NDM-1-PA have been identified worldwide, all belonging to ST235. The combination of ST235 and ExoU is a predictor of highly unfavorable prognosis. The potential spread of these high-risk clones in healthcare settings is worrisome because treatment options are limited. Early identification of high-risk clones could help in outbreaks investigation and infections control.
Physical Activity Intervention for Loneliness (PAIL) in community-dwelling older adults: a randomised feasibility study
Authors: Shvedko Anastasia V. , Thompson Janice L. , Greig Carolyn A. , Whittaker Anna C.
Published: May 2020

Background

Low quality social relationships in older adults are strongly associated with feelings of loneliness. Physical activity interventions could reduce loneliness and improve psychological well-being, among other health benefits. The aim of this study was to examine the feasibility of a Physical Activity Intervention for Loneliness (PAIL) in community-dwelling older adults at risk of loneliness.

Methods

The PAIL feasibility study was a 12-week randomized controlled feasibility trial (RCT) conducted in Birmingham, United Kingdom, from February 2018 to August 2018, and ran in two waves of data collection. Eligible participants were community-dwelling adults aged 60 years and older, sedentary (less than 20 min of moderate-to-vigorous PA (MVPA) a week), and at risk of loneliness. The intervention included once-weekly group walk and health education workshop up to 90 min per session in total, with a wait-listed (WL) control group. The primary feasibility outcomes were to estimate recruitment, retention rates and adherence to the intervention. Secondary outcome measures (not blinded assessment) were body mass index, blood pressure, physical activity and psychosocial variables. Process and outcome evaluations were conducted using focus groups interviews. The recruitment and retention progression criteria for the definitive large-scale RCT was set a-priori.

Results

Forty-eight participants were recruited over 4 months with a recruitment rate of 25% (48/195); 52% (25/48) met the inclusion criteria and 100% (25/25) were randomised into the intervention (n = 12) and WL control groups (n = 13). Participants were 25 older adults (mean (SD) 68.5(8.05) years), 14 (56%) female, and 18 (72%) white. At 12 weeks, 10/12 (83.3%) intervention and 10/13 (76.9%) control participants completed the final assessments. The average attendance rate was 58.3% for the intervention group (range 33.0%-75.0%) and 42.3% (range 23.1%–69.2%) among controls. The a priori recruitment and retention criteria for progression were not met. No serious adverse events occurred. The focus group results identified three themes which showed overall positive experiences of participation in PAIL in terms of (1) study design and intervention; (2) walking sessions; and (3) health education workshops.

Conclusions

The findings suggest that community-dwelling older adults at risk of loneliness found the intervention and measures acceptable and could safely participate. However, a more extensive and robust strategy would be needed to support adequate recruitment of lonely older adults and adherence into a definitive RCT.

Trial registration

Clinicaltrials.gov, NCT03458793
Improving the freight transport of a developing economy: a case of Boankra inland port
Authors: Ansah Richmond Kwesi , Obiri-Yeboah Kwabena , Akipelu Grace
Published: May 2020

Purpose

Shippers and Freight Forwarding Agents spend much time clearing their cargo from the Ghanaian ports. As a result, the cost of doing business in Ghana through the Tema and Takoradi ports is high. This research investigates the potential impact the establishment of an inland port will have on a reduction in congestion at the Tema and Takoradi ports and on the efficiency of the freight transport system.

Methodology/approach

This study used questionnaires to gather data through an experience survey conducted at the Ghana Sea Ports and Boankra inland port.

Findings

The study found out that for the inland Port to work effectively, there should be a connection from the Boankra inland port to the Takoradi and Tema Sea Ports as well as the container depots of the neighboring landlocked Sub-Saharan African Countries.. The study discovered that the implementation of the Boankra inland port will result in the decongestion and efficiency of Ghanaian seaports. Factors such as the increase in skills and experience of personnel; the use of management information systems; formulation of programmes and policies in decongesting the two main Ghanaian seaports; enhanced road network; adaptation of new technologies in the cargo handling process; and reduced bureaucracy in clearing processes at the ports are arbitrating factors through which the establishment of the Boankra inland port may have an impact on the seaports and the Freight transport industry at large. It was found that the challenges which may impede the improvement of freight transport in Ghana are inefficiencies and distortions in the trading system; unnecessary bureaucratic clearing processes; weak regulatory framework; Poor quality control;, inadequate staff; political interference, and lack of capital. It was found that for the Boankra Inland Port to be efficient, the officials and stakeholders must be trained; the various institutions in the transport chain must be empowered; corruption among port officials must be managed; there must be minimal political interference in the port operations; there must be more investment into the freight transport system; and there must be trade regulations to govern the freight transport system.

Originality

This novel study differentiates itself from existing studies on Port System by focusing on inland ports in Africa and their influence on the efficiency and decongestion of seaports.
Patient adherence to antihypertensive medications in upper Egypt: a cross-sectional study
Authors: Hussein Ahmed , Awad Mohammad Shafiq , Mahmoud Hossam Eldin M.
Published: May 2020

Background

Control of hypertension is a very difficult issue. Non-adherence to medications is a well-recognized factor contributing to uncontrolled hypertension. It is required to detect factors that affect adherence of patients to antihypertensive medications at different societies and good planning with the collaboration of governments, universities, media, pharmaceutical companies, and civil society to create intervention programs ensuring good adherence to medications. In our study, we aimed to determine different factors affecting adherence to antihypertensive medications in Upper Egypt societies.

Results

From September 2015 to September 2019, we conducted a large cross-sectional multi-center study among 2420 hypertensive patients attending the out-patient cardiac clinics at three different university hospitals. Data was collected through a personal interview with the patients using a questionnaire to cover a variety of items.

In the total of 2420 patients, we found that 1116 (46.12%) patients were adherent to medications and 1304 (53.88%) were non-adherent. From the final regression analysis of the results, we found that age > 65 years, illiterate patients, low income, associated comorbidities, using three or more antihypertensive pills, and living in rural areas were statistically significant socio-demographic factors associated with non-adherence to treatment. Also, missing doses of medication and lack of complying with dietary regimen were statistically significant behavioral causes associated with non-adherence.

Conclusion

Many factors are predictors of good adherence to antihypertensive drugs, including young age, urban residence, a smaller number of pills, absence of comorbid conditions, high income, and high education level. Also missed doses of drugs and absence of complies with dietary regimen were the significant causes of non-adherence. Health institutions and governmental efforts should be directed toward improving adherence by creating effective intervention programs targeting these factors. Therefore, it might be concluded that patients who are more health ware are more adherent to medications than non-health aware patients.
Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI+PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy.
Authors: Pires Da Silva Ines , Ahmed Tasnia , Lo Serigne , Reijers Irene L.M. , Weppler Alison , Betof Warner Allison , Patrinely James Randall , Serra-Bellver Patricio , Lebbe Celeste , Mangana Joanna , Nguyen Khang , Zimmer Lisa , Ascierto Paolo Antonio , Stout Dan , Lyle Megan , Klein Oliver , Gerard Camille Lea , Blank Christian U. , Menzies Alexander M. , Long Georgina V.
Published: May 2020

10005

Background: PD1 induces long-term responses in approximately 30% of MM pts, however 2/3 are resistant (innate or acquired) and will require further treatment. A subset of these pts will benefit from IPI or IPI+PD1, but these pts are yet to be identified. We sought to determine; i) response rate (RR) and survival to IPI+/-PD1 after PD1 progression, and ii) clinical predictors of response and survival to IPI+/-PD1. Methods: MM pts resistant to PD1 and then treated with IPI+/-PD1 were studied. Demographics, disease characteristics and baseline blood parameters were examined. Univariate, multivariate and backward elimination technique analyses were performed to create predictive models of response and overall survival (OS). Results: Of 330 MM pts resistant to PD1 (median time to prog 2.9 months [0.5 – 42.3], 12% adjuvant, 88% metastatic; 70% innate, 30% acquired), 161 (49%) had subsequent IPI and 169 (51%) had IPI+PD1. Characteristics at start of IPI+/-PD1 were similar in IPI vs IPI+PD1 groups (stage M1D 27% vs 34%; elevated LDH 38% vs 40%), except IPI group had more ECOG ≥1 (60% vs 34%) and less BRAF mutation (mut) (21% vs 37%). Median follow-up from start of IPI+/-PD1 was 22.3 months (19.8 - 25.8); RR was 22%, higher in IPI+PD1 (31%) vs IPI (12%) (p < 0.01). PFS and OS at 1 year were 20% and 48%, respectively; better with IPI+PD1 (27%/57%) vs IPI (13%/38%) (p < 0.01). PD1 setting (adjuvant/metastatic) and response did not impact response to IPI+/-PD1. Most pts progressing on adjuvant PD1 had IPI+PD1 (88%) and RR was 33%. Neither the interval between PD1 and IPI+/-PD1 nor use of other drugs affected response to IPI+/-PD1. RR was similar in BRAF WT (23%) vs BRAF mut (RR 21%) pts. In BRAF WT pts, RR was higher with IPI+PD1 vs IPI (38% vs 9%, p < 0.01), while RR was similar with IPI (24%) or IPI+PD1 (19%) in BRAF mut pts. One third of BRAF mut pts had BRAF inhibitors (BRAFi) prior to IPI+/-PD1 and lower RR (13%) vs those without BRAFi (RR = 25%, p > 0.05). High grade (≥G3) toxicity (tox) was similar with IPI+PD1 (30%) or IPI (34%, p = 0.48), and was not associated with response. Stage III/M1A/M1B, normal LDH and treatment with IPI+PD1 were the best predictors of response (AUC = 0.69). These factors, in addition to sex (male), ECOG PS = 0, BRAF mut, progressed/recurred > 3 months on PD1, and absence of bone mets were the best predictors of longer OS (AUC = 0.74). Conclusions: In pts resistant to PD1, IPI+PD1 has higher RR, longer survival, yet similar high grade tox than IPI alone. Predictive models of response & survival will help select pts for IPI+/-PD1 after progressing on PD1.
Autoantibodies as predictors for survival and immune-related adverse events in checkpoint inhibition therapy of metastasized melanoma.
Authors: Hassel Jessica Cecile , Zucht Hans-Dieter , Mangana Joanna , Dummer Reinhard , Pföhler Claudia , Wistuba-Hamprecht Kilian , Weide Benjamin , Hakim-Meibodi Lara Elena , Meier Friedegund Elke , Schulz Carsten , Bräutigam Manuel , Budde Petra
Published: May 2020

10011

Background: Increasing evidence suggests that the B cell response in cancer patients is an important component of anti-tumour immunity. Autoantibodies targeting tumour and self-antigens may serve as biomarkers of anti-tumour and auto-immunity. As they can be measured in patient' sera, they have great potential as clinical routine biomarkers. The objective of this study was to explore if autoantibodies are associated with survival and immune related adverse events (irAE) in patients with metastatic melanoma under checkpoint inhitibor (CPI) therapy. Methods: Pre-treatment serum samples from 333 metastatic melanoma patients receiving CPI therapy at 5 European centers were retrospectively used to identify autoantibody signatures for survival and irAE. We designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumour antigens as well as immune and cancer pathway proteins. Statistical tests were separately performed for patients treated with anti-CTLA4 (alone or in combination) and with anti-PD1 antibody monotherapy. Cox-regression analysis and univariate statistical tests were applied for biomarker discovery. Progression free and overall survival was measured from treatment initiation to tumor progression or death date. irAE were recorded including onset date and grade (CTC-AE). Results: For each therapy group we identified a set of autoantibody reactivities in untreated melanoma patients that were associated with the development of irAEs and/or survival. The identified autoantibodies target a diverse set of antigens comprising neoantigens (p53), cancer testis antigens (MAGEB4), paraneoplastic antigens (gephyrin), autoantigens (ribosomal proteins, Nor-90) and FGFR1. Autoantigens that correlated with irAE and survival were e.g. anti-MAGEB4 and anti-FGFR1. Elevated anti-MAGEB4 pre-treatment levels were associated with longer overall survival (p = 0.002, HR = 0.77) and the development of irAEs (p = 0.002, HR = 1.27) in ipilimumab +/- nivolumab treated patients. Higher pre-treatment anti-FGFR1 antibodies were associated with shorter survival (p = 0.008, HR = 1.27) and a lower a lower frequency of irAEs (p = 0.04, HR = 0.69) in these patients. Conclusions: We identified autoantibody targets suggesting a diverse B cell response to antigens expressed in tumours and those associated with autoimmunity. Depending on the specific antigen, the immune response towards those antigens may be associated with anti-tumour or pro-tumour responses.