bluuebunny/crossref_metadata_2025 huggingface dataset:
Burden of HPV related anogenital diseases in young women in Germany – an analysis of German statutory health insurance claims data from 2012 to 2017
Authors: Reuschenbach Miriam , Mihm Sarah , Wölle Regine , Schneider Kim Maren , Jacob Christian , Braun Sebastian , Greiner Wolfgang , Hampl Monika
Published: April 2020

Background

Most individuals are infected with human papillomavirus (HPV) at least once in their lifetime. Infections with low-risk types can cause genital warts, whereas high-risk types can cause malignant tumors. The aim of this study was to determine the burden of anogenital diseases potentially related to HPV in young women based on German statutory health insurance claims data.

Methods

We conducted a retrospective claims data analysis using the “Institute for Applied Health Research Berlin” (InGef) Research Database, containing claims data from approximately 4 million individuals. In the period from 2012 to 2017 all women born in1989–1992, who were continuously insured between the age of 23–25 years were identified. Using ICD-10-GM codes (verified diagnosis in the outpatient sector or primary or secondary diagnosis in the inpatient sector) the administrative prevalence (95% confidence interval) of genital warts (A63.0), anogenital diseases grade I (K62.8, N87.0, N89.0, N90.0), grade II (N87.1, N89.1, N90.1) and grade III (D01.3, D06.-, D06.0, D07.1, D07.2, N87.2, N89.2, N90.2) was calculated (women with diagnosis divided by all women).

Results

From 2012 to 2017, a total of 15,358 (birth cohort 1989), 16,027 (birth cohort 1990), 14,748 (birth cohort 1991) and 14,862 (birth cohort 1992) women at the age of 23–25 were identified. A decrease of the administrative prevalence was observed in genital warts (1.30% (1.12–1.49) birth cohort 1989 vs. 0.94% (0.79–1.10) birth cohort 1992) and anogenital diseases grade III (1.09% (0.93–1.26) birth cohort 1989 vs. 0.71% (0.58–0.86) birth cohort 1992). In anogenital diseases grade III, this trend was especially observed for severe cervical dysplasia (N87.2) (0.91% (0.76–1.07) birth cohort 1989 vs. 0.60% (0.48–0.74) birth cohort 1992). In contrast, anogenital diseases grade I (1.41% (1.23–1.61) birth cohort 1989 vs. 1.31% (1.14–1.51) birth cohort 1992) and grade II (0.61% (0.49–0.75) birth cohort 1989 vs. 0.52% (0.42–0.65) birth cohort 1992) remained stable.

Conclusions

A decrease of the burden of anogenital disease potentially related to HPV was observed in the younger birth cohorts. This was observed especially for genital warts and anogenital diseases grade III. Further research to investigate this trend for the upcoming years in light of varying HPV vaccination coverage for newer birth cohorts is necessary.
Comparison of choriocapillary flow density between fellow eyes of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration
Authors: Luo Mingyue , Zhao Xinyu , Zhao Nan , Yuan Mingzhen , Yang Jingyuan , Dai Rongping , Chen Youxin
Published: April 2020

Background

To compare the choriocapillary flow density (CFD) among the fellow eyes of polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), and healthy controls using spectral-domain optical coherence angiography tomography (SD-OCTA).

Methods

This is a cross-sectional study that includes the fellow eyes of 38 patients with unilateral PCV, 36 patients with unilateral nAMD, and 36 eyes from 36 healthy volunteers. The PCV group was further classified into polypoidal CNV (P-CNV) and typical PCV (T-PCV) for subgroup analysis. The age, subfoveal choroidal thickness (SFCT), Age-Related Eye Disease Study (AREDS) classification, and fellow eye diagnosis were acquired. All subjects underwent SD-OCTA with a 6.0-mm scan pattern. Circles with radius of 1.00, 1.50, and 3.00 mm were manually selected in the choriocapillaris (CC) slab, and the CFD was calculated as the percentage of the flow area to the whole selected area as CFD-1.00, 1.50, and 3.00, respectively. Univariate and multivariate analysis were performed to study the correlation between the aforementioned factors with CFD.

Results

The mean CFD-1.00, 1.50, and 3.00 of the nAMD group were 61.51, 63.18, and 66.20, respectively; these were significantly lower than those of the PCV group (65.90, 66.89, and 67.94; P < 0.001, P < 0.001, and P = 0.010; respectively) and control group (66.28, 66.96, and 68.42; P < 0.001, P < 0.001, and P = 0.001, respectively), and no difference was detected between the PCV and control group or between PCV subtypes. The AREDS classification and fellow eye diagnosis were correlated with CFD in univariate analysis; however, only the fellow eye diagnosis showed a significant correlation after multiple linear regression.

Conclusions

The CFD of nAMD fellow eyes was significantly lower than that of PCV and control eyes, and no difference was detected between PCV and control group, indicating that CC loss plays a different role in the early pathogenesis of nAMD and PCV.
Histopathologic study of extraocular muscles in thyroid-associated ophthalmopathy coexisting with ocular myasthenia gravis: a case report
Authors: Ma Ruiqi , Cheng Yun , Gan Lu , Zhou Xiaoting , Qian Jiang
Published: April 2020

Background

Coexistence of thyroid-associated ophthalmopathy (TAO) and ocular myasthenia gravis (OMG) is very rare. Little is known about the orbital histopathology associated with this condition. The authors reported a case of TAO coexisting with OMG and explored the histopathologic changes in extraocular muscles.

Case presentation

A 32-year-old man complaint of bilateral proptosis for 2 years. The patient was documented with a history of OMG and was treated with blepharoplasty to correct ptosis 3 years prior to presentation. Physical examination revealed right upper eyelid retraction resulting from the eyelid surgery. Computed tomographic scan demonstrated bilateral enlargement of the extraocular muscles. Thyroid function test confirmed hyperthyroid status. The patient was diagnosed with TAO (clinical activity score = 2/7) coexisting with OMG. Orbital decompression surgery reduced proptosis but resulted in new onset of left upper eyelid retraction because of the increased motor impulses to sustain eyelid elevation. Extraocular muscles were sampled during surgery and subjected to histopathologic stain. The stain results were analyzed against samples from age-, gender- matched TAO and control (non-TAO non-OMG) subjects. The measurement of myofiber size and glycosaminoglycan/collagen-occupied area was repeated in 3 randomly chosen fields of each slide. The variation of myofiber size was larger in the TAO + OMG (289.9 ± 142.5 μm2) samples than the TAO (544.1 ± 160.6 μm2) and control (157.0 ± 47.7 μm2) samples. Glycosaminoglycan was more abundant in the TAO + OMG (48.8 ± 12.2%) samples than the TAO (28.4 ± 3.6%) and control (3.3 ± 0.8%) samples. Collagen fibers accumulated in the TAO (60.5 ± 6.4%) samples but not in the TAO + OMG (36.1 ± 4.3%) and control (33.9 ± 2.7%) samples. Typical OMG changes were observed in the TAO + OMG samples but not in the TAO and control samples. These changes included central nuclei, aggregation of mitochondria and fiber type grouping. The histopathologic findings of TAO + OMG were summarized as inhomogeneously enlarged muscle fibers and predominantly endomysial accumulation of glycosaminoglycan.

Conclusion

This study highlights the possibility of TAO coexisting with OMG and demonstrates the histopathologic features in this rare condition.
Malaria elimination using the 1-3-7 approach: lessons from Sampov Loun, Cambodia
Authors: Kheang Soy Ty , Sovannaroth Siv , Barat Lawrence M. , Dysoley Lek , Kapella Bryan K. , Po Ly , Nguon Sokomar , Gimnig John , Slot Rida , Samphornarann Top , Meng Seak Kong , Dissanayake Gunawardena , AlMossawi Hala Jassim , Longacre Colleen , Kak Neeraj
Published: April 2020

Background

Cambodia has targeted malaria elimination within its territory by 2025 and is developing a model elimination package of strategies and interventions designed to achieve this goal.

Methods

Cambodia adopted a simplified 1-3-7 surveillance model in the Sampov Loun operational health district in western Cambodia beginning in July 2015. The 1-3-7 approach targets reporting of confirmed cases within one day, investigation of specific cases within three days, and targeted control measures to prevent further transmission within seven days. In Sampov Loun, response measures included reactive case detection (testing of co-travelers, household contacts and family members, and surrounding households with suspected malaria cases), and provision of health education, and insecticide-treated nets. Day 28 follow up microscopy was conducted for all confirmed P. falciparum and P. falciparum-mixed-species malaria cases to assess treatment efficacy.

Results

The number of confirmed malaria cases in the district fell from 519 in 2015 to 181 in 2017, and the annual parasite incidence (API) in the district fell from 3.21 per 1000 population to 1.06 per 1000 population. The last locally transmitted case of malaria in Sampov Loun was identified in March 2016. In response to the 408 index cases identified, 1377 contacts were screened, resulting in the identification of 14 positive cases. All positive cases occurred among index case co-travelers.

Conclusion

The experience of the 1-3-7 approach in Sampov Loun indicates that the basic essential malaria elimination package can be feasibly implemented at the operational district level to achieve the goal of malaria elimination in Cambodia and has provided essential information that has led to the refinement of this package.
Effectiveness and cost-effectiveness of stratified blended physiotherapy in patients with non-specific low back pain: study protocol of a cluster randomized controlled trial
Authors: Koppenaal Tjarco , Arensman Remco M. , van Dongen Johanna M. , Ostelo Raymond W. J. G. , Veenhof Cindy , Kloek Corelien J. J. , Pisters Martijn F.
Published: April 2020

Background

Patient education, advice on returning to normal activities and (home-based) exercise therapy are established treatment options for patients with non-specific low back pain (LBP). However, the effectiveness of physiotherapy interventions on physical functioning and prevention of recurrent events largely depends on patient self-management, adherence to prescribed (home-based) exercises and recommended physical activity behaviour. Therefore we have developed e-Exercise LBP, a blended intervention in which a smartphone application is integrated within face-to-face care. E-Exercise LBP aims to improve patient self-management skills and adherence to exercise and physical activity recommendations and consequently improve the effectiveness of physiotherapy on patients’ physical functioning. The aim of this study is to investigate the short- (3 months) and long-term (12 and 24 months) effectiveness on physical functioning and cost-effectiveness of e-Exercise LBP in comparison to usual primary care physiotherapy in patients with LBP.

Methods

This paper presents the protocol of a prospective, multicentre cluster randomized controlled trial. In total 208 patients with LBP pain were treated with either e-Exercise LBP or usual care physiotherapy. E-Exercise LBP is stratified based on the risk for developing persistent LBP. Physiotherapists are able to monitor and evaluate treatment progress between face-to-face sessions using patient input from the smartphone application in order to optimize physiotherapy care. The smartphone application contains video-supported self-management information, video-supported exercises and a goal-oriented physical activity module. The primary outcome is physical functioning at 12-months follow-up. Secondary outcomes include pain intensity, physical activity, adherence to prescribed (home-based) exercises and recommended physical activity behaviour, self-efficacy, patient activation and health-related quality of life. All measurements will be performed at baseline, 3, 12 and 24 months after inclusion. An economic evaluation will be performed from the societal and the healthcare perspective and will assess cost-effectiveness of e-Exercise LBP compared to usual physiotherapy at 12 and 24 months.

Discussion

A multi-phase development and implementation process using the Center for eHealth Research Roadmap for the participatory development of eHealth was used for development and evaluation. The findings will provide evidence on the effectiveness of blended care for patients with LBP and help to enhance future implementation of blended physiotherapy.

Trial registration

ISRCTN, ISRCTN94074203. Registered 20 July 2018 – Retrospectively registered.
Disseminating research findings using a massive online open course for maximising impact and developing recommendations for practice
Authors: Preston Nancy , Hasselaar Jeroen , Hughes Sean , Kaley Alex , Linge-Dahl Lisa , Radvanyi Ildiko , Tubman Phil , Van Beek Karen , Varey Sandra , Payne Sheila
Published: April 2020

Background

Developing recommendations for how we deliver healthcare is often left to leading experts in a field. Findings from the Integrated Palliative Care in cancer and chronic conditions (InSup-C) study, which aimed to identify best practice in integrated palliative care in cancer, chronic obstructive pulmonary disease (COPD) and heart failure, led to recommendations developed through an expert consultation process. We also wanted to develop these recommendations further with participants who were largely clinicians and members of the public.

Methods

Results from the InSup-C study were disseminated through a three-week massive open online course (MOOC) which ran in 2016, 2017 and 2019. The first course helped develop the final recommendations, which were ranked by MOOC participants in the subsequent courses. MOOC participants were predominantly clinicians, but also academics and members of the public. They rated how important each recommendation was on a 9 point scale (9 most important). Descriptive statistics were used to analyse the ratings. The results were compared to findings from the consultation.

Results

Five hundred fifteen completed the last part of the course where the recommendations were ranked, of which 195 (38%) completed the ratings. The top recommendations related to: need to expand palliative care to non-malignant conditions; palliative care needs to include different dimensions of care including physical, psychological and spiritual; policies and regulations assessments should be made regularly; palliative care integration should be mandatory; and there should be greater availability of medicines. These differed compared to the top ranked recommendations by the consultation panel in relation to the importance of leadership and policy making. This may indicate that clinicians are more focused on daily care rather than the (inter) national agenda.

Conclusions

Whilst both sets of recommendations are important, our study shows that we need to include the views of clinicians and the public rather than rely upon leading expert opinion alone. To keep recommendations fresh we need both the input of clinicians, the public and experts. When disseminating findings, MOOCs offer a useful way to gain greater reach with clinicians and the public, and importantly could be a vehicle to validate recommendations made by leading expert panels.
Transmissibility and pathogenicity of the emerging meningococcal serogroup W sequence type-11 complex South American strain: a mathematical modeling study
Authors: Domenech de Cellès Matthieu , Campbell Helen , Borrow Ray , Taha Muhamed-Kheir , Opatowski Lulla
Published: April 2020

Background

The recent emergence of strains belonging to the meningococcal serogroup W (MenW) sequence type-11 clonal complex and descending from the South American sub-lineage (MenW:cc11/SA) has caused significant shifts in the epidemiology of meningococcal disease worldwide. Although MenW:cc11/SA is deemed highly transmissible and invasive, its epidemiological characteristics have not yet been quantified.

Methods

We designed a mathematical model of MenW transmission, carriage, and infection to analyze the recent epidemiology of invasive disease caused by MenW:cc11/SA strains and by other MenW strains in England and in France. We confronted that model with age-stratified incidence data to estimate the transmissibility and the invasiveness of MenW:cc11/SA in England, using the data in France as a validation cohort.

Results

During the epidemiological years 2010/2011–2014/2015 in England, the transmissibility of MenW:cc11/SA relative to that of other MenW strains was estimated at 1.20 (95% confidence interval, 1.15 to 1.26). The relative invasiveness of MenW:cc11/SA was also found to exceed unity and to increase with age, with estimates ranging from 4.0 (1.6 to 9.7) in children aged 0–4 years to 20 (6 to 34) in adults aged ≥ 25 years. In France, the model calibrated in England correctly reproduced the early increase of MenW:cc11/SA disease during 2012/2013–2016/2017. Most recent surveillance data, however, indicated a decline in MenW:cc11/SA disease. In both countries, our results suggested that the transmission of MenW:cc11/SA carriage possibly started several months before the first reported case of MenW:cc11/SA disease.

Discussion

Our results confirm earlier suggestions about the transmission and the pathogenic potential of MenW:cc11/SA. The main limitation of our study was the lack of age-specific MenW carriage data to confront our model predictions with. Furthermore, the lesser model fit to the most recent data in France suggests that the predictive accuracy of our model might be limited to 5–6 years.

Conclusions

Our study provides the first estimates of the transmissibility and of the invasiveness of MenW:cc11/SA. Such estimates may be useful to anticipate changes in the epidemiology of MenW and to adapt vaccination strategies. Our results also point to silent, prolonged transmission of MenW:cc11/SA carriage, with potentially important implications for epidemic preparedness.
Effects of hydrolyzed fish protein and autolyzed yeast as substitutes of fishmeal in the gilthead sea bream (Sparus aurata) diet, on fish intestinal microbiome
Authors: Rimoldi S. , Gini E. , Koch J. F. A. , Iannini F. , Brambilla F. , Terova G.
Published: April 2020

Background

This study evaluated the effects of partial substitution of dietary fishmeal (FM) with either fish protein hydrolysate (FPH) or autolysed dried yeast (HiCell®, Biorigin, Brazil) on intestinal microbiota of gilthead sea bream (Sparus aurata). A total number of 720 fish of 122.18 ± 6.22 g were fed for 92 days with three different diets in triplicate (3 tanks/diet). A diet based on FM/vegetable meal was used as control. The other two diets were formulated by replacing FM with 5% of either FPH or HiCell®. To analyze the gut microbiota associated to autochthonous and allochthonous microbial communities, the Illumina MiSeq platform for sequencing of 16S rRNA gene and QIIME pipeline were used.

Results

A total number of 102 OTUs (operational taxonomic units) at 97% identity were identified in fish gut samples collected at the end of feeding trial. Fourteen OTUs constituted the core gut microbiota, i.e. those OTUs found in at least nine out of fifteen samples per group and shared regardless of the diet. Eight OTUs were assigned to Firmicutes represented by Lactobacillus, Staphylococcus, and Bacillus genera, and six to Proteobacteria phylum. Dietary dried yeast autolysate modulated the intestinal microbiota by promoting the growth of some beneficial bacteria. At order level, fish fed yeast showed an enrichment in Bacillales and Clostridiales as compared to the control group, whereas fish fed FPH showed a significantly lower amount of bacteria belonging to Alteromonadales and Enterobacteriales than the other two feeding groups. Although we did not observe any effect of 5% FM replacement with alternative nitrogen sources at phylum level, at lower taxonomical levels, the composition of gut microbiota, in terms of relative abundance of specific taxa, was significantly influenced by the dietary treatment.

Conclusions

The metabarcoding analysis revealed a clearly intestinal microbiota modulation in response to dietary autolyzed yeast. The abundance of some beneficial bacteria, i.e. indigestible carbohydrate degrading- and SCFA producing bacteria, was positively affected. Brewer’s yeast autolysate could be a valid alternative protein source to FM as well as a valid functional ingredient for aquafeed production.
Adherence to the dietary approaches to stop hypertension (DASH) diet in relation to all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective cohort studies
Authors: Soltani Sepideh , Arablou Tahereh , Jayedi Ahmad , Salehi-Abargouei Amin
Published: April 2020

Background

Although previous investigations have proposed an association between Dietary Approaches to Stop Hypertension (DASH)-style diet and lower mortality from chronic diseases, the exposure-response relationship is not clear. The present systematic review andmeta-analysis aimed to explore the linear and non-linear dose-responseassociation between adherence to the DASH diet andall-cause and cause-specific mortality.

Methods

Database search was performed in PubMed, Scopus, and EMBASE for prospective cohort studies investigating the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and risk of mortality. Summary hazard ratios (HRs) and 95% confidence intervals (CI) were estimated with the use of a random-effects model for the linear and nonlinear relationships. The two-stage hierarchical regression model was applied to test the potential non-linear dose-response associations.

Results

The inclusion criteria were met by 17 studies (13 publications). The scores reported for adherence to the DASH diet in different studies were converted to a conventional scoring method in which the adherence score might range between 8 to 40. The linear analysis revealed that summary HRs were 0.95 (95% CI: 0.94–0.96, I2 = 91.6%,n = 14) for all-cause, 0.96 (95% CI: 0.95–0.98, I2 = 82.4%,n = 12) for CVD, 0.97 (95% CI: 0.96–0.98, I2 = 0.00%,n = 2) for stroke, and 0.97 (95% CI: 0.95–0.98, I2 = 63.7%,n = 12) for cancer mortality per each 5-point increment of adherence to the DASH diet. There was also evidence of non-linear associations between the DASH diet and all-cause and cause-specific mortality as the associations became even more evident when the adherence scores were more than 20 points (P < 0.005).

Conclusion

Even the modest adherence to the DASH diet is associated with a lower risk of all-cause and cause-specific mortality. The higher adherence to the diet also strengthens the risk-reducing association.

Registration

This review was registered in the international prospective register of systematic reviews (PROSPERO) database (registration ID: CRD42018086500).
Reducing exposure to high levels of perfluorinated compounds in drinking water improves reproductive outcomes: evidence from an intervention in Minnesota
Authors: Waterfield Gina , Rogers Martha , Grandjean Philippe , Auffhammer Maximilian , Sunding David
Published: April 2020

Background

Per- and polyfluoroalkyl substances (PFASs) have been detected in drinking water supplies around the world and are the subject of intense regulatory debate. While they have been associated with several illnesses, their effects on reproductive outcomes remains uncertain.

Methods

We analyzed birth outcomes in the east Minneapolis-St. Paul metropolitan area from 2002 to 2011, where a portion of the population faced elevated exposure to PFASs due to long-term contamination of drinking water supplies from industrial waste disposal. Installation of a water filtration facility in the highly contaminated city of Oakdale, MN at the end of 2006 resulted in a sharp decrease in exposure to PFASs, creating a “natural experiment”. Using a difference-in-differences approach, we compare the changes in birth outcomes before and after water filtration in Oakdale to the changes over the same period in neighboring communities where the treatment of municipal water remained constant.

Results

Average birth weight and average gestational age were statistically significantly lower in the highly exposed population than in the control area prior to filtration of municipal water supply. The highly exposed population faced increased odds of low birth weight (adjusted odds ratio 1.36, 95% CI 1.25–1.48) and pre-term birth (adjusted odds ratio 1.14, 95% CI 1.09–1.19) relative to the control before filtration, and these differences moderated after filtration. The general fertility rate was also significantly lower in the exposed population (incidence rate ratio 0.73, 95% CI 0.69–0.77) prior to filtration and appeared to be rebounding post-2006.

Conclusions

Our findings provide evidence of a causal relationship between filtration of drinking water containing high levels of exposure to PFASs and improved reproductive outcomes.
Questions for future evidence-informed policy initiatives: insights from the evolution and aspirations of National Immunization Technical Advisory Groups
Authors: Buffardi Anne L. , Njambi-Szlapka Susan
Published: April 2020

Background

Attention to evidence-informed policy has grown; however, efforts to strengthen the quality and use of evidence are not starting from a blank slate. Changes in health architectures and financing pose different considerations for investments in evidence-informed policy than in the past. We identify major trends that have shifted the environment in which health policies are made, and use the evolution and future aspirations of National Immunization Technical Advisory Groups (NITAGs) in low- and middle-income countries to identify questions the sector must confront when determining how best to structure and strengthen evidence-informed health policy.

Discussion

Trends over the last two decades have resulted in a dense arena with many issue-specific groups, discrete initiatives to strengthen evidence-informed policy and increasing responsibility for subnational institutions. Many countries face a shifting resource base, which for some reduces the amount of resources for health. There is global momentum around universal health coverage, reflecting a broader systems approach, but few examples of how the vast array of stakeholders relate within it are available. NITAG aspirations reflect four interconnected themes related to their scope, their integration in national policy processes, health financing and relationships with ministries of finance, and NITAG positioning relative to other domestic and international entities, raising questions such as, What are the bounds of issue-specific groups and their relationship to allocation decision-making processes across health areas? How do technical advisory groups interface with what are inherently political processes? When are finances considered, by whom and how? What is the future of existing groups whose creation was intended to enhance national ownership but who need continued external support to function? When should new entities be created, in what form and with what mandate?

Conclusions

Countries must determine who makes decisions about resources, when, using what criteria, and how to do so in a robust yet efficient way given the existing and future landscape. While answers to these questions are necessarily country specific, they are collective matters that cannot be addressed by specialised groups alone and have implications for new investments in evidence-informed policy.
Effect of CIP2A and its mechanism of action in the malignant biological behavior of colorectal cancer
Authors: Chen Wei , Liang Jing-Lin , Zhou Kai , Zeng Qing-Li , Ye Jun-Wen , Huang Mei-Jin
Published: April 2020

Background

Increasing evidence has revealed a close correlation between cancerous inhibitor of protein phosphatase 2A (CIP2A) and cancer progression. CIP2A has been shown to participate in diverse biological processes, such as development, tumorigenic transformation and chemoresistance. However, the functions of CIP2A in colorectal cancer (CRC) and its underlying mechanisms of action are not yet completely understood. The purpose of this study was to explore its clinical significance, function and relevant pathways in CRC.

Methods

Quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC), western blotting and enzyme-linked immunosorbent assay (ELISA) were used to identify the expression of CIP2A in CRC tissues, sera and CRC cell lines. The association between the expressions of CIP2A and patient survival was analyzed using the Kaplan-Meier curves. Additionally, the functional role of CIP2A in the cell lines was identified through small interfering RNA (siRNA)-mediated depletion of the protein followed by analyses of proliferation and xenograft growth in vivo using short hairpin (sh) RNAs. Effects of the C-myc inhibitor 10,058-F4 on the expressions of C-myc, and CIP2A in CRC cell lines and its potential mechanisms of action were investigated. Finally, the potential molecular pathways associated with CIP2A were screened using the phosphokinase array and identified through western blotting.

Results

CIP2A mRNA and protein levels were upregulated in CRC tissues compared to those of the corresponding normal tissues. It can be used as an independent prognostic indicator to determine overall survival (OS) and disease-free survival (DFS). Depletion of CIP2A substantially suppressed the growth of CRC cells and colony formation in vitro, and inhibited the growth of xenograft tumors in vivo. Additionally, the levels of CIP2A in the sera of patients with CRC were higher than those of the control subjects. Multivariate analyses revealed that the levels of CIP2A in the sera were not independent prognostic indicators in patients with CRC. Moreover, 10,058-F4 could effectively inhibit the growth of CRC cells in vitro, which could be correlated with an inhibition in the expressions of C-myc, CIP2A and its downstream regulatory anti-apoptotic proteins. Furthermore, the Human Phosphokinase Antibody Array was used to gain insights into the CIP2A-dependent intermediary signaling pathways. The results revealed that several signaling pathways were affected and the protein levels of p-p53 (S392), p-STAT5a (Y694), Cyclin D1, p-ERK1/2 and p-AKT (T308) had decreased in CIP2A-shRNA group based on the results of the western blot analysis.

Conclusions

CIP2A could promote the development of CRC cells and predict poor prognosis in patients with CRC, suggesting that it may serve as a potential prognostic marker and therapeutic target against CRC.

Graphical abstract
Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia
Authors: He Xiao-Tao , Hu Xiao-Fan , Zhu Chao , Zhou Kai-Xiang , Zhao Wen-Jun , Zhang Chen , Han Xiao , Wu Chang-Le , Wei Yan-Yan , Wang Wei , Deng Jian-Ping , Chen Fa-Ming , Gu Ze-Xu , Dong Yu-Lin
Published: April 2020

Background

Robust activation of glial cells has been reported to occur particularly during the pathogenesis of bone cancer pain (BCP). Researchers from our group and others have shown that histone deacetylases (HDACs) play a significant role in modulating glia-mediated immune responses; however, it still remains unclear whether HDACs are involved in the activation of glial cells during the development of BCP.

Methods

BCP model was established by intra-tibia tumor cell inoculation (TCI). The expression levels and distribution sites of histone deacetylases (HDACs) in the spinal dorsal horn and dorsal root ganglia were evaluated by Western blot and immunofluorescent staining, respectively. Suberoylanilide hydroxamic acid (SAHA), a clinically used HDAC inhibitor, was then intraperitoneally and intrathecally injected to rescue the increased expression levels of HDAC1 and HDAC2. The analgesic effects of SAHA administration on BCP were then evaluated by measuring the paw withdrawal thresholds (PWTs). The effects of SAHA on activation of glial cells and expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the spinal dorsal horn and dorsal root ganglia of TCI rats were further evaluated by immunofluorescent staining and Western blot analysis. Subsequently, the effects of SAHA administration on tumor growth and cancer cell-induced bone destruction were analyzed by hematoxylin and eosin (HE) staining and micro-CT scanning.

Results

TCI caused rapid and long-lasting increased expression of HDAC1/HDAC2 in glial cells of the spinal dorsal horn and dorsal root ganglia. Inhibiting HDACs by SAHA not only reversed TCI-induced upregulation of HDACs but also inhibited the activation of glial cells in the spinal dorsal horn and dorsal root ganglia, and relieved TCI-induced mechanical allodynia. Further, we found that SAHA administration could not prevent cancer infiltration or bone destruction in the tibia, which indicated that the analgesic effects of SAHA were not due to its anti-tumor effects. Moreover, we found that SAHA administration could inhibit GSK3β activity in the spinal dorsal horn and dorsal root ganglia, which might contributed to the relief of BCP.

Conclusion

Our findings suggest that HDAC1 and HDAC2 are involved in the glia-mediated neuroinflammation in the spinal dorsal horn and dorsal root ganglia underlying the pathogenesis of BCP, which indicated that inhibiting HDACs by SAHA might be a potential strategy for pain relief of BCP.
Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1
Authors: Magnúsdóttir Elín I. , Grujic Mirjana , Bergman Jessica , Pejler Gunnar , Lagerström Malin C.
Published: April 2020

Background

Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETARs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch.

Methods

In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed.

Results

CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect.

Conclusion

Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1.
Sex-dependent effects of ambient PM2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice
Authors: Li Ran , Sun Qing , Lam Sin Man , Chen Rucheng , Zhu Junyao , Gu Weijia , Zhang Lu , Tian He , Zhang Kezhong , Chen Lung-Chi , Sun Qinghua , Shui Guanghou , Liu Cuiqing
Published: April 2020

Background & aims

Emerging evidence supports ambient fine particulate matter (PM2.5) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM2.5 exposure and investigate the underlying mechanism by which PM2.5 modulates hepatic lipid metabolism.

Methods

Both male and female C57BL/6 mice were randomly assigned to ambient PM2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM2.5 exposure-induced metabolic disorder.

Results

Female mice were more susceptible than their male counterparts to ambient PM2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM2.5-exposed mice as well. In addition, exposure to PM2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM2.5-induced metabolic dysfunction.

Conclusions

Ambient PM2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.
Inverted urothelial papilloma of the upper urinary tract: description of two cases with systematic literature review
Authors: Santi R. , Galli I. C. , Canzonieri V. , Lopez J. I. , Nesi G.
Published: April 2020

Background

Inverted urothelial papilloma (IUP) of the upper urinary tract is an uncommon benign tumour that occasionally presents as a polypoid mass causing urinary obstruction. Histologically, IUP is characterised by a proliferating urothelium arranged in cords and trabeculae, in continuity with overlying intact epithelium, and extending into the lamina propria in a non-invasive, endophytic manner. Cytological atypia is minimal or absent. Top differential diagnoses include urothelial carcinoma with inverted growth pattern and florid ureteritis cystica. Although urothelial carcinomas of the upper urinary tract with prominent inverted growth pattern commonly harbour microsatellite instability, the role of the mutator phenotype pathway in IUP development is still unclear. The aim of this study was to describe two additional cases of IUP of the upper urinary tract, along with an extensive literature review.

Case presentation

We observed two polypoid tumours originating in the renal pelvis and the distal ureter, respectively. Both patients, a 76-year-old woman and a 56-year-old man, underwent surgery because of the increased likelihood of malignancy. Histology was consistent with IUP and patients are alive and asymptomatic after long-term follow-up (6 years for the renal pelvis lesion and 5 years for the ureter lesion). The tumours retained the expression of the mismatch-repair protein MLH1, MSH2, and PMS2 whereas loss of MSH6 was found in both cases.

Conclusions

When completely resected, IUP does not require rigorous surveillance protocols, such as those for urothelial carcinoma and exophytic urothelial papilloma. It is therefore important for the surgical pathologist to be aware of this rare entity in order to ensure correct patient management.
The hidden risk of ionizing radiation in the operating room: a survey among 258 orthopaedic surgeons in Brazil
Authors: Pires Robinson Esteves , Reis Igor Guedes Nogueira , de Faria Ângelo Ribeiro Vaz , Giordano Vincenzo , Labronici Pedro José , Belangero William Dias
Published: April 2020

Background

This study aims to assess orthopaedic surgeon knowledge in Brazil about ionizing radiation and its health implications on surgical teams and patients.

Methods

A 15-question survey on theoretical and practical concepts of ionizing radiation was administered during the 23rd Brazilian Orthopaedic Trauma Association annual meeting. The survey addressed issues within orthopedic surgery, such as radiation safety concepts, protection, exposure, as well as the participant gender. Participants were either orthopedic surgeons or orthopedic surgery residents working at institutions in Brazil.

Results

One thousand surveys were distributed at the moment of the meeting registration, and 258 were answered completely (25.8% response rate). Only 5.8% of participants used basic radiation protection equipment; 47.3% used a dosimeter; 2.7% reached the annual maximum permissible radiation dose; 10.5% knew the period of increased risk to fetal gestation; 5.8% knew the maximum permissible radiation dose during pregnancy; 58.5% knew that the hands, eyes, and thyroid are the most exposed areas and at greater risk of radiation-related lesions; 25.2% knew the safe distance from a radiation-emitting tube is 3 m or more; 44.2% knew the safest positioning of the radiation-emitting tube; 25.2% knew that smaller tubes emit greater radiation at the entrance dose to magnify the image; and 55.4% knew that the surgery team receives more scattered radiation in surgical procedures performed on obese patients.

Conclusion

This study revealed inadequate theoretical and practical knowledge about radiation exposure among orthopaedic surgeons in Brazil. Only a minority of orthopaedic surgeons used basic radiation protection equipment. No significant differences in knowledge were found when comparing all orthopedic surgery specialties. Our findings indicate an urgent need for education to increase knowledge among orthopaedic surgeons about the hazards of ionizing radiation. Personal protection and implementation of the ALARA (as low as reasonably achievable) protocol in daily practice are important behaviors to prevent the harmful effects of ionizing radiation.
Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury
Authors: Chen Song-Feng , Pan Meng-Xian , Tang Jun-Chun , Cheng Jing , Zhao Dan , Zhang Ya , Liao Hua-Bao , Liu Rui , Zhuang Yang , Zhang Zhi-Feng , Chen Juan , Lei Rui-Xue , Li Shi-Fang , Li Huan-Ting , Wang Ze-Fen , Wan Qi
Published: April 2020

Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.
Circulating dipeptidyl peptidase-3 at admission is associated with circulatory failure, acute kidney injury and death in severely ill burn patients
Authors:   for the PRONOBURN group, Dépret François , Amzallag Juliette , Pollina Adrien , Fayolle-Pivot Laure , Coutrot Maxime , Chaussard Maïté , Santos Karine , Hartmann Oliver , Jully Marion , Fratani Alexandre , Oueslati Haikel , Cupaciu Alexandru , Benyamina Mourad , Guillemet Lucie , Deniau Benjamin , Mebazaa Alexandre , Gayat Etienne , Farny Boris , Textoris Julien , Legrand Matthieu
Published: April 2020

Background

Dipeptidyl peptidase-3 (DPP3) is a metallopeptidase which cleaves bioactive peptides, notably angiotensin II, and is involved in inflammation regulation. DPP3 has been proposed to be a myocardial depressant factor and to be involved in circulatory failure in acute illnesses, possibly due to angiotensin II cleavage. In this study, we evaluated the association between plasmatic DPP3 level and outcome (mortality and hemodynamic failure) in severely ill burn patients.

Methods

In this biomarker analysis of a prospective cohort study, we included severely ill adult burn patients in two tertiary burn intensive care units. DPP3 was measured at admission (DPP3admin) and 3 days after. The primary endpoint was 90-day mortality. Secondary endpoints were hemodynamic failure and acute kidney injury (AKI).

Results

One hundred and eleven consecutive patients were enrolled. The median age was 48 (32.5–63) years, with a median total body surface area burned of 35% (25–53.5) and Abbreviated Burn Severity Index (ABSI) of 8 (7–11). Ninety-day mortality was 32%. The median DPP3admin was significantly higher in non-survivors versus survivors (53.3 ng/mL [IQR 28.8–103.5] versus 27.1 ng/mL [IQR 19.4–38.9]; p < 0.0001). Patients with a sustained elevated DPP3 had an increased risk of death compared to patients with high DPP3admin but decreased levels on day 3. Patients with circulatory failure had higher DPP3admin (39.2 ng/mL [IQR 25.9–76.1] versus 28.4 ng/mL [IQR 19.8–39.6]; p = 0.001) as well as patients with AKI (49.7 ng/mL [IQR 30.3–87.3] versus 27.6 ng/mL [IQR 19.4–41.4]; p = 0.001). DPP3admin added prognostic value on top of ABSI (added chi2 12.2, p = 0.0005), Sequential Organ Failure Assessment (SOFA) score at admission (added chi2 4.9, p = 0.0268), and plasma lactate at admission (added chi2 6.9, p = 0.0086) to predict circulatory failure within the first 48 h.

Conclusions

Plasma DPP3 concentration at admission was associated with an increased risk of death, circulatory failure, and AKI in severely burned patients. Whether DPP3 plasma levels could identify patients who would respond to alternative hemodynamic support strategies, such as intravenous angiotensin II, should be explored.
Species and sex-specific chemosensory gene expression in Anopheles coluzzii and An. quadriannulatus antennae
Authors: Athrey Giridhar , Popkin-Hall Zachary , Cosme Luciano Veiga , Takken Willem , Slotman Michel Andre
Published: April 2020

Background

Olfactory cues drive mosquito behaviors such as host-seeking, locating sugar sources and oviposition. These behaviors can vary between sexes and closely related species. For example, the malaria vectorAnopheles coluzziiis highly anthropophilic, whereasAn. quadriannulatusis not. These behavioral differences may be reflected in chemosensory gene expression.

Methods

The expression of chemosensory genes in the antennae of both sexes ofAn. coluzziiandAn. quadriannulatuswas compared using RNA-seq. The sex-biased expression of several genes inAn. coluzziiwas also compared using qPCR.

Results

The chemosensory expression is mostly similar in the male antennae ofAn. coluzziiandAn. quadriannulatus,with only a few modest differences in expression. A handful of chemosensory genes are male-biased in both species; the highly expressed gustatory receptorAgGr33, odorant binding proteinsAgObp25,AgObp26and possiblyAgObp10.Although the chemosensory gene repertoire is mostly shared between the sexes, several highly female-biasedAgOrs,AgIrs, and oneAgObpwere identified, including several whose expression is biased towards the anthropophilicAn. coluzzii. Additionally, the expression of several chemosensory genes is biased towardsAn. coluzziiin both sexes.

Conclusions

Chemosensory gene expression is broadly similar between species and sexes, but several sex- biased/specific genes were identified. These may modulate sex- and species-specific behaviors. Although the male behavior of these species remains poorly studied, the identification of sex- and species-specific chemosensory genes may provide fertile ground for future work.