bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction to: Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study
Authors: Beeharry Maneesh Kumarsing , Zhu Zheng-Lun , Liu Wen-Tao , Yao Xue-Xin , Yan Min , Zhu Zheng-Gang
Published: December 2019

Following publication of the original article [1], the authors reported the following errors/updates.
Phenomenology of being a safe taxi driver
Authors: Mehri Mahsa , Khazaee-Pool Maryam , Arghami Shirazeh
Published: December 2019

Background

In developing countries, a great number of people typically utilize public transportation such as Taxis. Therefore, taxi drivers have an important role in residents’ well-being and safety. The aim of this study was to describe the subjective experiences and insights on safe driving among taxi drivers in Zanjan, Iran.

Method

In this qualitative study, 17 taxi drivers (23–54 years) were purposefully selected to participate in 11 semi-structured interviews, as well as one focus group (n = 6). The data was then analyzed based on a combination of Braun’s and Colaizzi’s methods.

Result

By analysis of the qualitative data, four main themes emerged from expressed experiences by taxi drivers, including 1) traffic chaos, 2) social prestige, 3) economic pressure, and 3) job satisfaction.

Conclusion

The emerging concepts of the present study imply a threefold structure of existence, which introduced by Heidegger, as taxi drivers’ (the self) feelings and experiences of being under pressure of traffic chaos (the world), accompanied by low social prestige, economic pressure and job dissatisfaction (being in). Thus, strategic planning for traffic safety should consider taxi drivers’ needs to feel a friendly world, as well as, to find themselves in a respectful and supportive environment.
Gorham-Stout disease of the malleolus: a rare case report
Authors: Zheng Chuanxi , Tang Fan , Min Li , Zhou Yong , Luo Yi , Tu Chongqi , Zhang Shiquan
Published: December 2019

Background

Gorham-Stout disease, also known as vanishing bone disease, idiopathic massive osteolysis, is a rare entity of unknown etiopathology. This disease is characterized by destruction of osseous matrix and proliferation of lymphatic vascular structures and associated with massive regional osteolysis. It has a variable clinical presentation and is commonly considered as a benign disease with a progressive tendency and an unpredictable prognosis. The diagnosis is made by exclusion and based on combination with histological, radiological, and clinical features. Despite that several therapeutic options have shown certain efficacy, the effective treatment still remains controversial and there is no standard treatment to be recommended.

Case presentation

A previously healthy 40-year-old man presented with right lateral malleolus pain after an ankle sprain and was referred to our hospital. The radiographs indicated rapid massive bone destruction in the distal right lateral malleolus with an unclear margin. Based on the combination with histological, radiological, and clinical features, the diagnosis of Gorham-Stout disease was made. Considering that the residual function of malleolus had to be protected, prior bisphosphonate was used to control the progression of lesion, followed by surgical resection and biological reconstruction with autologous fibular bone grafting. The patient was followed up 8 years after surgery, he presented without progression and recurrence.

Conclusions

We depict a case of Gorham-Stout disease at the right lateral malleolus and was successfully controlled by medication and surgical intervention. Based on the prior effective medical treatment, resection with biological reconstruction is a useful approach to treat Graham-Stout disease in bone.
Infection prevention preparedness and practices for female sterilization services within primary care facilities in Northern India
Authors: Kumar Abhishek , Gautam Abhishek , Dey Arnab , Saith Ruhi , Uttamacharya  , Achyut Pranita , Gautam Vandana , Agarwal Dinesh , Chakraverty Amit , Mozumdar Arupendra , Aruldas Kumudha , Verma Ravi , Nanda Priya , Krishnan Suneeta , Saggurti Niranjan
Published: December 2019

Background

In 2014, 16 women died following female sterilization operations in Bilaspur, a district in central India. In addition to those 16 deaths, 70 women were hospitalized for critical conditions (Sharma, Lancet 384,2014). Although the government of India’s guidelines for female sterilization mandate infection prevention practices, little is known about the extent of infection prevention preparedness and practice during sterilization procedures that are part of the country’s primary health care services. This study assesses facility readiness for infection prevention and adherence to infection prevention practices during female sterilization procedures in rural northern India.

Method

The data for this study were collected in 2016–2017 as part of a family planning quality of care survey in selected public health facilities in Bihar (n = 100), and public (n = 120) and private health facilities (n = 97) in Uttar Pradesh. Descriptive analysis examined the extent of facility readiness for infection prevention (availability of handwashing facilities, new or sterilized gloves, antiseptic lotion, and equipment for sterilization). Correlation and multivariate statistical methods were used to examine the role of facility readiness and provider behaviors on infection prevention practices during female sterilization.

Result

Across the three health sectors, 62% of facilities featured all four infection prevention components. Sterilized equipment was lacking in all three health sectors. In facilities with all four components, provider adherence to infection prevention practices occurred in only 68% of female sterilization procedures. In Bihar, 76% of public health facilities evinced all four components of infection prevention, and in those facilities provider’s adherence to infection prevention practices was almost universal. In Uttar Pradesh, where only 55% of public health facilities had all four components, provider adherence to infection prevention practices occurred in only 43% of female sterilization procedures.

Conclusion

The findings suggest that facility preparedness for infection prevention does play an important role in provider adherence to infection prevention practices. This phenomenon is not universal, however. Not all doctors from facilities prepared for infection prevention adhere to the practices, highlighting the need to change provider attitudes. Unprepared facilities need to procure required equipment and supplies to ensure the universal practice of infection prevention.
Correction to: Comparing methods to estimate incremental inpatient costs and length of stay due to methicillin-resistant Staphylococcus aureus in Alberta, Canada
Authors: Kirwin Erin , Varughese Marie , Waldner David , Simmonds Kimberley , Joffe A. Mark , Smith Stephanie
Published: December 2019

In the original publication of this article [1], the authors want to add the following sentence in the Acknowledgement section
A network view of microRNA and gene interactions in different pathological stages of colon cancer
Authors: Wen Jia , Hall Benika , Shi Xinghua
Published: December 2019

Background

Colon cancer is one of the common cancers in human. Although the number of annual cases has decreased drastically, prognostic screening and translational methods can be improved. Hence, it is critical to understand the molecular mechanisms of disease progression and prognosis.

Results

In this study, we develop a new strategy for integrating microRNA and gene expression profiles together with clinical information toward understanding the regulation of colon cancer. Particularly, we use this approach to identify microRNA and gene expression networks that are specific to certain pathological stages. To demonstrate the application of our method, we apply this approach to identify microRNA and gene interactions that are specific to pathological stages of colon cancer in The Cancer Genome Atlas (TCGA) datasets.

Conclusions

Our results show that there are significant differences in network connections between miRNAs and genes in different pathological stages of colon cancer. These findings point to a hypothesis that these networks signify different roles of microRNA and gene regulation in the pathogenesis and tumorigenesis of colon cancer.
Have inequalities in all-cause and cause-specific child mortality between countries declined across the world?
Authors: Cha Seungman , Jin Yan
Published: December 2019

Background

Comparing the distribution of all cause or cause-specific child mortality in countries by income and its progress over time has not been rigorously monitored, and hence remains unknown. We therefore aimed to analyze child mortality disparities between countries with respect to income level and progression for the period 2000–2015, and further explored the convergence of unequal income levels across the globe.

Methods

Four types of measures were used to assess the degree of inequality across countries: difference and ratio of child mortality rate, the concentration index, and the Erreygers index. To assess the longitudinal trend of unequal child mortality rate by wealth ranking, hierarchical mixed effect analysis was used to examine any significant changes in the slope of under-5 child mortality rate by GDP per capita between 2000 and 2015.

Results

All four measures reveal significant inequalities across the countries by income level. Compared with children in the least deprived socioeconomic quintile, the mortality rate for children in the most deprived socioeconomic quintile was nearly 20.7 times higher (95% Confidence Interval: 20.5–20.8) in 2000, and 12.2 times (95% CI: 12.1–12.3) higher in 2015. Globally, the relative and absolute inequality of child mortality between the first and fifth quintiles have declined over time in all diseases, but was more pronounced for infectious diseases (pneumonia, diarrhea, measles, and meningitis). In 2000, post-neonatal children in the first quintile had 105.3 times (95% CI: 100.8–110.0) and 216.3 times (95% CI: 202.5–231.2) higher risks of pneumonia- and diarrhea-specific child mortality than children in the fifth quintile. In 2015, the corresponding rate ratios had decreased to 59.3 (95% CI: 56.5–62.1) and 101.9 (95% CI: 94.3–110.0) times. However, compared with non-communicable disease, infectious diseases still show a far more severe disparity between income quintile. Mixed effect analysis demonstrates the convergence of under-5 mortality in 194 countries across income levels.

Conclusion

Grand convergence in child mortality, particularly in post neonatal children, suggests that the global community has witnessed success to some extent in controlling infectious diseases. To our knowledge, this study is the first to assess worldwide inequalities in cause-specific child mortality and its time trend by wealth.
Health-related quality of life of patients diagnosed with COPD in Extremadura, Spain: results from an observational study
Authors:   Collaborative Working Group EPOC-Extremadura, Merino María , Villoro Renata , Hidalgo-Vega Álvaro , Carmona Concepción
Published: December 2019

Background

COPD is a high prevalence chronic disease that involves large reductions of health-related quality of life (HRQL) of patients. This study aims to describe the HRQL of patients with COPD in Extremadura (Spain).

Methods

This is a cross-sectional observational study carried out using a representative sample of patients diagnosed with COPD in Extremadura. The inclusion criteria were patients of legal age, diagnosed with COPD at least 12 months prior to the visit, residing in Extremadura, with electronic medical records available for the 12 months prior to the visit and providing informed consent. The intervention aimed to elicit HRQL indicators obtained from two validated questionnaires: EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L), and St. George’s Respiratory Questionnaire-COPD (SGRQ-C). The main outcome measures were general HRQL (utility and visual analogue scale) and specific quality of life of COPD patients (total score and three component scores: Symptoms, Activity, and Impacts). Stepwise multiple regression analysis was applied to evaluate the association of EQ-5D-5L and SGRQ-C with respect to clinical and sociodemographic characteristics of the patients.

Results

We recruited 386 patients (mean age 71.8 ± 10.3 years, 76.2% males). In the EQ-5D-5L, participants reported greater problems with respect to mobility (56.5%) and pain/discomfort (48.2%). The mean utility was 0.72 ± 0.31, and the SGRQ-C total score was 40.9 ± 25.0. The results of both questionnaires were associated with number of exacerbations in the last 12 months, level of COPD severity, gender, and education level of the patient (p < 0.05).

Conclusions

The results for both utility and total SGRQ-C score indicate that having suffered exacerbations in the last year, presenting a higher level of severity, being a woman, and having a low education level are related to worse HRQL in patients with COPD.
Hypothesis: improving literacy about health workforce will improve rural health workforce recruitment, retention and capability
Authors: Martiniuk Alexandra , Colbran Richard , Ramsden Robyn , Karlson Dave , O’Callaghan Emer , Lowe Estrella , Edwards Michael , Bagnulo Sharif , Rothnie Imogene , Hardaker Laura , Gotch Bernadette , Wotherspoon Arna
Published: December 2019

Background

One of the key barriers to health in rural areas is health workforce. Poor understanding and communication about health workforce across all stakeholder groups (including the broad community) is very common and can negatively affect the health workforce, recruitment, experiences and outcomes.

Hypothesis

In this paper, we propose the concept of literacy about health workforce. We propose this as a specific, actionable extension of the existing and well accepted health literacy concept. We hypothesise that improving literacy about health workforce will improve, in particular, rural health workforce recruitment, retention and capability.

Implications of the hypothesis

We propose that literacy about health workforce is important for all members of the health and broader system (e.g. local GP, mayor, workforce agency, health manager, Aboriginal health worker, carers, community health facilitators, patients, schools, local businesses, cultural and recreation groups) because we hypothesise their literacy about health workforce affects their capacity to make informed decisions and take action to manage their health workforce needs in direct synchrony with the community’s health needs. We hypothesise that improving literacy about health workforce will improve the effectiveness and efficiency of attracting, recruiting, training, and retaining a high quality, capable, health workforce, and further, will support the development and acceptance of innovative solutions to health workforce crises such as new models of care. This hypothesis is action orientated, is testable and includes the consideration of methods to engage and improve literacy of those within and external to the health workforce.
Delusional parasitosis in dementia with Lewy bodies: a case report
Authors: Ochiai Sho , Sugawara Hiroko , Kajio Yusuke , Tanaka Hibiki , Ishikawa Tomohisa , Fukuhara Ryuji , Jono Tadashi , Hashimoto Mamoru
Published: December 2019

Background

Dementia with Lewy bodies (DLB) is characterized by fluctuating cognitive impairments, recurrent visual hallucinations, the motor symptoms of parkinsonism and REM sleep behavior disorder. Various neuropsychiatric symptoms including hallucination and delusions occur frequently; however, delusional parasitosis is rare in DLB. Here, we report a case of DLB patient with delusional parasitosis.

Case presentation

The patient was an 89-year-old woman. At the age of 88, she began to complain her oral cenesthopathy, and developed cognitive decline, delusional parasitosis and parkinsonism. As a result of examination, she was diagnosed as DLB and treated with combination of donepezil 5 mg/day and aripiprazole 1.5 mg/day, and her complaint was disappeared.

Conclusions

Further studies are needed to investigate the association between delusional parasitosis and underlying pathophysiology of DLB, and the utility of antipsychotics for delusional parasitosis in DLB has to be examined through more cases.
Impacts of intellectual property provisions in trade treaties on access to medicine in low and middle income countries: a systematic review
Authors: Islam Md. Deen , Kaplan Warren A. , Trachtenberg Danielle , Thrasher Rachel , Gallagher Kevin P. , Wirtz Veronika J.
Published: December 2019

Background

We present a systematic review describing ex-ante and ex-post evaluations of the impacts of intellectual property provisions in trade treaties on access to medicine in low and middle income countries. These evaluations focused on multilateral and bilateral trade agreements. We ascertained which IP provisions impacting access to medicines were the focus of these evaluations. We provide a further research agenda related to investigating the effect of trade agreement’s intellectual property provisions on access to medicines.

We followed systematic review guidelines with 7 different databases to identify post-2000 ex ante and ex post evaluations of trade treaties on access to medicines in low and middle-income countries. We included only quantitative ex-ante studies that used structural modeling and simulations to derive quantitative predictions and ex-post studies that utilized empirical data and econometric techniques to quantify the effects of intellectual property provisions in free trade agreements on host country’s pharmaceutical industry.

The search strategy identified 744 titles after removal of duplicates. We identified 14 studies that fulfilled all eligibility; 7 studies are ex-ante and 7 are ex-post. The studies looked at medicine price and cost, affordability, welfare effects and speed of medicine market launch. Changes in intellectual property policy due to the implementation of trade agreements affect price, medicines expenditure and sales, consumer welfare, and ultimately the affordability, of medicines. The direction and magnitude of the price effects differ between ex-ante and ex-post studies. Further, the reported impacts of policy changes due to trade agreements on medicine access seem clearly multifactorial.

Conclusion

Both ex ante and ex post methods have advantages and limitations and, on balance, both types report, for the most part, an increase in price and a decrease in consumer welfare with imposition of intellectual property protection in trade agreements. The main differences between these studies are in the magnitude of the changes. There is a gap in our empirical understanding of the mechanisms through which such changes affect access to medicines and which outcomes relevant to access are most affected by which type of changes in intellectual property policy and law.
Proteomic profiling of the neurons in mice with depressive-like behavior induced by corticosterone and the regulation of berberine: pivotal sites of oxidative phosphorylation
Authors: Gong Qin , Yan Xiao-Jin , Lei Fan , Wang Mu-Lan , He Lu-Ling , Luo Ying-Ying , Gao Hong-Wei , Feng Yu-Lin , Yang Shi-Lin , Li Jun , Du Li-Jun
Published: December 2019

Chronic corticosterone (CORT) stress is an anxiety and depression inducing factor that involves the dysfunction of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF), and neuronal plasticity. However, the regulation of proteomic profiles in neurons suffering CORT stress is remaining elusive. Thus, the proteomic profiles of mouse neuronal C17.2 stem cells were comprehensively investigated by TMT (tandem mass tag)-labeling quantitative proteomics. The quantitative proteomics conjugated gene ontology analysis revealed the inhibitory effect of CORT on the expression of mitochondrial oxidative phosphorylation-related proteins, which can be antagonized by berberine (BBR) treatment. In addition, animal studies showed that changes in mitochondria by CORT can affect neuropsychiatric activities and disturb the physiological functions of neurons via disordering mitochondrial oxidative phosphorylation. Thus, the mitochondrial energy metabolism can be considered as one of the major mechanism underlying CORT-mediated depression. Since CORT is important for depression after traumatic stress disorder, our study will shed light on the prevention and treatment of depression as well as posttraumatic stress disorder (PTSD).
Transcriptional activation of USP16 gene expression by NFκB signaling
Authors: Yang Shou , Wang Juelu , Guo Shipeng , Huang Daochao , Lorigados Isabel Bestard , Nie Xing , Lou Dandan , Li Yanhua , Liu Mingjing , Kang Yu , Zhou Weihui , Song Weihong
Published: December 2019

Ubiquitin Specific Peptidase 16 (USP16) has been reported to contribute to somatic stem-cell defects in Down syndrome. However, how this gene being regulated is largely unknown. To study the mechanism underlyingUSP16gene expression,USP16gene promoter was cloned and analyzed by luciferase assay. We identified that the 5′ flanking region (− 1856 bp ~ + 468 bp) of the humanUSP16gene contained the functional promotor to control its transcription. Three bona fide NFκB binding sites were found inUSP16promoter. We showed that p65 overexpression enhanced endogenousUSP16mRNA level. Furthermore, LPS and TNFα, strong activators of the NFκB pathway, upregulated theUSP16transcription. Our data demonstrate thatUSP16gene expression is tightly regulated at transcription level. NFκB signaling regulates the humanUSP16gene expression through threecis-acting elements. The results provide novel insights into a potential role of dysregulation ofUSP16expression in Alzheimer’s dementia in Down Syndrome.
Plasma membrane localization of MLC1 regulates cellular morphology and motility
Authors: Hwang Junmo , Vu Hung M. , Kim Min-Sik , Lim Hyun-Ho
Published: December 2019

Background

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare form of infantile-onset leukodystrophy. The disorder is caused primarily by mutations of MLC1 that leads to a series of phenotypic outcomes including vacuolation of myelin and astrocytes, subcortical cysts, brain edema, and macrocephaly. Recent studies have indicated that functional interactions among MLC1, GlialCAM, and ClC-2 channels play key roles in the regulation of neuronal, glial and vascular homeostasis. However, the physiological role of MLC1 in cellular homeostatic communication remains poorly understood. In the present study, we investigated the cellular function of MLC1 and its effects on cell–cell interactions.

Methods

MLC1-dependent cellular morphology and motility were analyzed by using confocal and live cell imaging technique. Biochemical approaches such as immunoblotting, co-immunoprecipitation, and surface biotinylation were conducted to support data.

Results

We found that the altered MLC1 expression and localization led to a great alteration in cellular morphology and motility through actin remodeling. MLC1 overexpression induced filopodia formation and suppressed motility. And, MLC1 proteins expressed in patient-derived MLC1 mutants resulted in trapping in the ER although no changes in morphology or motility were observed. Interestingly knockdown of Mlc1 induced Arp3-Cortactin interaction, lamellipodia formation, and increased the membrane ruffling of the astrocytes. These data indicate that subcellular localization of expressed MLC1 at the plasma membrane is critical for changes in actin dynamics through ARP2/3 complex. Thus, our results suggest that misallocation of pathogenic mutant MLC1 may disturbs the stable cell-cell communication and the homeostatic regulation of astrocytes in patients with MLC.
Influence of marital status on overall survival in patients with ovarian serous carcinoma: finding from the surveillance epidemiology and end results (SEER) database
Authors: Luo Pei , Zhou Jian-Guo , Jin Su-Han , Qing Ming-Song , Ma Hu
Published: December 2019

Objective

This study is to investigate the relationship between marital status and prognosis of patients with ovarian serous carcinoma.

Results

We performed data analysis from 19,276 patients identified from the SEER database of the National Cancer Center of the United States. 57.8% of the patients were married, 13.0% unmarried, and 29.2% separated/ divorced/widowed (SDW). The median overall survival time ofthe unmarried group and the married group are 48 months and 52 months respectively. Univariate Cox regression analysis showed that the patients with serous ovarian cancer in the unmarried group resulted in a hazard ratio (HR) of 1.14 (95% CI: 1.08–1.19%;P < 0.001), comparing to SDW group with a HR of 1.02 (95% CI: 0.98–1.19%;P = 0.26). However, the SDW group was not statistically significantly different from the married group. (median 32 vs 52 months). Multivariate Cox regression analysis presented the unmarried group leading to a HR of 1.05 (95% CI: 1.00–1.11%;P = 0.05), and the SDW group was not significant with a HR of 0.99 (95% CI: 0.95–1.03%;P = 0.57).

Conclusion

Unmarried patients with ovarian serous carcinoma have higherHRof overall survival. After controlling age, race, grade, radiation and year of diagnosis, unmarried patients were found to have a significantly higher risk of OS. Consequently, these patients are suggested to obtain more focused healthcare for the management of ovarian serous carcinoma.
Interval between secondary cytoreductive surgery and adjuvant chemotherapy is not associated with survivals in patients with recurrent ovarian cancer
Authors: Jeong Soo Young , Choi Chel Hun , Kim Tae Joong , Lee Jeong Won , Kim Byoung-Gie , Bae Duk Soo , Lee Yoo-Young
Published: December 2019

Background

Secondary cytoreductive surgery (SCS) is possible in selected patients with recurrent epithelial ovarian cancer (EOC). The goal of SCS is complete resection, although chemotherapy is always followed. Delayed intervals between primary debulking surgery and adjuvant chemotherapy was reported to be associated with poorer survivals, however, the role of intervals in recurrent disease is still unknown.

Materials and methods

This retrospective cohort study reviewed data from electronic medical records of women with recurrent EOC treated at Samsung Medical Centre, Seoul, Korea, between January 1, 2002, and December 31, 2015. Patients who underwent SCS with adjuvant chemotherapy for recurrent EOC were eligible. We defined intervals as the period between the day of SCS and the first cycle of adjuvant chemotherapy.

Results

Seventy-nine patients were eligible for this study. Their median age was 48 (range, 18–69) years and median interval between the date of SCS and initiation of adjuvant chemotherapy was 10 (range, 4–115) days. The rate of complete resection was 72.2% (57/79). Division of the patients by interval (Group 1, interval ≤ 10 days; Group 2, interval > 10 days) revealed no difference in clinical parameters. No gross residual disease after SCS (no vs. any gross residual, p = 0.002) and longer platinum-free survival (over 12 vs. 6–12 months, p = 0.023) were independent favorable prognostic factors in Cox model; however, the intervals did not affect survival.

Conclusions

Delayed intervals to adjuvant chemotherapy after secondary cytoreductive surgery is not associated with decreased survivals. It is important to identify recurrent EOC patients who might have no gross residual disease following SCS. Moreover, surgeons should strive for complete resection.
Non-pulsatile blood flow is associated with enhanced cerebrovascular carbon dioxide reactivity and an attenuated relationship between cerebral blood flow and regional brain oxygenation
Authors: Veraar Cecilia Maria , Rinösl Harald , Kühn Karina , Skhirtladze-Dworschak Keso , Felli Alessia , Mouhieddine Mohamed , Menger Johannes , Pataraia Ekaterina , Ankersmit Hendrik Jan , Dworschak Martin
Published: December 2019

Background

Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon—especially when CO2is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2reactivity (CVR) and regional brain oxygenation (rSO2).

Methods

In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2was determined during step changes of PaCO2between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2alterations were determined for each flow mode. Each patient served as her own control.

Results

MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO2slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8–16.9] and 10.4 cm/s/mmHg [CI 7.9–13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg,p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO2and ΔMCAv was less pronounced during non-pulsatile flow.

Conclusions

Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO2/ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed.

Trial registration

The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).
Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients
Authors:   on behalf of the POETIC Trial Management Group and Trialists, Gao Qiong , López-Knowles Elena , Cheang Maggie Chon U. , Morden James , Ribas Ricardo , Sidhu Kally , Evans David , Martins Vera , Dodson Andrew , Skene Anthony , Holcombe Chris , Mallon Elizabeth , Evans Abigail , Bliss Judith M. , Robertson John , Smith Ian , Martin Lesley-Ann , Dowsett Mitch
Published: December 2019

Background

Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance.

Methods

Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (controln = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67.

Results

High baselineESR1expression associated with better AI response in HER2+ tumours but not HER2− tumours. In HER2− tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) includingPERPandYWHAQ, the two most significant, and the transcription co-regulators (SAP130,HDAC4, andNCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, andIGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2− and HER2+ patients.

Conclusions

There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors.

Trial registration

ISRCTN,ISRCTN63882543, registered on 18 December 2007.
Endocrine-responsive lobular carcinoma of the breast: features associated with risk of late distant recurrence
Authors: Conforti Fabio , Pala Laura , Pagan Eleonora , Viale Giuseppe , Bagnardi Vincenzo , Peruzzotti Giulia , De Pas Tommaso , Bianco Nadia , Graffeo Rossella , Rocco Elena Guerini , Vingiani Andrea , Gelber Richard D. , Coates Alan S. , Colleoni Marco , Goldhirsch Aron
Published: December 2019

Background

Invasive lobular carcinomas (ILCs) account for 10–15% of all breast cancers. They are characterized by an elevated endocrine responsiveness and by a long lasting risk of relapse over time. Here we report for the first time an analysis of clinical and pathological features associated with the risk of late distant recurrence in ILCs.

Patients and methods

We retrospectively analyzed all consecutive patients with hormone receptor–positive ILC operated at the European Institute of Oncology (EIO) between June 1994 and December 2010 and scheduled to receive at least 5 years of endocrine treatment.

The aim was to identify clinical and pathological variables that provide prognostic information in the period beginning 5 years after definitive surgery. The cumulative incidence of distant metastases (CI-DM) from 5 years after surgery was the prospectively defined primary endpoint.

Results

One thousand eight hundred seventy-two patients fulfilled the inclusion criteria. The median follow-up was 8.7 years.

Increased tumor size and positive nodal status were significantly associated with higher risk of late distant recurrence, but nodal status had a significant lower prognostic value in late follow-up period (DM-HR, 3.21; 95% CI, 2.06–5.01) as compared with the first 5 years of follow-up (DM-HR, 9.55; 95% CI, 5.64–16.2; heterogeneitypvalue 0.002).

Elevated Ki-67 labeling index (LI) retained a significant and independent prognostic value even after the first 5 years from surgery (DM-HR, 1.81; 95% CI 1.19–2.75), and it also stratified the prognosis of ILC patients subgrouped according to lymph node status.

A combined score, obtained integrating the previously validated Clinical Treatment Score post 5 years (CTS5) and Ki-67 LI, had a strong association with the risk of late distant recurrence of ILCs.

Conclusion

We identified factors associated with the risk of late distant recurrence in ER-positive ILCs and developed a simple prognostic score, based on data that are readily available, which warrants further validation.
Salivary gland proteome analysis of developing adult female Haemaphysalis longicornis ticks: molecular motor and TCA cycle-related proteins play an important role throughout development
Authors: Ren Shuguang , Zhang Baowen , Xue Xiaomin , Wang Xiaoshuang , Zhao Huaqu , Zhang Xiaoli , Wang Minjing , Xiao Qi , Wang Hui , Liu Jingze
Published: December 2019

Background

Ticks are notorious blood-feeding arthropods that can spread a variety of deadly diseases. The salivary gland is an important organ for ticks to feed on blood, and this organ begins to develop rapidly when ixodid ticks suck blood. When these ticks reach a critical weight, the salivary glands stop developing and begin to degenerate. The expression levels of a large number of proteins during the development and degeneration of salivary glands change, which regulate the biological functions of the salivary glands. Furthermore, to the best of our knowledge, there are only a few reports on the role of molecular motor and TCA cycle-related proteins in the salivary glands of ticks.

Results

We used iTRAQ quantitative proteomics to study the dynamic changes in salivary gland proteins in femaleHaemaphysalis longicornisat four feeding stages: unfed, partially fed, semi-engorged and engorged. Using bioinformatics methods to analyze the dynamic changes of a large number of proteins, we found that molecular motor and TCA cycle-related proteins play an important role in the physiological changes of the salivary glands. The results of RNAi experiments showed that when dynein, kinesin, isocitrate dehydrogenase and citrate synthase were knocked down independently, the weight of the engorged female ticks decreased by 63.5%, 54.9%, 42.6% and 48.6%, respectively, and oviposition amounts decreased by 83.1%, 76.0%, 50.8%, and 55.9%, respectively, and the size of type III acini of females salivary glands decreased by 35.6%, 33.3%, 28.9%, and 20.0%, respectively.

Conclusions

The results showed that the expression of different types of proteins change in different characteristics in salivary glands during the unfed to engorged process of female ticks. Corresponding expression changes of these proteins at different developmental stages of female ticks are very important to ensure the orderly development of the organ. By analyzing these changes, some proteins, such as molecular motor and TCA cycle-related proteins, were screened and RNAi carried out. When these mRNAs were knocked down, the female ticks cannot develop normally. The research results provide a new protein target for the control of ticks and tick-borne diseases.
LINE-1 ORF2p expression is nearly imperceptible in human cancers
Authors: Ardeljan Daniel , Wang Xuya , Oghbaie Mehrnoosh , Taylor Martin S. , Husband David , Deshpande Vikram , Steranka Jared P. , Gorbounov Mikhail , Yang Wan Rou , Sie Brandon , Larman H. Benjamin , Jiang Hua , Molloy Kelly R. , Altukhov Ilya , Li Zhi , McKerrow Wilson , Fenyö David , Burns Kathleen H. , LaCava John
Published: December 2019

Background

Long interspersed element-1 (LINE-1, L1) is the major driver of mobile DNA activity in modern humans. When expressed, LINE-1 loci produce bicistronic transcripts encoding two proteins essential for retrotransposition, ORF1p and ORF2p. Many types of human cancers are characterized by L1 promoter hypomethylation, L1 transcription, L1 ORF1p protein expression, and somatic L1 retrotransposition. ORF2p encodes the endonuclease and reverse transcriptase activities required for L1 retrotransposition. Its expression is poorly characterized in human tissues and cell lines.

Results

We report mass spectrometry-based tumor proteome profiling studies wherein ORF2p eludes detection. To test whether ORF2p could be detected with specific reagents, we developed and validated five rabbit monoclonal antibodies with immunoreactivity for specific epitopes on the protein. These reagents readily detect ectopic ORF2p expressed from bicistronic L1 constructs. However, endogenous ORF2p is not detected in human tumor samples or cell lines by western blot, immunoprecipitation, or immunohistochemistry despite high levels of ORF1p expression. Moreover, we report endogenous ORF1p-associated interactomes, affinity isolated from colorectal cancers, wherein we similarly fail to detect ORF2p. These samples include primary tumors harboring hundreds of somatically acquired L1 insertions. The new data are available via ProteomeXchange with identifier PXD013743.

Conclusions

Although somatic retrotransposition provides unequivocal genetic evidence for the expression of ORF2p in human cancers, we are unable to directly measure its presence using several standard methods. Experimental systems have previously indicated an unequal stoichiometry between ORF1p and ORF2p, but in vivo, the expression of these two proteins may be more strikingly uncoupled. These findings are consistent with observations that ORF2p is not tolerable for cell growth.
Obesity-induced nucleosome release predicts poor cardio-metabolic health
Authors: Lo Re Oriana , Maugeri Andrea , Hruskova Jana , Jakubik Juraj , Kucera Jan , Bienertova-Vasku Julie , Oben Jude A. , Kubala Lukas , Dvorakova Adela , Ciz Milan , Vinciguerra Manlio
Published: December 2019

Objective

While circulating nucleosome levels are high in obese mouse models, it is unknown where these nucleosomes originate from and whether they are a marker of cardio-metabolic health in humans. Here, we aimed to determine whether an association exists between circulating nucleosomes and the risk of developing obesity, metabolic syndrome (MetS) and/or a dysfunctional cardiovascular performance.

Methods

We randomly selected 120 participants of the Kardiovize Brno 2030 study across three BMI strata: BMI 18–25, 25–30, and > 30. We assessed the association between circulating nucleosome levels and the risk of obesity, MetS, and poor cardiovascular health. We then cultured human neutrophils, adipocytes, and hepatoma cells to study nucleosome origins in a fat-rich environment.

Results

Circulating nucleosome levels positively correlated with BMI (R = 0.602, p < 0.05), fatty liver index (R = 0.622, p < 0.05), left ventricular mass (R = 0.457, p < 0.05), and associated with MetS (p < 0.001) and poor cardiovascular health (p < 0.001). Incubating neutrophils with 1–10 μM free fatty acids triggered nucleosome production without concomitant cell death. Nucleosomes were not produced during pre-adipocyte differentiation or upon incubation of hepatic cells with palmitic acid.

Conclusions

Neutrophils are a bona fide source of circulating nucleosomes in an obesogenic environment and in overweight/obese patients. High nucleosome levels are associated with MetS and cardiovascular performance, and might represent novel candidate biomarkers for cardio-metabolic health.
α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb
Authors: Rey Nolwen L. , Bousset Luc , George Sonia , Madaj Zachary , Meyerdirk Lindsay , Schulz Emily , Steiner Jennifer A. , Melki Ronald , Brundin Patrik
Published: December 2019

Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.

To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.

In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.
Extra upper limb practice after stroke: a feasibility study
Authors: Schneider Emma J. , Ada Louise , Lannin Natasha A.
Published: December 2019

Background

There is a need to provide a large amount of extra practice on top of usual rehabilitation to adults after stroke. The purpose of this study was to determine if it is feasible to add extra upper limb practice to usual inpatient rehabilitation and whether it is likely to improve upper limb activity and grip strength.

Method

A prospective, single-group, pre- and post-test study was carried out. Twenty adults with upper limb activity limitations who had some movement in the upper limb completed an extra hour of upper limb practice, 6 days per week for 4 weeks. Feasibility was measured by examining recruitment, intervention (adherence, efficiency, acceptability, safety) and measurement. Clinical outcomes were upper limb activity (Box and Block Test, Nine-Hole Peg Test) and grip strength (dynamometry) measured at baseline (week 0) and end of intervention (week 4).

Results

Of the 212 people who were screened, 42 (20%) were eligible and 20 (9%) were enrolled. Of the 20 participants, 12 (60%) completed the 4-week program; 7 (35%) were discharged early, and 1 (5%) withdrew. Participants attended 342 (85%) of the possible 403 sessions and practiced for 324 (95%) of the total 342 h. In terms of safety, there were no study-related adverse events. Participants increased 0.29 blocks/s (95% CI 0.19 to 0.39) on the Box and Block Test, 0.20 pegs/s (95% CI 0.10 to 0.30) on the Nine-Hole Peg Test, and 4.4 kg (95% CI 2.9 to 5.9) in grip strength, from baseline to end of intervention.

Conclusions

It appears feasible for adults who are undergoing inpatient rehabilitation and have some upper limb movement after stroke to undertake an hour of extra upper limb practice. The magnitude of the clinical outcomes suggests that further investigation is warranted and this study provides useful information for the design of a phase II randomized trial.

Trial registration

Australian and New Zealand Clinical Trial Registry (ACTRN12615000665538).
Modern Chinese nationalism and the awakening of self-consciousness of the Chinese Nation
Authors: Zheng Dahua
Published: December 2019

The concept of “Chinese nation” has a close relationship with the rise, development and upsurge of modern Chinese nationalism from its proposition to establishment, and to universal identification among people of all ethnic groups. The period of the late Qing Dynasty and the early Republic of China was the formation stage of modern Chinese nationalism and also the stage of the proposition and initial usage of the concept of “Chinese nation”: Modern Chinese nationalism developed around the period of the May 4th Movement. Under the impetus of the establishment of national self-determination theory, especially the rise of a national self-determination movement, the concept of “Chinese nation” was accepted and adopted by more and more people and finally established and formed. After the September 18th Incident, especially after the North China Incident and the July 7th Marco Polo Bridge Incident, the worsening national crisis promoted the upsurge of modern Chinese nationalism, and this upsurge made the concept of “Chinese nation” more widely and deeply disseminated and accepted.