bluuebunny/crossref_metadata_2025 huggingface dataset:
Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples
Authors: van Werkhoven Erik , Hinsley Samantha , Frangou Eleni , Holmes Jane , de Haan Rosemarie , Hawkins Maria , Brown Sarah , Love Sharon B
Published: June 2020

Background

Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples.

Methods

The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose.

We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies.

Results

In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion.

Conclusion

Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.
Increasing questionnaire response: evidence from a nested RCT within a longitudinal birth cohort study
Authors: Goodwin Michaela , Walsh Tanya , Whittaker William , Emsley Richard , Sutton Matt , Tickle Martin , Kelly Michael P. , Pretty Iain A.
Published: June 2020

Background

High response rates are essential when questionnaires are used within research, as representativeness can affect the validity of studies and the ability to generalise the findings to a wider population.

The study aimed to measure the response rate to questionnaires from a large longitudinal epidemiological study and sought to determine if any changes made throughout data collection had a positive impact on the response to questionnaires and addressed any imbalance in response rates by participants’ levels of deprivation.

Methods

Data were taken from a prospective, comparative study, designed to examine the effects of the reintroduction of water fluoridation on children’s oral health over a five-year period. Response rates were analysed for the first year of data collection. During this year changes were made to the questionnaire layout and cover letter to attempt to increase response rates. Additionally a nested randomised control trial compared the effect on response rates of three different reminders to complete questionnaires.

Results

Data were available for 1824 individuals. Sending the complete questionnaire again to non-responders resulted in the highest level of response (25%). A telephone call to participants was the only method that appeared to address the imbalance in deprivation, with a mean difference in deprivation score of 2.65 (95% CI -15.50 to 10.20) between the responders and non-responders.

Conclusions

Initially, low response rates were recorded within this large, longitudinal study giving rise to concerns about non-response bias. Resending the entire questionnaire again was the most effective way of reminding participants to complete the questionnaire. As this is a less labour intensive method than for example, calling participants, more time can then be spent targeting groups who are underrepresented. In order to address these biases, data can be weighted in order to draw conclusions about the population.
Research methodology and characteristics of journal articles with original data, preprint articles and registered clinical trial protocols about COVID-19
Authors: Fidahic Mahir , Nujic Danijela , Runjic Renata , Civljak Marta , Markotic Filipa , Lovric Makaric Zvjezdana , Puljak Livia
Published: June 2020

Background

The research community reacted rapidly to the emergence of COVID-19. We aimed to assess characteristics of journal articles, preprint articles, and registered trial protocols about COVID-19 and its causal agent SARS-CoV-2.

Methods

We analyzed characteristics of journal articles with original data indexed by March 19, 2020, in World Health Organization (WHO) COVID-19 collection, articles published on preprint servers medRxiv and bioRxiv by April 3, 2010. Additionally, we assessed characteristics of clinical trials indexed in the WHO International Clinical Trials Registry Platform (WHO ICTRP) by April 7, 2020.

Results

Among the first 2118 articles on COVID-19 published in scholarly journals, 533 (25%) contained original data. The majority was published by authors from China (75%) and funded by Chinese sponsors (75%); a quarter was published in the Chinese language. Among 312 articles that self-reported study design, the most frequent were retrospective studies (N = 88; 28%) and case reports (N = 86; 28%), analyzing patients’ characteristics (38%). Median Journal Impact Factor of journals where articles were published was 5.099.

Among 1088 analyzed preprint articles, the majority came from authors affiliated in China (51%) and were funded by sources in China (46%). Less than half reported study design; the majority were modeling studies (62%), and analyzed transmission/risk/prevalence (43%).

Of the 927 analyzed registered trials, the majority were interventional (58%). Half were already recruiting participants. The location for the conduct of the trial in the majority was China (N = 522; 63%). The median number of planned participants was 140 (range: 1 to 15,000,000). Registered intervention trials used highly heterogeneous primary outcomes and tested highly heterogeneous interventions; the most frequently studied interventions were hydroxychloroquine (N = 39; 7.2%) and chloroquine (N = 16; 3%).

Conclusions

Early articles on COVID-19 were predominantly retrospective case reports and modeling studies. The diversity of outcomes used in intervention trial protocols indicates the urgent need for defining a core outcome set for COVID-19 research. Chinese scholars had a head start in reporting about the new disease, but publishing articles in Chinese may limit their global reach. Mapping publications with original data can help finding gaps that will help us respond better to the new public health emergency.
Spatio-temporal analysis of socio-economic characteristics for pulmonary tuberculosis in Sichuan province of China, 2006–2015
Authors: Xia Lan , Zhu Sui , Chen Chuang , Rao Zheng-Yuan , Xia Yong , Wang Dan-Xia , Zhang Pei-Ru , He Jinge , Zhang Ju-Ying , Wu Jian-Lin
Published: June 2020

Background

The disease burden caused by pulmonary tuberculosis (TB) in Sichuan province still persisted at a high level, and large spatial variances were presented across regional distribution disparities. The socio-economic factors were suspected to affect the population of TB notification, we aimed to describe TB case notification rate (CNR) and identify which factors influence TB epidemic are necessary for the prevention and control of the disease in Sichuan province.

Methods

A retrospective cross-sectional study and an ecological spatial analysis was conducted to quantify the presence and location of spatial clusters of TB by the Moran’sIindex and examined these patterns with socio-economic risk factors by hierarchical Bayesian spatio-temporal model.

Results

A total of 630,009 pulmonary TB cases were notified from 2006 to 2015 in 181 counties of Sichuan province. The CNR decreased year by year since 2007, from 88.70 to 61.37 per 100,000 persons. The spatial heterogeneities of CNR were observed during the study periods. Global Moran’sIindex varied from 0.23 to 0.44 with allP-value < 0.001. The Bayesian spatio-temporal model with parametric spatio-temporal interactions was chosen as the best model according to the minimum of Deviance Information Criterion (DIC)(19,379.01), and in which the quadratic form of time was taken. The proportion of age group and education year were all associated with CNR after adjusting the spatial effect, temporal effect and spatio-temporal interactions. TB CNR increased by 10.2% [95% credible interval (CI): 6.7–13.7%] for every 1-standard-deviation increase in proportion of age group and decreased by 23% (95%CI: 13.7–32.7%) for every 1-standard-deviation increase in education year.

Conclusions

There were spatial clusters of TB notification rate in Sichuan province from 2006 to 2015, and heavy TB burden was mainly attributed to aging and low socioeconomic status including poor education. Thus, it is more important to pay more attention to the elderly population and improve socioeconomic status including promoting education level in Sichuan province to reduce the TB burden.
Fungal arthritis with adjacent osteomyelitis caused by Candida pelliculosa: a case report
Authors: Song Kwang Yun , Park Chulmin , Byun Ji-Hyun , Chun Hye-Sun , Choi Jung-Hyun , Han Eun Hee , Lee Seung Ok , Jeong Yeonjeong , Kim Youn Jeong , Kim Si-Hyun
Published: June 2020

Background

Candidasp. osteoarticular infection is rare and most often due to hematogenous seeding during an episode of candidemia in immunocompromised patients. However, the diagnosis can be delayed in patients with subtle symptoms and signs of joint infection without a concurrent episode of candidemia.

Case presentation

A 75-year-old woman presented with a three-year history of pain and swelling of the left knee.Candida pelliculosawas detected from the intraoperative tissue when the patient had undergone left total knee arthroplasty 32 months ago, but no antifungal treatment was performed. One year after the total knee arthroplasty,C. pelliculosawas repeatedly isolated from the left knee synovial fluid and antifungal treatment comprising amphotericin B deoxycholate and fluconazole was administered. However, joint infection had extended to the adjacent bone and led to progressive joint destruction. The patient underwent surgery for prosthesis removal and received prolonged antifungal treatment with micafungin and fluconazole.

Conclusions

This case shows thatC. pelliculosa, an extremely rare non-Candida albicans sp.,can cause fungal arthritis and lead to irreversible joint destruction owing to delayed diagnosis and treatment.
Twelve months of exercise training did not halt abdominal aortic calcification in patients with CKD – a sub-study of RENEXC-a randomized controlled trial
Authors: Zhou Yunan , Hellberg Matthias , Hellmark Thomas , Höglund Peter , Clyne Naomi
Published: June 2020

Background

Arteriosclerosis is prevalent in patients with chronic kidney disease (CKD). Our aims were to investigate (1) the effects of 12 months of either balance- or strength- both in combination with endurance training on abdominal aortic calcification (AAC); on some lipids and calcific- and inflammatory markers; and (2) the relationships between the change in AAC score and these markers in non-dialysis dependent patients with CKD stages 3 to 5.

Methods

One hundred twelve patients (mean age 67 ± 13 years), who completed 12 months of exercise training; comprising either balance- or strength training, both in combination with endurance training; with a measured glomerular filtration rate (mGFR) 22.6 ± 8 mL/min/1.73m2, were included in this study. AAC was evaluated with lateral lumbar X-ray using the scoring system described by Kauppila. Plasma fetuin-A, fibroblast growth factor 23 (FGF23) and interleukin 6 (IL6) were measured with Enzyme-linked immunosorbent assay (ELISA) kits.

Results

After 12 months of exercise training, the AAC score increased significantly in both groups; mGFR and lipoprotein (a) decreased significantly in both groups; parathyroid hormone (PTH) and 1,25(OH)2D3 increased significantly only in the strength group; fetuin-A increased significantly only in the balance group. Plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, FGF23, phosphate, calcium, IL6, C-reactive protein (CRP), albumin were unchanged. The increase in AAC score was positively related to ageing and the levels of baseline triglycerides and lipoprotein (a).

Conclusions

Exercise training did not prevent the progression of AAC; it might have contributed to the reduced levels of lipoprotein (a) and unchanged levels of calcific- and inflammatory markers in these patients with non-dialysis dependent CKD. Hypertriglyceridemia, high levels of lipoprotein (a) and ageing emerged as longitudinal predictors of vascular calcification in these patients.

Trial registration

NCT02041156 at www.ClinicalTrials.gov. Date of registration: January 20, 2014. Retrospectively registered.
Making therapies culturally relevant: translation, cultural adaptation and field-testing of the Thinking Healthy Programme for perinatal depression in China
Authors: Nisar Anum , Yin Juan , Yiping Nan , Lanting Huo , Zhang Jingjun , Wang Duolao , Rahman Atif , Li Xiaomei
Published: June 2020

Background

The prevalence of perinatal depression in China ranges from 15 to 20% and the vast majority of prenatally depressed women do not receive the intervention they require. Recent research evidence shows that evidence based, culturally–adapted psychosocial interventions are effective in reducing mental health problems. The World Health Organization (WHO) has endorsed the Thinking Healthy Programme (THP), which is an evidence based psychosocial intervention that can be delivered by non-mental health specialists. The aim of this study was to translate and adapt THP for the Chinese population and to establish its acceptability when delivered by non-specialists to a group of mothers with perinatal depression.

Methods

The study was conducted in two phases. The THP manual, handbook, and health calendar was translated and adapted based on 8 domains of the Bernal framework (language, metaphors, content, concepts, goals, context, people and methods). Pre-testing was done using cognitive interviewing in the first phase. In second phase of field-testing, THP sessions were delivered to the depressed women by local THP trained nurses. Post intervention, programme survey was used for evaluation.

Results

This study showed that the core structure, process and techniques of the THP were culturally compatible with the target Chinese population and did not require major changes. It was found that the adapted version of THP manual, handbook, and health calendar were acceptable, understandable, and culturally relevant to the Chinese women and their family members. Nurses were found as a suitable delivery agent by the mothers and their families.

Conclusion

The Thinking Healthy Programme is acceptable and transferable to the Chinese cultural and healthcare context and nurses are a suitable delivery agent. The translated and adapted version of THP can be used for further implementation and evaluation studies in the Chinese context. Further evaluation can help establish the effectiveness of the programme and barriers to scale-up in China.
Unlocking community capabilities for addressing social norms/practices: behavioural change intervention study to improve birth preparedness and complication readiness among pregnant women in rural Nigeria
Authors: Eze Irene Ifeyinwa , Mbachu Chinyere Ojiugo , Ossai Edmund Ndudi , Nweze Celestina Adaeze , Uneke Chigozie Jesse
Published: June 2020

Background

Maternal mortality is attributed to combination of contextual factors that cause delay in seeking care, leading to poor utilization of skilled health services. Community participation is one of the acknowledged strategies to improve health services utilization amongst the poor and rural communities. The study aimed at assessing the potentials of improving birth preparedness and complication readiness (BP/CR) using community-driven behavioural change intervention among pregnant women in rural Nigeria.

Methods

A pre-post intervention study was conducted from June 2018 to October 2019 on 158 pregnant women selected through multi-stage sampling technique from 10 villages. Data on knowledge and practices of birth preparedness and utilization of facility health services were collected through interviewer-administered pre-tested structured questionnaire. Behavioural change intervention comprising of stakeholders’ engagement, health education, facilitation of emergency transport and fund saving system, and distribution of educational leaflets/posters were delivered by twenty trained volunteer community health workers. The intervention activities focused on sensitization on danger signs of pregnancy, birth preparedness and complication readiness practices and emergency response. Means, standard deviations, and percentages were calculated for descriptive statistics; and T-test and Chi square statistical tests were carried out to determine associations between variables. Statistical significance was set atp-value < 0.05.

Results

The result showed that after the intervention, mean knowledge score of danger signs of pregnancy increased by 0.37 from baseline value of 3.94 (p < 0.001), and BP/CR elements increased by 0.27 from baseline value of 4.00 (p < 0.001). Mean score for BP/CR practices increased significantly by 0.22 for saving money. The proportion that had antenatal care (76.6%) and had facility delivery (60.0%) increased significantly by 8.2 and 8.3% respectively. Participation in Community-related BP/CR activities increased by 11.6% (p = 0.012).

Conclusion

With the improvements recorded in the community-participatory intervention, birth preparedness and complication readiness should be promoted through community, household and male-partner inclusive strategies. Further evaluation will be required to ascertain the sustainability and impact of the programme.
Amplification of KRAS and its heterogeneity in non-Asian gastric adenocarcinomas
Authors: Rehkaemper Jan , Korenkov Michael , Quaas Alexander , Rueschoff Josef , Pamuk Aylin , Zander Thomas , Hillmer Axel M. , Buettner Reinhard , Hoelscher Arnulf Heinrich , Bruns Christiane Josephine , Loeser Heike , Alakus Hakan , Schoemig-Markiefka Birgid
Published: June 2020

Background

Gastric cancer is one of the deadliest cancer entities worldwide. While surgery is the only curative treatment option in early tumors, for locally advanced and metastatic patients further therapeutic targets are needed. Several studies not only reported mutations but also amplifications of the KRAS locus in different cancer entities. More recently, KRAS amplification was discussed as a new therapeutic target. Little is known about the (prognostic) relevance and (heterogenic) distribution of KRAS amplification in gastric adenocarcinomas, especially in Non-Asian patients.

Methods

Amplification of the KRAS locus and corresponding protein expression was analyzed in 582 gastric adenocarcinomas employing fluorescence in-situ hybridization (FISH) and immunohistochemistry. Amplification status was correlated with clinico-pathological features, clinical outcome and molecular tumor data including a correlation to the TCGA subtypes of gastric carcinoma.

Results

KRAS amplification was detected in 27 out of 470 analysable tumors (5.7%) and correlated with protein expression of KRAS in all amplified tumors. Within the KRAS amplified gastric tumors 14/27 (51.9%) showed a heterogeneous distribution with also KRAS non-amplified tumor parts. According to TCGA 24 tumors (88.8%) were related to chromosomal instable tumors (CIN). The survival analysis of the entire patient cohort did not show any difference in overall survival in dependence on the KRAS status. However, a significant survival difference with a worse outcome for patients with KRAS amplified tumors was identified when analysing patients without neoadjuvant pre-treatment.

Conclusions

We confirm the unfavorable prognosis of KRAS amplified tumors reported by other studies in (Asian) patient groups, at least in patients without neoadjuvant pre-treatment. Within KRAS amplified tumors we revealed intratumoral heterogeneity that may define a (more aggressive) tumor cell population which is more frequently observed in patients with lymph node metastases. Despite the heterogeneous distribution of KRAS amplified tumor clones, KRAS amplified locally advanced or metastasized gastric adenocarcinomas represent a therapeutically highly relevant tumor subgroup.
A severe presentation of chronic non-infectious osteomyelitis associated with ulcerative colitis: a case report
Authors: Lorenze Alyssa , Meadows Lukas , Kehinde Temitope , Menchini Cortney Ballengee
Published: June 2020

Background

Chronic Non-Infectious Osteomyelitis (CNO) is a chronic, relapsing, self-limiting inflammation of the bone. Although it is rare, CNO has been associated with inflammatory bowel disease and frequently precedes the initial diagnosis. We present a case of CNO in a patient with known ulcerative colitis in clinical remission who presented with purulent multifocal joint effusions in the setting of elevated inflammatory markers and fever suspicious for bacterial osteomyelitis.

Case presentation

Our patient is a 12-year-old girl with ulcerative colitis who presented with fevers and insidious onset of joint pain at multiple sites. She had multiple joint effusions on imaging and blood and joint cultures were negative. Biopsy of the left acromion demonstrated acute and chronic osteomyelitis with areas of necrosis and granulomatous inflammation suggestive of CNO. Patient was started on high dose corticosteroids as well as methotrexate injections with marked improvement in symptoms.

Conclusion

This case highlights that while purulent effusions are often indicative of bacterial osteomyelitis, the consideration of CNO in a patient with inflammatory bowel disease (IBD) with multifocal small bone involvement and negative blood cultures should be considered.
The impact of sleep deprivation and alcohol on driving: a comparative study
Authors: Lowrie Joanna , Brownlow Helen
Published: June 2020

Background

There is concern about the detrimental effects of shift-workers’ increasing working hours particularly when driving sleep deprived. The approach to measuring the magnitude of driving impairment caused by sleep deprivation was by comparing it to alcohol. The study compared driving performance after 24-h of wakefulness to performance with a BrAC of just over 22 μg/100mls of breath which is equal to 50 mg of alcohol per 100mls of blood (Scottish drink-drive limit). The effectiveness of coffee as a countermeasure for driver fatigue and the association between subjective impairment and actual performance was also investigated.

Methods

A study of 30 participants (11 male and 19 female; mean age 21) was conducted. Subjects were tested under three conditions: fully rested, sleep deprived, and alcohol intoxicated – BrAC mean [SD] 25.95 μg [2.78]. Under each condition, subjects were tested before and after coffee ingestion. This involved driving simulation (Lane Change Task and Reaction Test) and subjective Likert scales (Karolinska Sleepiness Scale and driver impairment scale). Outcome measures included lane tracking adaptive mean deviation, reaction time, and subjective sleepiness and impairment ratings.

Results

Compared to alcohol, sleep deprived mean reaction times were slower (2.86 s vs. 2.34 s) and lateral control of the vehicle was reduced (lane tracking adaptive mean deviation: 0.5 vs. 0.3). Coffee did not produce an improvement when sleep deprived, and instead, performance deteriorated. Females were less impaired following sleep deprivation than males. Following prolonged wakefulness, the correlation between subjective impairment and actual performance was significant.

Conclusions

It was concluded that sleep deprivation has a greater impact on driving performance than a BrAC of 22 μg/100mls of breath, as measured by driving simulation. Coffee is not an effective countermeasure for sleep deprived driving and drivers’ ability to judge this impairment is suggested to be limited.
Socioeconomic and demographic determinants of familial social capital inequalities: a cross-sectional study of young people in sub-Saharan African context
Authors: Addae Evelyn Aboagye
Published: June 2020

Background

Social capital is broadly acknowledged as a vital ‘health asset’ that promotes young people’s health and wellbeing and has the potential to prevent social- and health-related risk behaviours in the life-course. However, limited research has investigated the determinants of social capital for young people in sub-Saharan Africa. This study examines the role of socioeconomic and demographic factors in establishing inequalities in familial social capital among young people in Ghana.

Methods

The study utilised a cross-sectional survey data involving 2068 in-school adolescents (13-18 years) in the Upper West Region, Ghana. Familial social capital was assessed by ‘family sense of belonging’, ‘family autonomy support’ and ‘family control’. Multinomial logistic regressions established the relationships between socioeconomic and demographic factors and the measures of familial social capital.

Results

Adolescents from low affluence households had about 63 and 61% lower odds of attaining a high family sense of belonging (FSB) (OR = 0.373; 95%CI: 0.27–0.513) and high family autonomy support (FAS) (OR = 0.387; 95%CI: 0.270–0.556) respectively but had 67% higher odds of reporting high family control (FC) (OR = 1.673; 95%CI: 1.187–2.359) than their counterparts. Males had about 55 and 71% higher odds to possess high FSB (OR = 1.549; 95%CI: 1.210–1.983) and high FAS (OR = 1.705; 95%CI: 1.272–2.284) respectively but had 38% lower odds to report high family control (OR = 0.624; 95%CI: 0.474–0.822) than females. The odd of young adolescents to attain high FSB than older adolescents were about 66% higher (OR = 1.662; 95%CI: 1.168–2.367). Religion, educational level, ethnicity, family structure, and marital status were also significant predictors of adolescents’ family sense of belonging, family autonomy support and, family control.

Conclusions

Socioeconomic and demographic factors influence inequalities in the amount of familial social capital possessed by young people which suggests possible risks of social inequality. The family context is possibly failing some cohorts of young people with particular reference to female and poor adolescents regarding familial cognitive social capital. Public health strategies should include families in addressing socioeconomic and demographic differences in social capital with a key focus on the cohorts of young people at risk of social capital inequality.
Physician preferences for non-metastatic castration-resistant prostate cancer treatment
Authors: Srinivas Sandy , Mohamed Ateesha F. , Appukkuttan Sreevalsa , Botteman Marc , Ng Xinyi , Joshi Namita , Horodniceanu Erica , Waldeck A. Reginald , Simmons Stacey J
Published: June 2020

Background

Recent approvals of second-generation androgen receptor inhibitors (SGARIs) have changed the treatment landscape for non-metastatic castration-resistant prostate cancer (nmCRPC). These SGARIs have similar efficacy but differ in safety profiles. We used a discrete choice experiment to explore how United States physicians make treatment decisions between adverse events (AEs) and survival gains in nmCRPC, a largely asymptomatic disease.

Methods

Treating physicians (n = 149) participated in an online survey that included 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied in terms of 5 safety and 2 efficacy attributes. We described safety attributes (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency, and efficacy attributes (overall survival [OS] and time to pain progression) in terms of duration of effect. We used a random parameters logit model to estimate preference weights and importance scores for each attribute. We also estimated the amount of survival gain physicians were willing to trade for a reduction in specific AEs between treatment options.

Results

Physicians placed more importance on survival than on time to pain progression, and viewed a reduction in cognitive problems from severe to none, a reduction in risk of a serious fracture from 8% to none, and a reduction in fatigue from severe to none as the most important safety attributes. Physicians were willing to forego 9.1 and 6.6 months of OS, respectively, to reduce cognitive problems and fatigue from severe to mild-to-moderate. To reduce the risk of a serious fracture from 8 to 5% and 5% to none, physicians were willing to trade 3.9 and 5.3 months of OS, respectively.

Conclusions

Physicians were willing to trade substantial amounts of survival to avoid AEs between hypothetical treatments. These results emphasize the importance of carefully balancing therapies’ benefits and risks to ultimately optimize the overall quality of nmCRPC patients’ survival. Nonetheless, it is noted that the results from the study sample of 149 physicans may not be representative of the viewpoints of all nmCRPC-treating physicians.
Expression of epithelial-Mesenchymal transition related markers in Plasmacytoid Urothelial carcinoma of the urinary bladder
Authors: Nomura Shunichiro , Suzuki Yasutomo , Akatsuka Jun , Endo Yuki , Shimizu Akira , Hamasaki Tsutomu , Kimura Go , Kondo Yukihiro
Published: June 2020

Background

Plasmacytoid urothelial carcinoma (PUC) of the urinary bladder is a variant of urothelial carcinoma that carries a poor prognosis. The epithelial-mesenchymal transition (EMT) has been demonstrated to contribute to tumor progression. As the cause of the increased aggressiveness of PUC is unknown, we investigated PUC and EMT-related marker expression.

Methods

A total of 633 bladder carcinoma cases diagnosed from 2006 to 2015 at the Nippon Medical School Hospital were analyzed. Twelve patients were found to have plasmacytoid histology and diagnosed with PUC. Slides were evaluated for percentage of plasmacytoid variant, and stained for E-cadherin, N-cadherin, Vimentin, Fibronectin and Snail expression.

Results

The incidence of PUC was 1.9% (12/633). The median patient age at diagnosis was 71 years (range, 60–80 years) and the male-female ratio was 11:1. All but three patients had stage T2b or higher. The median overall survival was 10 months. In 10/12 cases, Snail and N-cadherin were positive. Vimentin was positive in 9/12 cases. Fibronectin was positive in 8/12 cases. While E-cadherin was negative in 10/12 cases. Nine cases showed > 10% plasmacytoid component. Eight of the nine patients (88.9%) with > 10% plasmacytoid component died.

Conclusions

The results indicate that PUC may induce EMT and may be associated with high invasion.
Repair of osteochondral defect using icariin-conditioned serum combined with chitosan in rabbit knees
Authors: Zhang Juntao , Ming Dong , Ji Qiang , Liu Aifeng , Zhang Chao , Jiao Jianjie , Shang Man
Published: June 2020

Background

Osteochondral defects caused by an acute traumatic injury or articular degeneration remains difficult to be manipulated. Repair of articular defects is still a great challenge for both tissue engineers and orthopedic surgeons. Therefore, combination of biomaterials with cartilage promotive drugs is well worth being developed to support the regeneration of both cartilage and subchondral bone.

Methods

Rabbits undergoing osteochondral defect surgery were intrarticularly injected with icariin-conditioned serum (ICS), chitosan (CSSH) and combination of ICS with CSSH, respectively. Gait analysis was performed using VICON motion capture system. ICRS score and immunohistochemical (IHC) analysis including H&E, Safranin O, toluidine blue and collagen II staining was employed to evaluate macroscopic cartilage regeneration and determine the morphologic repair of cartilage.

Results

Rabbits with the treatment of ICS or CSSH alone showed mild improvement in hopping time and range of joint angles while ICS-CSSH group exhibited longer jumping time and larger range of joint angles. In addition, femoral condyle in ICS-CSSH rabbits could be seen with more native cartilage and subchondral bone regeneration in both macroscopic observation and IHC analysis.

Conclusion

ICS combined with CSSH could promote the repair of osteochondral defect in rabbit knees. Combination of biomaterials with cartilage promotive drugs may ultimately have profound implications in the management of cartilage defect.
Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma
Authors: García-Romero N. , Palacín-Aliana I. , Madurga R. , Carrión-Navarro J. , Esteban-Rubio S. , Jiménez B. , Collazo A. , Pérez-Rodríguez F. , Ortiz de Mendivil A. , Fernández-Carballal C. , García-Duque S. , Diamantopoulos-Fernández J. , Belda-Iniesta C. , Prat-Acín R. , Sánchez-Gómez P. , Calvo E. , Ayuso-Sacido A.
Published: June 2020

Background

Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival.

Methods

We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment.

Results

We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance.

Conclusions

Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.
Chromatin run-on sequencing analysis finds that ECM remodeling plays an important role in canine hemangiosarcoma pathogenesis
Authors: Mukai Chinatsu , Choi Eunju , Sams Kelly L. , Klampen Elena Zu , Anguish Lynne , Marks Brooke A. , Rice Edward J. , Wang Zhong , Choate Lauren A. , Chou Shao-Pei , Kato Yukinari , Miller Andrew D. , Danko Charles G. , Coonrod Scott A.
Published: June 2020

Background

Canine visceral hemangiosarcoma (HSA) is a highly aggressive cancer of endothelial origin that closely resembles visceral angiosarcoma in humans, both clinically and histopathologically. Currently there is an unmet need for new diagnostics and therapies for both forms of this disease. The goal of this study was to utilize Chromatin run-on sequencing (ChRO-seq) and immunohistochemistry (IHC) to identify gene and protein expression signatures that may be important drivers of HSA progression.

Results

ChRO-seq was performed on tissue isolated from 17 HSA samples and 4 normal splenic samples. Computational analysis was then used to identify differentially expressed genes and these factors were subjected to gene ontology analysis. ChRO-seq analysis revealed over a thousand differentially expressed genes in HSA tissue compared with normal splenic tissue (FDR < 0.005). Interestingly, the majority of genes overexpressed in HSA tumor tissue were associated with extracellular matrix (ECM) remodeling. This observation correlated well with our histological analysis, which found that HSA tumors contain a rich and complex collagen network. Additionally, we characterized the protein expression patterns of two highly overexpressed molecules identified in ChRO-seq analysis, podoplanin (PDPN) and laminin alpha 4 (LAMA4). We found that the expression of these two ECM-associated factors appeared to be largely limited to transformed endothelial cells within the HSA lesions.

Conclusion

Outcomes from this study suggest that ECM remodeling plays an important role in HSA progression. Additionally, our study identified two potential novel biomarkers of HSA, PDPN and LAMA4. Interestingly, given that function-blocking anti-PDPN antibodies have shown anti-tumor effects in mouse models of canine melanoma, our studies raise the possibility that these types of therapeutic strategies could potentially be developed for treating canine HSA.
Clinical, haematological and biochemical findings in tigers infected by Leishmania infantum
Authors: Cavalera Maria Alfonsa , Iatta Roberta , Laricchiuta Pietro , Passantino Giuseppe , Abramo Francesca , Mendoza-Roldan Jairo Alfonso , Otranto Domenico , Zatelli Andrea
Published: June 2020

Background

A large number of animal species are susceptible to Leishmania infantum (Kinetoplastida, Trypanosomatidae) in endemic areas, including domestic and wild felids such as tigers (Panthera tigris). Knowledge on the infection of this endangered species is still at its infancy, and therefore this study aims to identify clinical presentation and clinicopathological findings of tigers naturally infected by L. infantum.

Results

Tigers either L. infantum-positive (group A) or -negative (group B) were apparently healthy or presented visceral leishmaniasis unrelated conditions, except for one animal in which a large non-healing cutaneous lesion was observed. However, histological exam and immunohistochemistry carried out on the lesion excluded the presence of L. infantum amastigotes. Biochemical analysis showed that the average concentration of total proteins, globulins and haptoglobin were significantly higher (p < 0.01, p = 0.01 and p = 0.02, respectively), while the albumin/globulin ratio significantly lower (p = 0.05) in group A compared with group B. The biochemical alterations were partially confirmed by the serum protein electrophoresis results revealing a significant increase in the total protein value (p = 0.01) and hypergammaglobulinemia (p = 0.03) but an unmodified albumin/globulin ratio in group A.

Conclusions

In this study tigers infected by L. infantum have shown to be mainly asymptomatic. The absence of clinical signs may lead veterinarians to overlook leishmaniasis in animals kept in captivity. Therefore, diagnostic and screening tests as serology should be part of routinely surveillance programs to be performed on tigers in zoological gardens located in endemic areas. Though only few protein-related laboratory abnormalities were recorded in infected animals, they could provide diagnostic clues for a first suspicion of L. infantum infection in tigers. Indeed, considering the high risk of zoonotic transmission in heavily frequented environment as zoos, a prompt diagnosis of L. infantum infection is of pivotal importance.
Rapid differentiation of PEDV wild-type strains and classical attenuated vaccine strains by fluorescent probe-based reverse transcription recombinase polymerase amplification assay
Authors: Wang Zhilin , Li Xuerui , Shang Youjun , Wu Jinyan , Dong Zhen , Cao Xiaoan , Liu Yongsheng , Lan Xi
Published: June 2020

Background

Porcine epidemic diarrhea virus (PEDV), an intestinal coronavirus that causes acute diarrhea and high mortality in suckling piglets, can result in high economic losses in the swine industry. In recent years, despite the use of China’s current vaccine immunization strategy, multiple types of PEDV strains were still found in immunized swine herds. Our research aims to explore a new rapid differentiation method to distinguish the different types of PEDV strains and assess the safety evaluation of classical attenuated vaccine strains in swine herds.

Results

In the study, a differential one-step quantitative real-time fluorescent reverse transcription recombinase polymerase amplification (real-time RT-RPA) method based on the PEDV universal real-time RT-RPA assay was established according to the ORF1 deletion sequences of three classical attenuated vaccine strains (PEDV attenuated vaccine KC189944, attenuated CV777 and DR13) and five Vero cell-adapted isolates (JS2008, SDM, SQ2014, SC1402, HLJBY), which could effectively differentiate PEDV classical attenuated vaccine strains from wild-type strains (PEDV classical wild strains and variant strains). The detection limits of PEDV RNA in the both PEDV real-time RT-RPA assays were 300 copies within 20 min at 39 °C, and the detection limits of classical attenuated vaccine strain CV777, Vero-cell-adapted isolate JS2008, and PEDV wild-type strain DX were 100.5 TCID50/100 μL, 101.1 TCID50/100 μL, and 101.2 TCID50/100 μL, respectively. Both assays were highly specific for PEDV, showing no cross-reactivity with other enteral viruses.

Conclusion

This RPA method we developed is simple, time-effective, and safe and provides a reliable technical tool for the differential diagnosis and clinical epidemic surveillance of PEDV classical attenuated vaccine strains and wild-type strains.
Pulmonary complications in dogs with acute presentation of pancreatitis
Authors: Gori Eleonora , Pierini Alessio , Ceccherini Gianila , Citi Simonetta , Mannucci Tommaso , Lippi Ilaria , Marchetti Veronica
Published: June 2020

Background

In humans, respiratory complications in patients with acute pancreatitis (AP) are a common life-threatening comorbidity. Since possible lung impairment has not been individually evaluated in canine AP, the aims of the present study were to: (1) describe the prevalence, types and severity of pulmonary complications in dogs with acute presentation of AP, and (2) evaluate their association with mortality. AP diagnosis was based on compatible clinical and laboratory parameters, abnormal canine pancreatic-lipase test, and positive abdominal ultrasound within 48 h from admission. The canine acute pancreatitis severity score (CAPS) was calculated for each dog at admission. Arterial blood gas analysis and thoracic radiography were performed at admission. Thoracic radiography was classified on the basis of pulmonary pattern (normal, interstitial or alveolar) and a modified lung injury score (mLIS) was applied to the ventrodorsal projections for each dog. VetALI/VetARDS were diagnosed using current veterinary consensus. Dogs were divided into non-survivors or survivors (hospital discharge). Clinical, radiological and blood gas parameters collected at presentation were compared between survivors and non-survivors and associated with mortality.

Results

This prospective cohort study included twenty-six client-owned dogs with AP. Twelve out of twenty-six dogs (46%) died or were euthanized. At admission, thirteen dogs showed respiratory distress at physical examination, which was associated with death (P < 0.001). Radiographic abnormalities were found in twenty-one dogs: alveolar (n = 11) and interstitial pattern (n = 10). Radiographic alterations and mLIS score were both associated with death (P = 0.02 andP = 0.0023). The results of the arterial blood-gas evaluation showed that non-survivors had lower PaCO2and HCO3−levels, and higher A-a gradient than survivors (P = 0.0014,P = 0.019 andP = 0.004, respectively). Specifically, three dogs had aspiration pneumonia, and VetALI was diagnosed in nine dogs (34.6%), and no dogs met the criteria for VetARDS. The presence of VetALI was associated with mortality (P < 0.001).

Conclusions

As with humans, possible lung impairments, such as VetALI, should be investigated in dogs with acute presentation of pancreatitis.
A study to assess the correlation between plasma, oral fluid and urine concentrations of flunixin meglumine with the tissue residue depletion profile in finishing-age swine
Authors: Bates Jessica L. , Karriker Locke A. , Rajewski Suzanne M. , Lin Zhoumeng , Gehring Ronette , Li Mengjie , Riviere Jim E. , Coetzee Johann F.
Published: June 2020

Background

Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data.

Results

Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4–16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing.

Conclusions

Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue statuses of flunixin in pigs at earlier time points (≤24 h) by using a PBPK model.