bluuebunny/crossref_metadata_2025 huggingface dataset:
The History of *=a
Authors: Daniels Don , Brooks Joseph
Published: February 2020

This paper discusses the historical borrowing of an enclitic across unrelated Papuan languages spoken along the lower Sogeram River in the Middle Ramu region of present-day Madang Province, Papua New Guinea. The enclitic *=a, which attached to the right edge of a prosodic unit, was borrowed from the Ramu family into the ancestor of three modern Sogeram languages. Both morphological and prosodic substance were borrowed, as was the dual functionality of the enclitic – as a pragmatic marker in independent utterances and a linking device on dependent domains. We discuss the clitic’s formal and functional properties as evidence for its contact-induced origin and subsequent historical development in western Sogeram, as well as the implications of these developments for our understanding of morphological and pragmatic borrowing. The complexities of this borrowing event highlight the potential for theories of language contact to benefit from collaborative research on previously unstudied contact areas.
On the Intrusion of the Spanish Preposition de into the Languages of Mexico
Authors: Hober Nicole
Published: February 2020

In this article, I examine the intrusion of the Spanish preposition de into the languages of Mexico. Following Matras and Sakel (2007), I apply the distinction of matter (mat) and pattern (pat). The exploration of the 35 Archivo de lenguas indígenas de México publications which serve as a comparable database shows that Chontal, Mexicanero, Nahuatl de Acaxochitlán, Otomi, Yucatec, Zoque, and Zapotec, have borrowed de or a variant thereof. All languages give evidence of combined mat/pat-borrowing, while five of the seven languages also exhibit mat-borrowing only. The results demonstrate that none of the replica languages fully complies with the Spanish pattern regarding the usage of de. Indeed, it is essential to identify the functional domain of de in each recipient language separately. Further, the findings are briefly reviewed in light of processing factors corroborating the prominent role of frequency in language change.
Taxonomic notes on Ilex sect. Ilex (Aquifoliaceae) from China II: Revision of I. fargesii and related species based on molecular and morphological evidence

Authors: YANG YI , CHEN LI , SUN LU , PENG HUA
Published: February 2020

Based on the results of phylogenetic reconstructions employing two nuclear ribosomal DNA loci (ITS and ETS), as well as morphological observation and comparisons of branches, leaves, inflorescences/infructescences and pyrenes, a taxonomic revision of three species of Ilex from China is conducted and presented herein. Ilex fargesii is subdivided into I. fargesii subsp. fargesii and I. fargesii subsp. melanotricha, with I. fargesii var. angustifolia and I. fargesii var. brevifolia newly treated as synonyms of the type subspecies. The split of the two subspecies of I. fargesii in the molecular phylogeny is conformed with their divergence in distribution, which is clearly separated by the Tanaka-Kaiyong Line. Similar geographic disjunction is also revealed in the two subspecies of I. wattii, i.e. I. wattii subsp. wattii and I. wattii subsp. marlipoensis. Meanwhile, I. gintungensis and I. venosa newly reduced to the synonyms of I. wattii subsp. wattii, and I. marlipoensis and I. cupreonitens to I. wattii subsp. marlipoensis. Furthermore, we confirm I. pubifructa to be a newly recorded species in China and I. denticulata to be excluded from China. Both our molecular and morphological analyses do not support the synonymization of I. chartaceifolia (including I. chartaceifolia var. glabra) and I. micropyrena with I. fargesii. However, the specific status of I. chartaceifolia and I. micropyrena is not resumed in this study because of their intricate and unclear relationships with I. dunniana, I. intermedia and I. subodorata.
A checklist of aquatic nematodes from Cuban Archipelago
Authors: PÉREZ-GARCÍA JOSÉ ANDRÉS , RUIZ-ABIERNO ALEXEI , ARMENTEROS MAICKEL
Published: February 2020

The diversity of free-living aquatic nematodes is largely unknown for the Gulf of Mexico and Caribbean Sea. The Cuban Archipelago is an important part of this because of its large area and diversity of habitats. We analyzed the free-living nematodes from 83 sites from seven aquatic habitats around Cuba, to produce a checklist for many habitats, including seagrass meadows, coral degradation zones, algal turf, bare sands, unvegetated muds, freshwater and anchihaline caves, and deep-sea sediments. The checklist contains 469 species, 229 genera, 50 families, and 9 orders. Chromadorida, Enoplida, and Monhysterida were the best represented orders with 112, 100, and 83 species respectively. The most abundant species were Euchromadora vulgaris, Terschellingia longicaudata, Desmodora pontica, Sabatieria pulchra , and Epsilonema sp. Most of the listed species were new records for the region. There were differences in the number of species recorded in each habitat type, with seagrass meadows having 280 species, coral degradation zones having 139 species, deep waters having 116 species, algal turf having 114 species, bare sands having 100 species, unvegetated muds having 78 species, freshwater caves having 19 species, anchihaline caves having 16 species, and freshwater streams having 6 species. The checklist is the most comprehensive recent report of the diversity of free-living nematodes in the regions of Gulf of Mexico and Caribbean Sea. The reported diversity is higher than many other regional checklists likely reflecting the intense sampling effort and the variety of microhabitats in Cuban Archipelago.
Comparative transcriptome profiling provides insights into plant salt tolerance in seashore paspalum (Paspalum vaginatum)
Authors: Wu Peipei , Cogill Steven , Qiu Yijian , Li Zhigang , Zhou Man , Hu Qian , Chang Zhihui , Noorai Rooksana E. , Xia Xiaoxia , Saski Christopher , Raymer Paul , Luo Hong
Published: February 2020

Background

Seashore paspalum (Paspalum vaginatum), a halophytic warm-seasoned perennial grass, is tolerant of many environmental stresses, especially salt stress. To investigate molecular mechanisms underlying salinity tolerance in seashore paspalum, physiological characteristics and global transcription profiles of highly (Supreme) and moderately (Parish) salinity-tolerant cultivars under normal and salt stressed conditions were analyzed.

Results

Physiological characterization comparing highly (Supreme) and moderately (Parish) salinity-tolerant cultivars revealed that Supreme’s higher salinity tolerance is associated with higher Na+ and Ca2+ accumulation under normal conditions and further increase of Na+ under salt-treated conditions (400 mM NaCl), possibly by vacuolar sequestration. Moreover, K+ retention under salt treatment occurs in both cultivars, suggesting that it may be a conserved mechanism for prevention of Na+ toxicity. We sequenced the transcriptome of the two cultivars under both normal and salt-treated conditions (400 mM NaCl) using RNA-seq. De novo assembly of about 153 million high-quality reads and identification of Open Reading Frames (ORFs) uncovered a total of 82,608 non-redundant unigenes, of which 3250 genes were identified as transcription factors (TFs). Gene Ontology (GO) annotation revealed the presence of genes involved in diverse cellular processes in seashore paspalum’s transcriptome. Differential expression analysis identified a total of 828 and 2222 genes that are responsive to high salinity for Supreme and Parish, respectively. “Oxidation-reduction process” and “nucleic acid binding” are significantly enriched GOs among differentially expressed genes in both cultivars under salt treatment. Interestingly, compared to Parish, a number of salt stress induced transcription factors are enriched and show higher abundance in Supreme under normal conditions, possibly due to enhanced Ca2+ signaling transduction out of Na+ accumulation, which may be another contributor to Supreme’s higher salinity tolerance.

Conclusion

Physiological and transcriptome analyses of seashore paspalum reveal major molecular underpinnings contributing to plant response to salt stress in this halophytic warm-seasoned perennial grass. The data obtained provide valuable molecular resources for functional studies and developing strategies to engineer plant salinity tolerance.
Charting the landscape of graphical displays for meta-analysis and systematic reviews: a comprehensive review, taxonomy, and feature analysis
Authors: Kossmeier Michael , Tran Ulrich S. , Voracek Martin
Published: February 2020

Background

Data-visualization methods are essential to explore and communicate meta-analytic data and results. With a large number of novel graphs proposed quite recently, a comprehensive, up-to-date overview of available graphing options for meta-analysis is unavailable.

Methods

We applied a multi-tiered search strategy to find the meta-analytic graphs proposed and introduced so far. We checked more than 150 retrievable textbooks on research synthesis methodology cover to cover, six different software programs regularly used for meta-analysis, and the entire content of two leading journals on research synthesis. In addition, we conducted Google Scholar and Google image searches and cited-reference searches of prior reviews of the topic. Retrieved graphs were categorized into a taxonomy encompassing 11 main classes, evaluated according to 24 graph-functionality features, and individually presented and described with explanatory vignettes.

Results

We ascertained more than 200 different graphs and graph variants used to visualize meta-analytic data. One half of these have accrued within the past 10 years alone. The most prevalent classes were graphs for network meta-analysis (45 displays), graphs showing combined effect(s) only (26), funnel plot-like displays (24), displays showing more than one outcome per study (19), robustness, outlier and influence diagnostics (15), study selection andp-value based displays (15), and forest plot-like displays (14). The majority of graphs (130, 62.5%) possessed a unique combination of graph features.

Conclusions

The rich and diverse set of available meta-analytic graphs offers a variety of options to display many different aspects of meta-analyses. This comprehensive overview of available graphs allows researchers to make better-informed decisions on which graphs suit their needs and therefore facilitates using the meta-analytic tool kit of graphs to its full potential. It also constitutes a roadmap for a goal-driven development of further graphical displays for research synthesis.
Tele-transitions of care (TTOC): a 12-month, randomized controlled trial evaluating the use of Telehealth to achieve triple aim objectives
Authors: Noel Kimberly , Messina Catherine , Hou Wei , Schoenfeld Elinor , Kelly Gerald
Published: February 2020

Background

Poor transitions of care leads to increased health costs, over-utilization of emergency room departments, increased re-hospitalizations and causes poor patient experiences and outcomes. This study evaluated Telehealth feasibility in improving transitions of care.

Methods

This is a 12-month randomized controlled trial, evaluating the use of telehealth (remote patient monitoring and video visits) versus standard transitions of care with the primary outcomes of hospital readmission and emergency department utilization and secondary outcomes of access to care, medication management and adherence and patient engagement. Electronic Medical Record data, Health Information Exchange data and phone survey data was collected. Multi-variable logistic regression models were created to evaluate the effect of Telehealth on hospital readmission, emergency department utilization, medication adherence. Chi-square tests or Fisher’s exact tests were used to compare the percentages of categorical variables between the Telehealth and control groups. T tests or Wilcoxon rank sum tests were used to compared means and medians between the two randomized groups.

Results

The study conducted between June 2017 and 2018, included 102 patients. Compared with the standard of care, Telehealth patients were more likely to have medicine reconciliation (p = 0.013) and were 7 times more likely to adhere to medication than the control group (p = 0.03). Telehealth patients exhibited enthusiasm (p = 0.0001), and confidence that Telehealth could improve their healthcare (p = 0.0001). Telehealth showed no statistical significance on emergency department utilization (p = 0.691) nor for readmissions (p = 0.31). 100% of Telehealth patients found the intervention to be valuable, 98% if given the opportunity, reported they would continue using telehealth to manage their healthcare needs, and 94% reported that the remote patient monitoring technology was useful.

Conclusions

Telehealth can improve transitions of care after hospital discharge improving patient engagement and adherence to medications. Although this study was unable to show the effect of Telehealth on reduced healthcare utilization, more research needs to be done in order to understand the true impact of Telehealth on preventing avoidable hospital readmission and emergency department visits.

Trial registration

ClinicalTrials.Gov ID: NCT03528850 Date Registered (Retrospective): 5/18/2018.

Status: Completed.

IRB #: 970227.
STI in times of PrEP: high prevalence of chlamydia, gonorrhea, and mycoplasma at different anatomic sites in men who have sex with men in Germany
Authors:   MSM Screening Study group, Jansen Klaus , Steffen Gyde , Potthoff Anja , Schuppe Ann-Kathrin , Beer Daniel , Jessen Heiko , Scholten Stefan , Spornraft-Ragaller Petra , Bremer Viviane , Tiemann Carsten
Published: February 2020

Background

Men who have sex with men (MSM) are disproportionally affected by sexually transmitted infections (STI). STI are often extragenital and asymptomatic. Both can delay diagnosis and treatment. Approval of HIV pre-exposure prophylaxis (PrEP) might have influenced sexual behaviour and STI-prevalence of HIV- MSM. We estimated STI-prevalence and risk factors amongst HIV- and HIV+ MSM in Germany to plan effective interventions.

Methods

We conducted a nationwide, cross-sectional study between February and July 2018. Thirteen MSM-friendly STI-practices screened MSM for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Neisseria gonorrhea (NG), and Trichomonas vaginalis (TV) using self-collected rectal and pharyngeal swabs, and urine samples. APTIMA™ STI-assays (Hologic™ Inc., San Diego, USA) were used for diagnostics, and samples were not pooled. We collected information on socio-demographics, HIV-status, clinical symptoms, sexual behaviour within the last 6 months, and PrEP use. We combined HIV status and PrEP use for defining risk groups, and used directed acyclic graphs and multivariable logistic regression to identify risk factors for STI.

Results

Two thousand three hundred three MSM were included: 50.5% HIV+, median age 39 [18–79] years. Median number of male sex partners within the last 6 months was five. Sex without condom was reported by 73.6%, use of party drugs by 44.6%. 80.3% had a STI history, 32.2% of STI+ MSM reported STI-related symptoms. 27.6% of HIV- MSM used PrEP.

Overall STI-prevalence was 30.1, 25.0% in HIV−/PrEP- MSM (CT:7.2%; MG:14.2%; NG:7.4%; TV:0%), 40.3% in HIV−/PrEP+ MSM (CT:13.8%; MG:19.4%; NG:14.8%; TV:0.4%), and 30.8% in HIV+ MSM (CT:10.1%; MG:18.4%; NG:8.6%; TV:0.1%).

Being HIV+ (OR 1.7, 95%-CI 1.3–2.2), using PrEP (OR 2.0, 95%-CI 1.5–2.7), having > 5 sex partners (OR:1.65; 95%-CI:1.32–2.01.9), having condomless sex (OR:2.11.9; 95%-CI:1.65–2.86), and using party drugs (OR:1.65; 95%-CI:1.32–2.0) were independent risk factors for being tested positive for at least one STI.

Conclusions

We found a high STI-prevalence in MSM in Germany, especially in PrEP users, frequently being asymptomatic. As a relevant proportion of PrEP users will not use a condom, counselling and comprehensive STI screening is essential and should be low threshold and preferably free of cost. Counselling of PrEP users should also address use of party drugs.
Reliability and validity of the Japanese version of the INSPIRE measure of staff support for personal recovery in community mental health service users in Japan
Authors: Kotake Risa , Kanehara Akiko , Miyamoto Yuki , Kumakura Yousuke , Sawada Utako , Takano Ayumi , Chiba Rie , Ogawa Makoto , Kondo Shinsuke , Kasai Kiyoto , Kawakami Norito
Published: February 2020

Background

Supporting personal recovery in people with mental health difficulties is central to mental health services. This study aimed to develop the Japanese version of INSPIRE and Brief INSPIRE measure of staff support for personal recovery and to evaluate its reliability and validity.

Methods

A questionnaire survey was conducted from October to December 2015. The authors asked users to participate in the survey of 14 community mental health services in the Kanto region of Japan. The service users completed self-administered questionnaires that include the Japanese version of INSPIRE, the Recovery Assessment Scale, the Client Satisfaction Questionnaire, the patient version of the Scale to Assess Therapeutic Relationship in Community Mental Health care and the Short Form Health Survey. Internal consistency was assessed using Cronbach’s alpha coefficient, and test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and weighted kappa. Convergent validity was examined by assessing correlation with other scales. Factor validity was evaluated by exploratory factor analysis (EFA) with generalized least-squares mean and oblimin rotation. In addition, confirmatory factor analysis was used to check the fitness of the factor structure models derived from the EFA.

Results

A total of 195 out of 212 users gave written informed consent and participated in the study. Data from 190 respondents were analyzed (response rate 89.6%). INSPIRE, Brief INSPIRE, and the subscales all showed Cronbach’s alpha coefficient over 0.78. ICC and weighted kappa derived more than 0.92 for subscales and Brief INSPIRE. These numerical values indicated good reliability. The convergent validity of Brief INSPIRE and the subscales was significantly positively correlated with the other scales. Different from the previous study, the factor structure was extracted using EFA. Both factor structures were checked by CFA, but the degree of fitness index was not good in either. Therefore, the factor analysis did not show goodness of fit.

Conclusions

This study found the Japanese version of INSPIRE and Brief INSPIRE to be reliable and valid for use among community mental health service users in Japan.
Decision-making about antidepressant medication use in pregnancy: a comparison between women making the decision in the preconception period versus in pregnancy
Authors: Barker Lucy C. , Dennis Cindy-Lee , Hussain-Shamsy Neesha , Stewart Donna E. , Grigoriadis Sophie , Metcalfe Kelly , Oberlander Tim F. , Schram Carrie , Taylor Valerie H. , Vigod Simone N.
Published: February 2020

Background

Decisions about antidepressant use in pregnancy are complex. Little is known about how pregnancy-planning and already pregnant women making these decisions differ.

Methods

In 95 Canadian women having difficulty deciding whether to take antidepressants in pregnancy, we compared sociodemographic factors, clinical characteristics, and treatment intent between women planning pregnancy (preconception women) and currently-pregnant women.

Results

About 90% of preconception women (n = 55) were married or cohabitating and university-educated, and over 60% had an annual income of > 80,000 CAD/year; this was not different from currently-pregnant women (n = 40). Almost all women had previously used antidepressants, but preconception women were more likely to report current use (85.5% vs. 45.0%). They were more likely to have high decisional conflict (83.6% vs. 60.0%) and less likely to be under the care of a psychiatrist (29.1% vs. 52.5%). Preconception women were more likely than pregnant women to report the intent to use antidepressants (60% vs. 32.5%, odds ratio 3.11, 95% confidence interval 1.33–7.32); this was partially explained by between-group differences in current antidepressant use.

Conclusions

Preconception women were more likely than pregnant women to intend to use antidepressants in pregnancy, in part because more of them were already using this treatment. Strategies to enhance support for decision-making about antidepressant medication use in pregnancy may need to be tailored differently for pregnancy-planning and already pregnant women.
Prevalence of intimate partner violence against women and associated factors in Ethiopia
Authors: Chernet Ayele Gebeyehu , Cherie Kebadu Tadesse
Published: February 2020

Background

Violence against women is a major public health problem that affects the physical, sexual, mental, and social wellbeing of more than one third of all women globally. Violence against women in Ethiopia is widely acknowledged to be of great concern from human rights, economic and health perspective. The aim of this study was to assess the prevalence of intimate partner violence (IPV) against women and associated factors in Ethiopia.

Method

The data was obtained from 2016 Ethiopia Demographic and Health Survey which is the fourth survey conducted in Ethiopia as part of the worldwide project. The sample was selected using a stratified; two-stage cluster sampling design and the data was analyzed using logistic regression model.

Result

A total of 4714 ever-married women in reproductive age who reported their experience of spousal violence were considered from nine regional states and two city administratives. Over 30% of study participants were subjected to IPV. Living in rural areas, divorced, primary and secondary education, 25–39 years old, being poor are found to be predictors of IPV against women in Ethiopia.

Conclusion

The prevalence of IPV was found high in Ethiopia and government and any concerned bodies should design appropriate strategy and work hard to tackle the problem. There is a need of giving special attention for women living in rural area, women from poor family and 25–39 years old women to decrease the burden of IPV.
Prenatal exposure to legacy contaminants and visual acuity in Canadian infants: a maternal-infant research on environmental chemicals study (MIREC-ID)
Authors: Polevoy C. , Arbuckle T. E. , Oulhote Y. , Lanphear B. P. , Cockell K. A. , Muckle G. , Saint-Amour D.
Published: February 2020

Background

Prenatal exposure to environmental contaminants can have deleterious effects on child development. While psychomotor, cognitive and behavioural outcomes have been investigated in relation to chronic exposure, the associations with visual functions remains unclear. The present study’s aim was to assess the associations of prenatal exposure to legacy persistent organic pollutants and heavy metals with visual acuity in Canadian infants. The potential protective effects of selenium against mercury toxicity were also examined.

Methods

Participants (mean corrected age = 6.6 months) were part of the Maternal-Infant Research on Environmental Chemicals (MIREC) study. Concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), lead and mercury were measured in maternal blood during pregnancy, as well as in the cord blood. The Teller acuity card test (TAC) (n = 429) and the visual evoked potentials in a sub-group (n = 63) were used to estimate behavioural and electrophysiological visual acuity, respectively. Multivariable linear regression models were used to investigate the relationship between exposure to each contaminant and visual acuity measures, while controlling for potential confounders. Breastmilk selenium, which was available for about half of the TAC and VEP samples, was also taken into account in the mercury models as exploratory analyses.

Results

We observed no significant associations between exposure to any contaminants and TAC. Analyses revealed a negative trend (p values < 0.1) between cord blood lead and mercury and electrophysiological visual acuity, whereas PCB and PBDE showed no association. When adding breastmilk selenium concentration to the mercury models, this association became statistically significant for cord concentrations (β = − 3.41, 95% CI = − 5.96,-0.86), but also for blood levels at 1st and 3rd trimesters of pregnancy (β = − 3.29, 95% CI = − 5.69,-0.88). However, further regression models suggested that this change in estimates might not be due to adjustment for selenium, but instead to a change in the study sample.

Conclusions

Our results suggest that subtle, but detectable alterations of infant electrophysiological visual acuity can be identified in a population prenatally exposed to low mercury concentrations. Compared to behavioural visual acuity testing, electrophysiological assessment may more sensitive in detecting visual neurotoxicity in relation with prenatal exposure to mercury.
Evaluation of serum MUC5AC in combination with CA19-9 for the diagnosis of pancreatic cancer
Authors: Zhang Jiayu , Wang Yue , Zhao Tiancheng , Li Yezhou , Tian Leilei , Zhao Jinming , Zhang Jingxin
Published: February 2020

Background

Pancreatic cancer (PC) is a highly aggressive tumor with a poor prognosis that lacks specific diagnostic markers. Mucin 5AC (MUC5AC) is a member of the mucin family, a heterogeneous group of high molecular weight, heavily glycosylated proteins that could be either membrane-bound or secreted. This multi-central study is to evaluate the performance of serum MUC5AC in combination with carbohydrate antigen 19-9 (CA19-9) for the diagnosis of PC in Asian.

Methods

Sixty-one patients with PC (comprised of early pancreatic cancer [n = 30] and late pancreatic cancer [n = 31] patients), 29 benign control, 35 choledocholithiasis, 25 chronic pancreatitis, and 34 healthy controls, were recruited from two hospitals. Serum levels of MUC5AC were evaluated by commercial ELISA kits. CA19-9 was measured by chemiluminescence immunoassay. The cutoff value of MUC5AC was determined based on optimal sensitivity and specificity.

Results

Serum MUC5AC in patients with PC (210.1 [100.5–423.8] ng/mL) presented higher levels than those in controls. The combined biomarker panel (MUC5AC and CA19-9) presented better performance and improved specificity to differentiate PC from controls (AUC 0.894; 95% CI (0.844–0.943), sensitivity 0.738, specificity 0.886) than CA19-9 (p = 0.043) or MUC5AC alone (p = 0.010); however, the latter two had no difference (p = 0.824).

Conclusions

Serum MUC5AC is a potential biomarker for PC. The combination with CA19-9 presents improved specificity and better performance.
Surgery for spontaneous intracerebral hemorrhage
Authors: de Oliveira Manoel Airton Leonardo
Published: February 2020

Spontaneous intracerebral hemorrhage is a devastating disease, accounting for 10 to 15% of all types of stroke; however, it is associated with disproportionally higher rates of mortality and disability. Despite significant progress in the acute management of these patients, the ideal surgical management is still to be determined. Surgical hematoma drainage has many theoretical benefits, such as the prevention of mass effect and cerebral herniation, reduction in intracranial pressure, and the decrease of excitotoxicity and neurotoxicity of blood products.

Several surgical techniques have been considered, such as open craniotomy, decompressive craniectomy, neuroendoscopy, and minimally invasive catheter evacuation followed by thrombolysis. Open craniotomy is the most studied approach in this clinical scenario, the first randomized controlled trial dating from the early 1960s. Since then, a large number of studies have been published, which included two large, well-designed, well-powered, multicenter, multinational, randomized clinical trials. These studies, The International Surgical Trial in Intracerebral Hemorrhage (STICH), and the STICH II have shown no clinical benefit for early surgical evacuation of intraparenchymal hematoma in patients with spontaneous supratentorial hemorrhage when compared with best medical management plus delayed surgery if necessary. However, the results of STICH trials may not be generalizable, because of the high rates of patients’ crossover from medical management to the surgical group. Without these high crossover percentages, the rates of unfavorable outcome and death with conservative management would have been higher. Additionally, comatose patients and patients at risk of cerebral herniation were not included. In these cases, surgery may be lifesaving, which prevented those patients of being enrolled in such trials. This article reviews the clinical evidence of surgical hematoma evacuation, and its role to decrease mortality and improve long-term functional outcome after spontaneous intracerebral hemorrhage.
The effects of once- versus twice-weekly sessions on psychotherapy outcomes in depressed patients
Authors: Bruijniks Sanne J. E. , Lemmens Lotte H. J. M. , Hollon Steven D. , Peeters Frenk P. M. L. , Cuijpers Pim , Arntz Arnoud , Dingemanse Pieter , Willems Linda , van Oppen Patricia , Twisk Jos W. R. , van den Boogaard Michael , Spijker Jan , Bosmans Judith , Huibers Marcus J. H.
Published: February 2020

Background

It is unclear what session frequency is most effective in cognitive–behavioural therapy (CBT) and interpersonal psychotherapy (IPT) for depression.

Aims

Compare the effects of once weekly and twice weekly sessions of CBT and IPT for depression.

Method

We conducted a multicentre randomised trial from November 2014 through December 2017. We recruited 200 adults with depression across nine specialised mental health centres in the Netherlands. This study used a 2 × 2 factorial design, randomising patients to once or twice weekly sessions of CBT or IPT over 16–24 weeks, up to a maximum of 20 sessions. Main outcome measures were depression severity, measured with the Beck Depression Inventory-II at baseline, before session 1, and 2 weeks, 1, 2, 3, 4, 5 and 6 months after start of the intervention. Intention-to-treat analyses were conducted.

Results

Compared with patients who received weekly sessions, patients who received twice weekly sessions showed a statistically significant decrease in depressive symptoms (estimated mean difference between weekly and twice weekly sessions at month 6: 3.85 points, difference in effect size d = 0.55), lower attrition rates (n = 16 compared with n = 32) and an increased rate of response (hazard ratio 1.48, 95% CI 1.00–2.18).

Conclusions

In clinical practice settings, delivery of twice weekly sessions of CBT and IPT for depression is a way to improve depression treatment outcomes.
Correlation of mesothelin (MSLN) expression with future peritoneal metastases (PM) in colorectal cancer (CRC).
Authors: Malla Midhun , Rozich Noah , Hassan Ayesha , Hayat Maham , Chen Sixia , Nusrat Sanober , Goldberg Richard M. , Morris Katherine Teresa
Published: February 2020

176

Background: CRC patients with PM have a significantly worse median overall survival (OS) when compared to those with liver and lung metastases. We studied MSLN protein expression using immunohistochemistry (IHC) on primary resected CRC (PRC), its correlation with future development of PM and its effect on OS. Our hypothesis is that PRC tumors from patients who later developed PM will have an increased proportion of positive MSLN scores based on IHC. Methods: We performed a retrospective case control study of all localized CRC (Stage I, II, III) patients who underwent curative resection from 2000- 2017 at the University of Oklahoma. The target population consisted of PRC patients who had distant recurrence during surveillance. Control group comprised of patients who never recurred after a minimum of 5 years of surveillance. MSLN score was calculated by the sum of staining percentage and intensity scores on each MSLN stained slide. Kaplan-Meier method was used to estimate OS and differences in survival were estimated using log-rank test. Results: Among 100 patients with recurrent CRC, 19 patients had PM, 51 had solid organ only metastases (SOM) and 66 are in the control group. MSLN staining results by IHC were satisfactory in 87 patients (Table). 91%, 46% and 21% of the patients in PM, SOM, and control groups had a positive MSLN score on PRC respectively. A significant association between MSLN score and future development of PM was observed (p<0.001) based on Fisher’s exact test. Sensitivity of MSLN as a marker for future PM was 93% and specificity was 58%. Patients with a positive MSLN score had a poor OS when compared to those with a negative MSLN score on univariate analysis (95% CI: 4.1-NR (not reached), p <0.001), which lost significance on multi-variable cox proportional analyses. Conclusions: A higher proportion of patients in the PM group had a positive MSLN score on PRC when compared to the SOM and control groups. MSLN was found to be a highly sensitive marker for future PM in CRC. We intend to expand this work by examining an additional cohort to validate these findings.

[Table: see text]
Potency of CD8+ T-cell mediated antitumor immunity from intratumoral immunotherapy with STING agonist, ADU-S100, in an esophageal adenocarcinoma model.
Authors: Babar Laila , Zaidi Ali Hussainy , Kelly Ronan Joseph , Omstead Ashten N. , Zheng Ping , Kosovec Juliann E. , Ayazi Shahin , Finley Gene Grant , Jobe Blair Anderson , Goel Ajay , Gorbunova Anastasia , Salvitti Madison
Published: February 2020

408

Background: Esophageal adenocarcinoma (EAC) is a deadly disease with poor prognosis due to limited treatment options. STING is a transmembrane protein that activates the transcription of type I IFN genes, resulting in the stimulation of APCs and enhanced CD8+ T-cell infiltration. Recently, STING agonists have demonstrated durable anticancer activity in solid tumors when used alone and in combination with either chemotherapy, radiation or immunotherapy. In this study we evaluated the efficacy and immunomodulatory effects of STING agonist +/- radiation in an established EAC model. Methods: Esophagojejunostomy was performed on rats to induce reflux leading to the development EAC. At 32 weeks post operatively, rats received either STING (ADU-S100) or placebo (PBS), +/- 16Gy radiation. Drug efficacy was evaluated by pre- and post- treatment MRI, serial biopsies, histology and RT-PCR. Additionally, immunofluorescence was performed using CD8 and PD-L1 antibodies. Results: A comparison of MRIs in the study groups between 32 and 40 weeks demonstrated a mean increase in percentage tumor volume of 76.7 % and 152.4% in the P and P+R arms and a decrease of 30.1 % and 50.8% in the S and S+R arms, respectively (ANOVA test p < 0.0001) Overall, the S+R group demonstrated the best results with maximum mean volume reduction with all cases responding. Downstream gene expression, pre, on, and post- treatment demonstrated significant upregulation of IFNβ, TNFα, IL-6 and CCL-2 in the treatment groups compared with placebo. On and post treatment, radiation alone, ADU-S100 alone and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by higher densities of IFNγ producing CD8+ T-cells (p < 0.01). Conclusions: ADU-S100 +/- radiation exhibits potent anti-tumor efficacy and a promising immunomodulatory profile in a de novo EAC model providing the rationale for clinical testing, likely concurrently in combination with immune checkpoint inhibitors.
Eligibility for second-line therapy in patients with advanced hepatocellular carcinoma (aHCC): A BC Cancer population-based study.
Authors: Tsang Erica S. , Davies Janine Marie , Loree Jonathan M. , Lim Howard John , Renouf Daniel John , Gill Sharlene
Published: February 2020

491

Background: Evidence supporting second-line therapies has become available for aHCC, including regorafenib, cabozantinib, ramucirumab, and nivolumab. The optimal second-line treatment regimen is unknown, and there remains limited real-world data about the eligibility of patients for second-line therapies in aHCC. We aimed to characterize the real-world eligibility and use of second-line therapies post sorafenib. Methods: We identified all patients with aHCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 across 6 centers in British Columbia (BC), Canada. All patients were required to be Child-Pugh class A for initiation of sorafenib in BC. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. Results: Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range 32.2-83.4) and 85% were male. Median duration of sorafenib was 2.6 months. 12 patients (8%) went on to receive second-line treatment. 37 patients (26%) were deemed eligible for second-line systemic therapy. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease. (Table). Kaplan-Meier analysis demonstrated that eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 months; p<0.01). Conclusions: Only a minority of real-world patients with aHCC were eligible for second-line therapies based on second-line trial criteria. Given the high-rate of attrition, improved first-line treatment options are urgently needed.

[Table: see text]
Subsequent anticancer procedures following first-line lenvatinib (LEN): A post hoc analysis from the phase III REFLECT study in unresectable hepatocellular carcinoma (uHCC).
Authors: Alsina Angel , Kudo Masatoshi , Vogel Arndt , Cheng Ann-Lii , Tak Won Young , Ryoo Baek-Yeol , Evans T.R. Jeffry , Lopéz Lopéz Carlos , Daniele Bruno , Blanc Jean-Frédéric , Ren Min , Baldwin Rae Lynn , Izumi Namiki , Qin Shukui , Finn Richard S.
Published: February 2020

520

Background: The availability of newer therapeutic options has shifted the treatment paradigm for uHCC, evoking questions regarding the sequencing of anticancer therapies. REFLECT was a phase 3 study comparing the efficacy and safety of LEN versus sorafenib (SOR) in first-line treatment of patients (pts) who have uHCC. In this post hoc analysis, we investigated overall survival (OS) during the follow-up survival period between treatment arms for pts who did and did not receive subsequent anticancer procedures and for responders to first-line LEN who received subsequent anticancer procedures. Methods: Pts in REFLECT were randomized 1:1 to LEN or SOR. The follow-up period commenced at the first visit after stopping study medications. Pts were followed-up every 12 weeks until data cutoff (Nov 13, 2016) or death. OS was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). Pts receiving subsequent radiotherapy were excluded from the OS analysis. Results: Of the 954 pts enrolled in REFLECT, 122/478 (26%) LEN- and 130/476 (27%) SOR-treated pts received subsequent anticancer procedures, with the most common being transarterial chemotherapy embolization (LEN n = 69 [14.4%]; SOR n = 81 [17.0%]) and hepatic intra-arterial chemotherapy (LEN n = 23 [4.8%]; SOR n = 25 [5.3%]). Eastern Cooperative Oncology Group performance status scores and laboratory assessments, including liver function, were comparable between arms at first-line treatment discontinuation. Of the pts who received subsequent anticancer procedures, those randomized to first-line LEN (n = 99) had a longer median OS (23.0 vs 19.6 months, respectively; hazard ratio [HR]: 0.71; 95% CI: 0.51–1.01) than those randomized to first-line SOR (n = 112). Responders to first-line LEN who received subsequent anticancer procedures (n = 45) had a median OS of 27.2 months (95% CI: 20.7–29.8). There were too few SOR responders (n = 10) who received subsequent anticancer procedures to evaluate OS. Conclusions: Pts randomized to first-line LEN who received subsequent anticancer procedures had longer OS compared with the similar sequence for pts taking first-line SOR. Clinical trial information: NCT01761266.
A pilot study of durvalumab/tremelimumab (durva/treme) and radiation (XRT) for metastatic biliary tract cancer (mBTC): Preliminary safety and efficacy.
Authors: Hong Theodore S. , Goyal Lipika , Parikh Aparna Raj , Yeap Beow Y. , Ulysse Christine A. , Drapek Lorraine C. , Allen Jill N. , Clark Jeffrey William , Christopher Benjamin , Bolton Christine , Ryan David P. , Corcoran Ryan Bruce , Meyerhardt Jeffrey A. , Wo Jennifer Yon-Li , Zhu Andrew X.
Published: February 2020

547

Background: Metastatic biliary tract cancer (mBTC) is a lethal malignancy with median 5 year OS of less than 10%. Immunotherapy, particularly single agent anti-PD-1/PD-L1, has limited efficacy in mBTC with ORR~9-15%. Recently presented data shows responses in metastatic MSS pancreatic or colon cancer with combination anti-PD-1/CTLA-4 and radiation (XRT) to produce systemic response (abscopal effect) (Parikh A, GI ASCO 2019, ASCO 2019.). We evaluate safety and efficacy of dual PD-1/CTLA-4 inhibition with XRT in MSS mBTC. Methods: 15 of a planned 15 mBTC patients were enrolled. Eligible pts had histologically-confirmed mBTC, ECOG-PS 0/1, and must have progressed on at least one line of previous therapy or refused standard therapy. Safety cohort of 6 pts of durva 1500 mg/treme 75 mg q4w was enrolled. If > 2 DLTs, patients were enrolled subsequently to dose level -1 (durva 1125 mg/ treme 75 mg q4w). 3 fractions of 8 Gy of radiation at C2D1 every other day to a single metastatic site. Durva/treme continued for 4 cycles, followed by 4 cycles of maintenance durva until progressive disease, discontinuation or withdrawal. Endpoints include disease control rate (DCR (SD+PR+CR)), PFS and OS and safety. Radiological evaluations were done q2 mo. Results: 15 mBTC pts enrolled and evaluable from May 2018 to March 2019. Median age 63 years (range 48-75), 47% male. DLTs occurred in 3 patients during the safety run-in. One patient experienced DLT at dose level -1 and subsequent expansion. 3 patients did NOT reach radiation therapy. DCR was 27% with a 13% PR and 7% CR. Of those who reached radiation, DCR was 33% with a 17% PR and 8% CR. At time of analysis, median PFS was 54 days for ITT mBTC. Duration of response for 4 patients with DCR was 26, 52, 122, 254+ days. Treatment-related adverse events were reported in 12/15 patients (80%). Grade ≥3 toxicities were seen in 9/15 pts (60%) with lymphopenia (5 grade 3) and elevated LFTs (2 grade 4 and 4 grade 2) being the main adverse events. All patients with disease control were not MSI. Conclusions: Combination of durva/treme XRT is feasible and shows preliminary activity in metastatic BTC. An expansion cohort is being planned to confirm activity. Clinical trial information: NCT03482102.
Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + BL-8040 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).
Authors: Oh Do-Youn , Ajani Jaffer A. , Bang Yung-Jue , Chung Hyun Cheol , Lacy Jill , Lee Jeeyun , Macarulla Teresa , Manji Gulam Abbas , O'Reilly Eileen Mary , Allen Simon , Al-Sakaff Nedal Jaffer Abdulla , Barak Hila , Patel Jilpa , Pintoffl Jan Peter , Shemesh Colby , Zhang Wei , Zhang Xiaosong , Chau Ian
Published: February 2020

712

Background: The MORPHEUS platform comprises multiple Ph Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Due to the immune-mediated effects of BL-8040, a high-affinity antagonist for CXCR4, it was tested with atezo (anti-PD-L1) in pts with advanced/metastatic (m) PDAC and GC. Methods: In 2 separate randomized trials, pts with mPDAC or advanced/mGC who progressed on 1L chemo received either atezo + BL-8040 (BL-8040 1.25 mg/kg SC D1-5, then BL-8040 1.25 mg/kg SC TIW + atezo 1200 mg IV Q3W) or control tx (M-PDAC: mFOLFOX-6 or gemcitabine + nab-paclitaxel; M-GC: paclitaxel + ramucirumab). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: Efficacy from evaluable pts followed for ≥18 wks in M-PDAC and ≥8 wks in M-GC is summarized in the table; 24-wk M-GC data will be presented. There were 15 safety-evaluable pts in each M-PDAC arm, as well as 13 in the atezo + BL-8040 and 12 in the control arm of M-GC. Gr 3-5 AEs were seen in 47% of pts on atezo + BL-8040 and 67% on control in M-PDAC, and 77% on atezo + BL-8040 and 67% on control in M-GC. Tx-related SAEs in M-PDAC occurred in 7% of pts on atezo + BL-8040 and 20% on control, and in M-GC, in 8% of pts on control. No Gr 5 AEs occurred in atezo + BL-8040 arms. Tx-related AEs led to 7% and 8% of pts discontinuing tx in the M-PDAC and M-GC control arms, respectively, and 15% discontinuing BL-8040 in M-GC due to Gr 3 injection-related reactions. Biomarker and PK data will be presented. Conclusions: Atezo + BL-8040 had limited efficacy for PDAC or GC. Tx-related AEs with atezo + BL-8040 were consistent with each agent’s known safety profile. Clinical trial information: NCT03281369; NCT03193190 . [Table: see text]
Hyperactive LH Pulses and Elevated Kisspeptin and NKB Gene Expression in the Arcuate Nucleus of a PCOS Mouse Model
Authors: Esparza Lourdes A , Schafer Danielle , Ho Brian S , Thackray Varykina G , Kauffman Alexander S
Published: February 2020

Polycystic ovary syndrome (PCOS), a common reproductive disorder in women, is characterized by hyperandrogenemia, chronic anovulation, cystic ovarian follicles, and luteinizing hormone (LH) hyper-pulsatility, but the pathophysiology isn’t completely understood. We recently reported a novel mouse model of PCOS using chronic letrozole (LET; aromatase inhibitor). Letrozole-treated females demonstrate multiple PCOS-like phenotypes, including polycystic ovaries, anovulation, and elevated circulating testosterone and LH, assayed in “one-off” measures. However, due to technical limitations, in vivo LH pulsatile secretion, which is elevated in PCOS women, was not previously studied, nor were the possible changes in reproductive neurons. Here, we used recent technical advances to examine in vivo LH pulse dynamics of freely moving LET female mice versus control and ovariectomized (OVX) mice. We also determined whether neural gene expression of important reproductive regulators such as kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. Letrozole-treated mice also had markedly elevated Kiss1, Tac2, and Pdyn expression and increased Kiss1 neuronal activation in the hypothalamic arcuate nucleus. Notably, the hyperactive LH pulses and increased kisspeptin neuron measures of LET mice were not as elevated as OVX females. Our findings indicate that LET mice, like PCOS women, have markedly elevated LH pulsatility, which likely drives increased androgen secretion. Increased hypothalamic kisspeptin and NKB levels may be fundamental contributors to the hyperactive LH pulse secretion in the LET PCOS-like condition and, perhaps, in PCOS women.