bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initiation of abortion before there is definitive ultrasound evidence of intrauterine pregnancy: A systematic review with meta‐analyses
Authors: Schmidt‐Hansen Mia , Cameron Sharon , Lord Jonathan , Hasler Elise 
Published: December 2019

AbstractIntroductionWomen are increasingly presenting for abortion at very early gestation. However, providers may be reluctant to conduct abortion at this stage as they may be concerned that they cannot exclude an ectopic pregnancy or that they may terminate a non‐viable pregnancy, or may be concerned that both medical and surgical methods may be less effective at this stage of gestation. This provider concern may result in delays in the abortion as additional investigations may be required until an intrauterine pregnancy can be confirmed. Additional unnecessary visits may be distressing for women and waste health service resources. The objective of this systematic review was to determine whether it is safe and effective to initiate abortion before there is ultrasound evidence of an intrauterine pregnancy.Material and methodsWe searched Embase Classic, Embase; Ovid MEDLINE® Epub Ahead‐of‐Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily, Ovid MEDLINE®; and Cochrane Library on 25 October 2019. Eligible studies were randomized and non‐randomized comparative studies, published in English from 1985, comparing initiation of abortion before there is definitive evidence of an intrauterine pregnancy with initiation afterwards. We assessed risk‐of‐bias using the Newcastle‐Ottowa scale. All outcomes were analyzed as risk ratios (RR) and meta‐analyzed using the Mantel‐Haenszel method. The quality of the evidence was assessed using GRADE.ResultsTwo non‐randomized studies (n = 3785) showed no differences in “missed ectopic pregnancy” (RR = 0.26, 95% CI 0.03‐2.12), “ongoing pregnancy” (RR = 1.06, 95% CI 0.34‐3.34), or “complete abortion without surgical intervention” (RR = 1, 95% CI 0.98‐1.02) between initiation of medical abortion before or after ultrasound evidence of an intrauterine pregnancy. A third non‐randomized study (n = 1530) showed no differences between initiation of surgical abortion before or after ultrasound evidence of an intrauterine pregnancy in “missed ectopic pregnancy” (no events), “ongoing pregnancy” (RR = 0.56, 95% CI 0.03‐11.59) or “complete abortion without repeat surgical intervention” (RR = 1, 95% CI 0.99‐1.01). The quality of evidence was very low.ConclusionsInitiation of abortion before there is definitive ultrasound evidence of an intrauterine pregnancy in women without signs or symptoms of an ectopic pregnancy should be considered.
Short stay unit for patients in acute mental health crisis: A case‐control study of readmission rates
Authors: Sveticic Jerneja , Turner Kathryn , Bethi Shailendhra , Krishnaiah Ravikumar , Williams Lee , Almeida‐Crasto Alice , Stapelberg Nicolas J. C. , Roy Samit 
Published: December 2019

AbstractIntroductionPast evaluations of psychiatric short stay units have shown positive outcomes for patients, yet very little is known about the factors related to readmissions.MethodsA Short Stay Pathway (SSP) has been introduced on the Gold Coast, Australia, for patients in acute mental health crisis with admissions of up to 3 days. Rates of readmissions within 28 days were compared for SSP patients (N = 678), and a diagnosis‐matched control group of patients from acute mental health beds (N = 1356). Demographic and clinical factors were considered as predictors of subsequent readmissions.ResultsAverage length of stay for SSP patients was 3.4 days, compared to 7.6 days in the control group. 10.6% of SSP patients and 18.4% of the control group were readmitted within 28 days (P < .001). For both groups, a 7‐day follow up significantly reduced readmissions (P < .05). Indigenous patients on SSP had higher odds of readmissions than non‐Indigenous patients (P < .05), and a diagnosis of a personality disorder increased readmission in the control group but not the SSP group (P < .001).DiscussionSSP reduced repeated hospitalizations for patients in acute crisis by 42%. An identification of factors related to future admissions can inform future tailoring of this model of care to subgroups of patients.
White matter microstructure in youth with and at risk for bipolar disorder
Authors: Linke Julia O. , Stavish Caitlin , Adleman Nancy E. , Sarlls Joelle , Towbin Kenneth E. , Leibenluft Ellen , Brotman Melissa A. 
Published: December 2019

AbstractObjectivesBipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto‐limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation.MethodsTo determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first‐degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging.ResultsIndividuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age‐related in‐creases in BD compared to REL and HV. Further, individuals with BD and REL showed in‐creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation.DiscussionAlterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation—a core characteristic of BD.
Operating characteristics of the rank‐based inverse normal transformation for quantitative trait analysis in genome‐wide association studies
Authors: McCaw Zachary R. , Lane Jacqueline M. , Saxena Richa , Redline Susan , Lin Xihong 
Published: December 2019

AbstractQuantitative traits analyzed in Genome‐Wide Association Studies (GWAS) are often nonnormally distributed. For such traits, association tests based on standard linear regression are subject to reduced power and inflated type I error in finite samples. Applying the rank‐based inverse normal transformation (INT) to nonnormally distributed traits has become common practice in GWAS. However, the different variations on INT‐based association testing have not been formally defined, and guidance is lacking on when to use which approach. In this paper, we formally define and systematically compare the direct (D‐INT) and indirect (I‐INT) INT‐based association tests. We discuss their assumptions, underlying generative models, and connections. We demonstrate that the relative powers of D‐INT and I‐INT depend on the underlying data generating process. Since neither approach is uniformly most powerful, we combine them into an adaptive omnibus test (O‐INT). O‐INT is robust to model misspecification, protects the type I error, and is well powered against a wide range of nonnormally distributed traits. Extensive simulations were conducted to examine the finite sample operating characteristics of these tests. Our results demonstrate that, for nonnormally distributed traits, INT‐based tests outperform the standard untransformed association test, both in terms of power and type I error rate control. We apply the proposed methods to GWAS of spirometry traits in the UK Biobank. O‐INT has been implemented in the R package RNOmni, which is available on CRAN.
Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker
Authors: Kloos Robin , van der Sluis Inge M. , Mastrobattista Enrico , Hennink Wim , Pieters Rob , Verhoef Jan‐Jaap 
Published: December 2019

SummaryPolyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG‐moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL‐11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti‐PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti‐PEG antibodies exclusively. Pre‐existing anti‐PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS‐linker were predominantly detected during induction (50% IgG; 42% IgM). Anti‐asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti‐PEG and anti‐SS‐linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.
The molecular biology of medulloblastoma metastasis
Authors: Van Ommeren Randy , Garzia Livia , Holgado Borja L. , Ramaswamy Vijay , Taylor Michael D. 
Published: December 2019

AbstractMedulloblastoma (MB) is the most common primary malignant brain tumor of childhood and a significant contributor to pediatric morbidity and death. While metastatic dissemination is the predominant cause of morbidity and mortality for patients with this disease, most research efforts and clinical trials to date have focused on the primary tumor; this is due mostly to the paucity of metastatic tumor samples and lack of robust mouse models of MB dissemination. Most current insights into the molecular drivers of metastasis have been derived from comparative molecular studies of metastatic and non‐metastatic primary tumors. However, small studies on matched primary and metastatic tissues and recently developed mouse models of dissemination have begun to uncover the molecular biology of MB metastasis more directly. With respect to anatomical routes of dissemination, a hematogenous route for MB metastasis has recently been demonstrated, opening new avenues of investigation. The tumor micro‐environment of the primary and metastatic niches has also been increasingly scrutinized in recent years, and further investigation of these tumor compartments is likely to result in a better understanding of the molecular mediators of MB colonization and growth in metastatic compartments.
Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects
Authors: Robles‐Vera Iñaki , Toral Marta , de la Visitación Néstor , Sánchez Manuel , Gómez‐Guzmán Manuel , Muñoz Raquel , Algieri Francesca , Vezza Teresa , Jiménez Rosario , Gálvez Julio , Romero Miguel , Redondo Juan Miguel , Duarte Juan 
Published: December 2019

Background and PurposeHypertension is associated with gut dysbiosis. Here we have evaluated the effects of the angiotensin receptor antagonist losartan on gut microbiota in spontaneously hypertensive rats (SHR) to assess their contribution to its antihypertensive effects.Experimental ApproachTwenty‐week‐old Wistar Kyoto rats (WKY) and SHR were treated with losartan for 5 weeks (SHR‐losartan). Faecal microbiota transplantation (FMT) was performed from donor SHR‐losartan group to recipient untreated‐SHR. Blood pressure (BP) was measured using tail‐cuff plethysmography. Composition of the gut microbiota was assessed by amplification of the V3‐V4 region of 16S rRNA gene. T cells were analysed in gut/aorta by flow cytometry.Key ResultsFaeces from SHR showed gut dysbiosis, characterised by higher Firmicutes/Bacteroidetes ratios, lower acetate‐ and higher lactate‐producing bacteria, and lower levels of strict anaerobic bacteria, effects which were restored to normal by losartan. Improvement of gut dysbiosis was linked to higher colonic integrity and lower sympathetic drive in the gut. In contrast, hydralazine reduced BP, but it neither restored gut dysbiosis nor colonic integrity. FMT from SHR‐losartan to SHR reduced BP, improved the aortic endothelium‐dependent relaxation to ACh, and reduced NADPH oxidase activity. These vascular changes were accompanied by both increased Treg and decreased Th17 cell populations in the vascular wall.Conclusion and ImplicationsIn SHR, losartan treatment reduced gut dysbiosis and sympathetic drive in the gut, thus improving gut integrity. The changes induced by losartan in gut microbiota contributed, in part, to protecting the vasculature and reducing BP, possibly by modulating the immune system in the gut.
β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents
Authors: He Yi , Galaj Ewa , Bi Guo‐Hua , Wang Xiao‐Fei , Gardner Eliot , Xi Zheng‐Xiong 
Published: December 2019

Background and Purposeβ‐Caryophyllene (BCP) is a plant‐derived terpenoid used as a food additive for many decades. Recent studies indicate that BCP is a cannabinoid CB2 receptor agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.Experiment ApproachWe used pharmacological, transgenic, and optogenetic approaches to systematically evaluate the effects of BCP on nicotine‐taking and nicotine‐seeking behaviour in animal models of drug self‐administration, electrical, and optical brain‐stimulation reward.Key ResultsSystemic administration of BCP dose‐dependently inhibited nicotine self‐administration and motivation for nicotine seeking in rats and mice. The reduction in nicotine self‐administration was blocked by AM630, a selective CB2 receptor antagonist, but not by AM251, a selective CB1 receptor antagonist, suggesting involvement of a CB2 receptor mechanism. Genetic deletion of CB2 receptors in mice blocked the reduction in nicotine self‐administration produced only by low doses, but not by high doses, of BCP, suggesting involvement of both CB2 and non‐CB2 receptor mechanisms. Furthermore, in the intracranial self‐stimulation paradigm, BCP attenuated electrical brain‐stimulation reward and nicotine‐enhanced brain‐stimulation reward in rats. Lastly, BCP also attenuated brain‐stimulation reward maintained by optogenetic stimulation of dopaminergic neurons in the ventral tegmental area in DAT‐cre mice, suggesting the involvement of a dopamine‐dependent mechanism in BCP's action.Conclusions and ImplicationsThe present findings suggest that BCP has significant anti‐nicotine effects via both CB2 and non‐CB2 receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.
Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101
Authors: Uemura Motohide , Tomita Yoshihiko , Miyake Hideaki , Hatakeyama Shingo , Kanayama Hiro‐omi , Numakura Kazuyuki , Takagi Toshio , Kato Tomoyuki , Eto Masatoshi , Obara Wataru , Uemura Hirotsugu , Choueiri Toni K. , Motzer Robert J. , Fujii Yosuke , Kamei Yoichi , Umeyama Yoshiko , di Pietro Alessandra , Oya Mototsugu 
Published: December 2019

AbstractThe phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment‐naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression‐free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD‐L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD‐L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD‐L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD‐L1+ tumors and irrespective of PD‐L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD‐L1 expression. Common treatment‐emergent adverse events (all grade; grade ≥3) in each arm were hand‐foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment‐naive Japanese patients with advanced RCC, which is consistent with results in the overall population.
TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma
Authors: Yamada Yuta , Kimura Naoki , Takayama Ken‐ichi , Sato Yusuke , Suzuki Takashi , Azuma Kotaro , Fujimura Tetsuya , Ikeda Kazuhiro , Kume Haruki , Inoue Satoshi 
Published: December 2019

AbstractTRIM44 has oncogenic roles in various cancers. However, TRIM44 expression and its function in renal cell carcinoma (RCC) are still unknown. Here in this study, we investigated the clinical significance of TRIM44 and its biological function in RCC. TRIM44 overexpression was significantly associated with clinical M stage, histologic type (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028, respectively). Moreover, TRIM44 overexpression was significantly associated with poor prognosis in terms of cancer‐specific survival (P = .019). Gain‐of‐function and loss‐of‐function studies using TRIM44 and siTRIM44 transfection showed that TRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1 and 769P. To further investigate the role of TRIM44 in RCC, we performed integrated microarray analysis in Caki1 and 769P cells and explored the data in the Oncomine database. Interestingly, FRK was identified as a promising candidate target gene of TRIM44, which was downregulated in RCC compared with normal renal tissues. We found that cell proliferation was inhibited by TRIM44 knockdown and then recovered by siFRK treatment. Taken together, the present study revealed the association between high expression of TRIM44 and poor prognosis in RCC patients and that TRIM44 promotes cell proliferation by regulating FRK.
Arctigenin promotes bone formation involving PI3K/Akt/PPARγ signaling pathway
Authors: Li Hongbo , Yang Chunli , Lan Min , Liao Xingen , Tang Zhiming 
Published: December 2019

AbstractThis study investigated the mechanisms through which arctigenin promotes osteogenesis. Bone marrow mesenchymal stem cells (BMSCs) from ovariectomized (OVX) rats were differentiated into osteoblasts, and osteogenesis was evaluated via Alizarin Red S (ARS) staining and alkaline phosphatase (ALP) measurements in cultured BMSCs. The levels of phosphorylated AKT serine/threonine kinase 1 (p‐Akt), and peroxisome proliferator‐activated receptor gamma (PPARγ) expression were quantified by Western blot analysis. The levels of urine calcium (U‐Ca), urine phosphorus (U‐P), serum ALP, and bone mineral density (BMD) of OVX rats were assessed in vivo. The results showed that treatment with arctigenin in rat BMSCs enhanced mineralization, increased ALP activity, increased the expression of Akt and p‐Akt, and decreased PPARγ expression, consistent with its ability to promote osteoblast differentiation. Furthermore, arctigenin prevented OVX‐induced osteoporosis in rats by increasing BMD and ALP activity and inhibiting the loss of Ca and P. In contrast, treatment with LY294002, a selective inhibitor of the phosphatidylinositol 3‐kinase (PI3K), produced the opposite phenotype. These data suggest that the protective effects of arctigenin on BMSCs and OVX rat models result from the induction of osteogenesis involving the PI3K/Akt/PPARγ axis.
Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein
Authors: Rughani Ankur , Zhang Dongsheng , Vairamani Kanimozhi , Dauber Andrew , Hwa Vivian , Krishnan Sowmya 
Published: December 2019

AbstractObjectiveTo report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.ContextLaron syndrome (LS) is a well‐described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin‐like growth factor (IGF)‐1, IGF binding protein (IGFBP)‐3 and GH binding protein (GHBP).DesignCase presentation with in vitro functional studies.PatientsA young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.MeasurementsGrowth hormone stimulation tests revealed baseline GH level of 20.9 µg/L and maximum stimulated GH level of 52.7 µg/L and GHBP level of 4868 pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G > A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH‐induced STAT5 signalling that was overcome with increasing doses of recombinant human GH.ResultsUsing an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH.ConclusionsTo our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH‐induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.
Neuroinflammation and the blood–brain interface: New findings in brain pathology
Authors: Kelley Keith W. , Shimada Atsuyoshi 
Published: December 2019

AbstractTwo fundamental concepts have impeded the development of research in brain, behavior and immunity during the past century. They have been presented in neuroscience textbooks since the beginning of the 20th century. Recent discoveries require that both views are in serious need of being updated in the scientific literature and medical textbooks. These two age‐old concepts are lack of lymphatic drainage in the brain and immune privilege of the central nervous system associated with impermeability of the blood–brain barrier.