bluuebunny/crossref_metadata_2025 huggingface dataset:
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

The 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

TRIM44 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

This 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

Objective

To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.

Context

Laron 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).

Design

Case presentation with in vitro functional studies.

Patients

A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.

Measurements

Growth 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.

Results

Using 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.

Conclusions

To 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

Two 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.
Principles of neuroanatomical architecture supporting brain–immune cell–cell interactions
Authors: Shimada Atsuyoshi
Published: December 2019

The brain interacts with the immune system under inflammatory and non‐inflammatory conditions. Brain cells have the capacity to produce a variety of cytokines in response to systemic immune activation. Therefore, we hypothesized that brain cells and immune cells move close to each other, so that they can carry out intercellular interactions. In the present article, I review our studies to determine the site for the brain–immune cell–cell interactions. The leptomeninges, choroid plexus stroma and epithelium, attachments of the choroid plexuses, vascular endothelial cells, cells of the perivascular space, and astrocytic end‐feet compose the histological architecture that supports interactions between bone marrow‐derived myeloid cells and brain parenchymal cells under non‐inflammatory conditions. This architecture also functions as the interface at which systemic inflammation‐induced responses can be conveyed to the brain parenchyma under inflammatory conditions. It should be noted that such brain–immune interactions occur in the absence of florid inflammatory cell infiltrates in the brain parenchyma, and with relative preservation of the blood‐brain barrier. Rather, cells comprising the blood‐brain barrier act as the interface linking peripheral immune activation and brain responses. These responses, known as “neuroinflammation”, are unique to the brain. Neuroinflammation differs from the histological inflammation that is accompanied by a florid infiltration of the leptomeninges (meningitis) and/or brain parenchyma (encephalitis) by inflammatory cells. In this review, the relevance of histological studies to unravel the mechanisms linking systemic inflammation, brain–immune interface cells and brain parenchymal cells, with a special emphasis on sepsis‐associated encephalopathy, is discussed.
Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene
Authors: Desprairies Camille , Valence Stéphanie , Maurey Hélène , Helal Suzette I. , Weckhuysen Sarah , Soliman Hala , Mefford Heather C. , Spentchian Myrtille , Héron Delphine , Leguern Eric , Nava Caroline , Bouilleret Viviane , Moretti Raffaella , Mignot Cyril
Published: December 2019

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3‐5 months concomitant with developmental arrest or regression, other seizure types and drug‐resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1‐related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1‐related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.
Prognostic ability of the distance‐saturation product in the 6‐minute walk test in patients with chronic obstructive pulmonary disease
Authors: Gurbani Nikita , Figueira Gonçalves Juan Marco , García Bello Miguel Ángel , García‐Talavera Ignacio , Afonso Díaz Andrea
Published: December 2019

Introduction

The product (DSP) of the distance walked (meters) and minimum oxygen saturation obtained during the 6‐minute walk test (6MWT) has been proposed as a predictor of mortality in idiopathic pulmonary fibrosis and in bronchiectasis not related to cystic fibrosis.

Objective

The aim of this study was to determine the DSP's ability to predict mortality in patients with chronic obstructive pulmonary disease (COPD) at the outpatient level and compare it to the BODE index and meters walked in the 6MWT.

Material and methods

Descriptive observational study in a cohort of patients with COPD being treated at outpatient pulmonology clinics. Each of the patients completed the 6MWT following ATS/ERS protocols and their BODE index and DSP were calculated.

Results

About 103 patients were included. The average length of follow‐up was 36 months. Patients who died showed a lower number of meters walked in the 6MWT (P < 0.001), as well as a lower DSP (P < 0.001). A 6MWT < 334 m, a DSP < 290 and a BODE ≥ 4 showed good prognostic ability at 3 years (AUC 71%, 69% and 70.4%, respectively). The 6MWT was superior to the BODE index in predicting mortality during the first year of follow‐up (P = 0.023). We did not find any differences between DSP and meters walked in the 6MWT.

Conclusions

The DSP is a good predictor of mortality, although it does not offer a better prognostic ability than that of meters walked in the 6MWT.
Usefulness of a newly developed distal attachment: Super soft hood (Space adjuster) in therapeutic endoscopy
Authors: Fujiyoshi Yusuke , Shimamura Yuto , Inoue Haruhiro
Published: December 2019

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Efficacy and safety of endoscopic submucosal dissection using a scissors‐type knife with prophylactic over‐the‐scope clip closure for superficial non‐ampullary duodenal epithelial tumors
Authors: Dohi Osamu , Yoshida Naohisa , Naito Yuji , Yoshida Takuma , Ishida Tsugitaka , Azuma Yuka , Kitae Hiroaki , Matsumura Shinya , Takayama Shun , Ogita Kazuyuki , Mizuno Naoki , Nakano Takahiro , Majima Atsushi , Hirose Ryohei , Inoue Ken , Kamada Kazuhiro , Uchiyama Kazuhiko , Takagi Tomohisa , Ishikawa Takeshi , Konishi Hideyuki , Morinaga Yukiko , Kishimoto Mitsuo , Itoh Yoshito
Published: December 2019

Background and study aim

This study aimed to assess the safety and feasibility of endoscopic submucosal dissection (ESD) using a scissors‐type knife with prophylactic closure using over‐the‐scope clip (OTSC) for superficial non‐ampullary duodenal epithelial tumors (SNADETs).

Patients and methods

Consecutive patients who underwent ESD for SNADETs >10 mm between January 2009 and July 2019 were retrospectively enrolled. We performed ESD using either a needle‐type knife (Flush Knife‐ESD) or a scissors‐type knife (Clutch Cutter‐ESD). Mucosal defects were prophylactically closed using three methods: conventional clip, laparoscopic closure, or OTSC.

Results

A total of 84 lesions were resected using the Flush Knife‐ESD and the Clutch Cutter‐ESD (37 and 47 patients, respectively), and conventional clip, laparoscopic closure, and OTSC for mucosal defect closure after ESD were applied in 13, 13, and 56 lesions, respectively. The R0 resection rate was significantly higher in the Clutch Cutter‐ESD than that in the Flush Knife‐ESD (97.9% vs 83.8%, respectively, P = 0.040). The intraoperative perforation rate was significantly lower in the Clutch Cutter‐ESD than in the Flush Knife‐ESD (0% vs 13.5%, respectively, P = 0.014). Complete closure rates of conventional clip, laparoscopic closure, and OTSC were 76.9%, 92.3%, and 98.2%, respectively (P = 0.021); and delayed perforation rates were 15.4%, 7.7%, and 1.8%, respectively (P = 0.092).

Conclusions

Endoscopic submucosal dissection using a scissors‐type knife with prophylactic OTSC closure is safe and feasible for the low‐invasive treatment of SNADETs.
Risk factor analysis for adverse events and stent dysfunction of endoscopic ultrasound‐guided choledochoduodenostomy
Authors: Matsumoto Shimpei , Hara Kazuo , Mizuno Nobumasa , Kuwahara Takamichi , Okuno Nozomi , Obata Masahiro , Kurita Yusuke , Koda Hiroki , Tajika Masahiro , Tanaka Tsutomu , Hirayama Yutaka , Onishi Sachiyo , Toriyama Kazuhiro , Niwa Yasumasa
Published: December 2019

Background and Aims

Although the technique of endoscopic ultrasound‐guided choledochoduodenostomy (EUS‐CDS) is becoming standardized, its safety issues have not been sufficiently investigated. Therefore, we aimed to identify factors associated with adverse events and stent patency in EUS‐CDS.

Methods

Consecutive patients who underwent EUS‐CDS between September 2003 and July 2017 were included. Technical/clinical success, adverse events and stent dysfunctions were analyzed retrospectively.

Results

A total of 151 patients underwent EUS‐CDS. In nine patients, procedures were discontinued before puncture. Technical and clinical success rates were 96.5% (137/142) and 98.5% (135/137), respectively. The adverse event rate was 20.4% (29/142). As a risk factor for peritonitis, plastic stents (PS) showed a significantly high odds ratio (OR) compared with covered self‐expandable metal stents (CSEMS; OR, 4.31; P = 0.030). CSEMS cases showed a significantly longer patency period than PS cases (329 vs 89 days; HR, 0.35; P < 0.001). As a risk factor for early stent dysfunction (within 14 days), stent direction to the oral side showed a significantly high OR (OR, 43.47; P < 0.001). In cases with oblique‐viewing EUS, double penetration of the duodenum occurred at significantly higher frequency than in cases with forward‐viewing EUS (7.0 vs 0.0%; P = 0.024).

Conclusions

Plastic stents and stent direction to the oral side were risk factors for peritonitis and early stent dysfunction, respectively. Using covered self‐expandable metal stents and changing stent direction to the anal side seemed appropriate to prevent peritonitis and early stent dysfunction.
Improvement of clinical outcome in patients with ST‐elevation myocardial infarction between 1999 and 2016 in China: The Prospective, Multicentre Registry MOODY study
Authors: Chen Mengxuan , Kan Jing , Zhang Jun‐Jie , Tian Nailiang , Ye Fei , Yang Song , Chen Shao‐Liang ,   On behalf of MOODY Regustry study Investigators
Published: December 2019

Background

Reports showed no change of 7‐day mortality after primary percutaneous coronary intervention (PCI) for ST‐elevation myocardial infarction (STEMI) between 2001 and 2011 in China. National rolling one‐year interventional standardized training programme began in September 2009. However, the improvement in clinical outcome following STEMI PCI after 2011 remains unclear.

Methods and Results

This multicentre MOODY registry study aimed to analyse the clinical improvement after STEMI PCI. Of a total of 9265 acute MI patients registered from 24 centres, 3142 STEMIs having a first medical contact time ≤12 hours and undergoing primary PCI were assigned to the Pre Group (n = 1014, between March 1999 and October 2010) or the Post Group (n = 2128, between 2010 November and 2016 October). The primary endpoint was in‐hospital cardiac death. Study endpoints were also compared between trained and untrained operators and between experienced (≥50 primary PCIs/year) and inexperienced personnel. In‐hospital death after PCI was 3.0% in the Pre Group, significantly higher than 1.6% in the Post Group (P = .035). The improvements in clinical outcome after PCI between the 2016 and Pre Groups were stably sustained through one‐year follow‐up. The significant reduction for in‐hospital death was noted when primary PCI was performed by trained (1.4% vs 5.4%, P < .001) or experienced (2.7% vs 4.8%, P = .001) operators, compared to untrained or inexperienced operators, respectively. Inclusion of the untrained operator into the conventional risk model strongly enhanced the prediction for endpoints. Age, Killip Class 3, diabetes, trans‐radial approach and system delay were five predictors of in‐hospital death after primary PCI.

Conclusion

PCI for STEMI by a trained and experienced operator was associated with significant reduction of in‐hospital death. Our results strongly warrant the need for promoting the current system response and patient education.
Threats to at‐risk salmonids of the Canadian Rocky Mountain region
Authors: Sinnatamby R. Niloshini , Cantin Ariane , Post John R.
Published: December 2019

Trout and charr, members of the salmonid family, have high conservation value but are also susceptible to anthropogenic threats in part due to the specificity of their habitat requirements. Understanding historical and future threats facing these species is necessary to promote their recovery. Of freshwater trout and charr in the Canadian Rocky Mountain region, westslope cutthroat trout (Oncorhynchus clarkii lewisi), bull trout (Salvelinus confluentus; a charr species) and Athabasca rainbow trout (Oncorhynchus mykiss) are of conservation concern. And indeed, range contractions and declining populations are evident throughout much of their ranges. Range contraction was most evident in the southern Alberta designatable unit (DU) of westslope cutthroat trout. Diminished populations were also evident in the downstream watersheds of the Alberta bull trout range, and throughout the Athabasca rainbow trout range. We assessed historical and future threats to evaluate the relative importance of individual threats to each DU and compare their impact among species. Individual threats fall into the broad categories of angling, non‐native species and genes, habitat loss and alteration, and climate change. Severity of each threat varies by DU and reflects the interaction between species’ biology and the location of the DU. Severity of threats facing each DU has changed over time, reflecting extirpation of native populations, changes in management and industry best practices, expansion of non‐native species and progressing climate change. The overall threat impact for each DU indicates a high probability of substantial and continuing declines and calls for immediate action.
N400 event‐related brain potential as an index of real‐world and neurocognitive function in patients at clinical high risk for schizophrenia
Authors: Lepock Jennifer R. , Ahmed Sarah , Mizrahi Romina , Gerritsen Cory J. , Maheandiran Margaret , Bagby R. Michael , Korostil Michele , Kiang Michael
Published: December 2019

Aim

The N400 event‐related potential is a neurophysiological index of cognitive processing of real‐world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This ‘N400 semantic priming effect’ is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real‐world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group.

Methods

We measured N400 semantic priming in 35 CHR patients who viewed prime words each followed by a related or unrelated target word, at stimulus‐onset asynchrony (SOA) of 300 or 750 ms. We measured academic/occupational and social function with the global function (GF): Role and Social scales, and cognitive function with the MATRICS Consensus Cognitive Battery (MCCB).

Results

Decreased N400 semantic priming at the 300‐ms SOA correlated with lower GF:Role scores. Decreased N400 semantic priming at the 750‐ms SOA correlated with lower MCCB composite scores.

Conclusions

Deficits in activating contextually related concepts in SM over short time intervals may contribute to functional impairment in CHR patients. Furthermore, N400 priming deficits over longer intervals may be a biomarker of global cognitive dysfunction in this population. Longitudinal studies are needed to determine whether these deficits are associated with schizophrenia risk within this population.
A Way through the woods: Development of an integrated care pathway for adolescents with depression
Authors: Courtney Darren , Bennett Kathryn , Henderson Joanna , Darnay Karleigh , Battaglia Marco , Strauss John , Watson Priya , Szatmari Peter
Published: December 2019

Aims

Depression in adolescents is common and debilitating. Treatment approaches vary widely across clinics and may not reflect evidence‐based care. Integrated care pathways (ICPs) are implementation tools to facilitate bridging the gap between rigorous but often complex clinical practice guidelines and what is actually practiced. We describe the development of an ICP for the treatment of Adolescents with Major Depressive Disorder (MDD‐A) based on the best‐available clinical practice guidelines and derived in collaboration with clinicians, administrators, youth partners and caregivers.

Methods

With clinician and health service manager input, we took the recommendations from a high quality clinical practice guideline (the National Institute of Health and Care Excellence Clinical Practice Guideline for Depression in Children and Young People) and translated them into an ICP. Feedback from youth partners and clinicians was iteratively incorporated into the current version of the pathway using a collaborative approach.

Results

The current iteration of the pathway at a Canadian tertiary care teaching hospital is described. All youth (and caregivers, if applicable) are offered a multi‐family psychoeducation session, a 16‐session Group Cognitive Behaviour Therapy and team reviews every 4 weeks that include measurement‐based care. Conditional branches of the pathway include a medication algorithm and an 8‐session group for caregivers.

Conclusions

The resulting ICP provides a tool to facilitate bridging the gap between evidence and clinical practice.
Screening for the at‐risk mental state in educational settings: A systematic review
Authors: Howie Clare , Potter Claire , Shannon Ciaran , Davidson Gavin , Mulholland Ciaran
Published: December 2019

Aim

The at‐risk mental state (ARMS) allows clinicians to identify individuals who have an increased risk of developing psychosis. At present, most screening for psychosis‐risk is carried out within help‐seeking populations; however, screening within educational settings may allow clinicians to identify individuals at‐risk earlier and to increase the rate of detection. This review aimed to examine screening for the ARMS in educational settings, with the key questions: what screening tools have been used in educational settings, can screening in educational settings detect individuals with ARMS, what threshold scores in screening tools indicate a positive screen in educational settings, are there comorbid mental health conditions associated with the ARMS in educational settings?

Methods

Searches were carried out in PsycINFO, MEDLINE, EMBASE, Scopus and Web of Science and reference lists of included articles searched. Results were summarized using narrative synthesis.

Results

Nine papers were included for narrative synthesis. A variety of screening tools have been used when screening for the ARMS in educational settings. The majority of studies have been conducted in schools. The prevalence of the ARMS reported in ranges from 1% to 8%.

Conclusions

The ARMS indicates the presence of distressing symptoms for which intervention may be beneficial. Screening programmes within educational settings may allow outreach for prodromal symptoms at an earlier stage than clinical settings currently provided for.
A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Authors: Hajek Roman , Pour Ludek , Ozcan Muhit , Martin Sánchez Jesus , García Sanz Ramon , Anagnostopoulos Achilles , Oriol Albert , Cascavilla Nicola , Terjung Andreas , Lee Yihua , Briso Eva M. , Dobkowska Edyta , Hauns Bernhard , Špička Ivan
Published: December 2019

Objective

We evaluated ibrutinib, a once‐daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1‐3 prior therapies.

Methods

This was a phase 2, single‐arm, open‐label, multicentre study (NCT02902965). The primary endpoint was progression‐free survival (PFS).

Results

Seventy‐six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow‐up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2‐10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45‐68), and median duration of response was 9.5 months (95% CI: 6.9‐10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk‐minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs.

Conclusion

Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated.
B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis
Authors: Gagelmann Nico , Ayuk Francis , Atanackovic Djordje , Kröger Nicolaus
Published: December 2019

Introduction

Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in clinical studies for relapsed/refractory multiple myeloma (RRMM). We performed a systematic literature review to summarize the current body of evidence on the role of anti‐BCMA CAR T cells for RRMM.

Objectives and Methods

Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included using a conventional meta‐analysis. Main efficacy outcomes were response, relapse, and survival. Safety outcomes were cytokine release syndrome (CRS) and neurotoxicity.

Results

Anti‐BCMA CAR T cells resulted in a pooled overall response of 82% (95% confidence interval [CI], 74%‐88%) and complete response of 36% (24%‐50%). Higher CAR+ cell doses were associated with higher response rates. The pooled relapse rate of responders was 45% (27%‐64%), and median progression‐free survival was 10 months. Present extramedullary disease did not show worse outcome. Severe CRS grades 3‐4 and neurotoxicity occurred in 15% (10%‐23%) and 18% (10%‐31%).

Conclusion

Anti‐BCMA CAR T cells showed high response rates, even in patients with present extramedullary disease, while relapse occurred in half of the patients who achieved a response. Larger studies with longer follow‐up especially evaluating the association of response and survival are needed.
Changes in gene expression in brain structures related to visceral sensation, autonomic functions, food intake, and cognition in melanoma‐bearing mice
Authors: Horvathova Lubica , Tillinger Andrej , Padova Alexandra , Bizik Jozef , Mravec Boris
Published: December 2019

The brain exerts complex effects on the initiation and progression of cancer in the body. However, the influence of cancer localized in peripheral tissues on the brain has been only partially described. Therefore, we investigated gene expression in brain structures that participate in transmitting viscerosensory signals, regulating autonomic functions and food intake, as well as cognition in C57Bl/6J mice with B16‐F10 melanoma. In addition, we investigated the relationship between peripheral inflammation and neuroinflammation. We found increased neuronal activity in the nucleus of the solitary tract of tumor‐bearing mice, whereas neuronal activity in the A1/C1 catecholaminergic cell group, parabrachial nucleus, lateral hypothalamic area, ventromedial nucleus of the hypothalamus, paraventricular nucleus of the hypothalamus, and hippocampus was decreased. In the majority of investigated brain structures, we found increased gene expression of IL‐1β, whereas gene expression of IL‐6 and NF‐κB was reduced or unchanged compared with controls. Melanoma‐bearing mice also showed increased gene expression of tyrosine hydroxylase in the A1/C1 catecholaminergic cell group, nucleus of the solitary tract, and locus coeruleus, as well as reduced mRNA levels of hypocretin neuropeptide precursor protein in the lateral hypothalamic area, and proopiomelanocortin in the arcuate nucleus. In addition, we found reduced mRNA levels of Bcl‐2, brain‐derived neurotrophic factor, and doublecortin in the hippocampus. Our data indicate that skin melanoma induces complex changes in the brain, and these changes are most probably caused by cancer‐related signals mediated by pro‐inflammatory cytokines.
Neuroprotective effects of brain‐derived neurotrophic factor against amyloid beta 1‐40‐induced retinal and optic nerve damage
Authors: Mohd Lazaldin Mohd Aizuddin , Iezhitsa Igor , Agarwal Renu , Bakar Nor Salmah , Agarwal Puneet , Mohd Ismail Nafeeza
Published: December 2019

Brain‐derived neurotrophic factor (BDNF) could be considered a potential neuroprotective therapy in amyloid beta (Aβ)‐associated retinal and optic nerve degeneration. Hence, in this study we investigated the neuroprotective effect of BDNF against Aβ1‐40‐induced retinal and optic nerve injury. In this study, exposure to Aβ1‐40 was associated with retinal and optic nerve injury. TUNEL staining showed significant reduction in the apoptotic cell count in the BDNF‐treated group compared with Aβ1‐40 group. H&E‐stained retinal sections also showed a striking reduction in neuronal cells in the ganglion cell layer (GCL) of retinas fourteen days after Aβ1‐40 exposure. By contrast, number of retinal cells was preserved in the retinas of BDNF‐treated animals. After Aβ1‐40 exposure, visible axonal swelling was observed in optic nerve sections. However, the BDNF‐treated group showed fewer changes in optic nerve; axonal swelling was less frequent and less marked. In the present study, exposure to Aβ was associated with oxidative stress, whereas levels of retinal glutathione (GSH), superoxide dismutase (SOD) and catalase were significantly increased in BDNF‐treated than in Aβ1‐40‐treated rats. Both visual object recognition tests using an open‐field arena and a Morris water maze showed that BDNF improved rats’ ability to recognise visual cues (objects with different shapes) after Aβ1‐40 exposure, thus demonstrating that the visual performance of rats was relatively preserved following BDNF treatment. In conclusion, intravitreal treatment with BDNF prevents Aβ1‐40‐induced retinal cell apoptosis and axon loss in the optic nerve of rats by reducing retinal oxidative stress and restoring retinal BDNF levels.
Ensembling crowdsourced seizure prediction algorithms using long‐term human intracranial EEG
Authors: Reuben Chip , Karoly Philippa , Freestone Dean R. , Temko Andriy , Barachant Alexandre , Li Feng , Titericz Gilberto , Lang Brian W. , Lavery Daniel , Roman Kelly , Broadhead Derek , Jones Gareth , Tang Qingnan , Ivanenko Irina , Panichev Oleg , Proix Timothée , Náhlík Michal , Grunberg Daniel B. , Grayden David B. , Cook Mark J. , Kuhlmann Levin
Published: December 2019

Seizure prediction is feasible, but greater accuracy is needed to make seizure prediction clinically viable across a large group of patients. Recent work crowdsourced state‐of‐the‐art prediction algorithms in a worldwide competition, yielding improvements in seizure prediction performance for patients whose seizures were previously found hard to anticipate. The aim of the current analysis was to explore potential performance improvements using an ensemble of the top competition algorithms. The results suggest that minor increments in performance may be possible; however, the outcomes of statistical testing limit the confidence in these increments. Our results suggest that for the specific algorithms, evaluation framework, and data considered here, incremental improvements are achievable but there may be upper bounds on machine learning–based seizure prediction performance for some patients whose seizures are challenging to predict. Other more tailored approaches that, for example, take into account a deeper understanding of preictal mechanisms, patient‐specific sleep‐wake rhythms, or novel measurement approaches, may still offer further gains for these types of patients.
A simplified neutrosophic multiplicative set‐based TODIM using water‐filling algorithm for the determination of weights
Authors: Köseoğlu Ali , Şahin Rıdvan , Merdan Mehmet
Published: December 2019

Due to the technological developments around the world, the amount of information that researchers work on increases continuously. This information density contains incomplete and uncertain data that cannot be fully expressed with crisp numbers. Fuzzy sets, intuitionistic fuzzy sets, and neutrosophic sets are useful tools to manage such information, but these concepts use a symmetrical and uniform scale to express data, whereas real‐life problems contain nonsymmetrical and non‐uniform information. Intuitionistic multiplicative sets (IMSs) are effective tools for dealing with these real‐life problems. However, IMSs cannot handle real‐life problems completely because indeterminate information depends on membership and non‐membership information of IMSs, which is a restriction for decision makers and also for decision problems. To overcome this limitation, this paper generalizes the IMSs by using simplified neutrosophic set and introduces a novel approach that is called simplified neutrosophic multiplicative sets (SNMSs). Firstly, we define SNMS, show their set‐based operations, and then give a description of simplified neutrosophic multiplicative numbers (SNMNs). Based on SNMNs, we develop two simplified neutrosophic multiplicative aggregation operators on SNMNs that are called simplified neutrosophic multiplicative weighted arithmetic average operator and simplified neutrosophic multiplicative weighted geometric average operator. Furthermore, we define some simplified neutrosophic multiplicative distance measures. Finally, using a model based on water‐filling algorithm for determining criteria weights, we give a numerical example to demonstrate the effectiveness of the introduced concept with the proposed simplified neutrosophic multiplicative simplified neutrosophic multiplicative‐TODIM method.
Abundance and distribution of the white shark in the Mediterranean Sea
Authors: Moro Stefano , Jona‐Lasinio Giovanna , Block Barbara , Micheli Fiorenza , De Leo Giulio , Serena Fabrizio , Bottaro Massimiliano , Scacco Umberto , Ferretti Francesco
Published: December 2019

Conservation of apex predators is a key challenge both in marine and terrestrial ecosystems. The white shark is a rare but persistent inhabitant of the Mediterranean Sea and it is currently assessed as “critically endangered” in the region. However, the population trends and dynamics of this species in the area are still unknown. Little is known about white shark distribution, habitat use and population abundance trends, aspects that are critical for conservation and management. In this study, we built the most comprehensive database of white shark occurrence records in the region. We collected 773 different records from different sources and used them to characterize the spatial and temporal patterns of abundance of Mediterranean white sharks between 1860 and 2016. We analysed these data by using generalized additive models and used spatially disaggregated information on human population abundance as a proxy of observation effort. Our results suggest a complex trajectory of population change characterized by a historical increase and a more recent reduction (61%, range 58%–72%) since the second half of the 20th century. In particular, analyses reveal a 52% (range 37%–88%) to 96% (range 92%–100%) overall decline in different Mediterranean sectors and a contraction in spatial distribution. Here, we provide the first reconstruction of abundance trends and offer new hypotheses regarding the drivers of change of white sharks in the Mediterranean. Our approach can be broadly applied to data‐poor contexts to reconstruct change and inform the conservation of endangered top predators in the Mediterranean Sea and other intensely used marine regions.
High affinity of 4‐(4‐(dimethylamino)styryl)‐N‐methylpyridinium transport for assessing organic cation drugs in hepatocellular carcinoma cells
Authors: Jinakote Metee , Ontawong Atcharaporn , Soodvilai Sunhapas , Pimta Jeerawat , Pasachan Tipthida , Chatsudthipong Varanuj , Srimaroeng Chutima
Published: December 2019

Human organic cation transporter 1 (hOCT1) and human organic cation transporter 3 (hOCT3) are highly expressed in hepatocytes and play important roles in cationic drug absorption, distribution, and elimination. A previous study demonstrated that downregulation of hOCT1 and hOCT3 mRNA was related to hepatocellular carcinoma (HepG2) prognosis and severity. Whether these transporters expressed in HepG2 cells serve for cationic drug delivery has not been investigated. Besides radioactive transport, options for assessing hOCTs in hepatocytes are limited. This study clarified the significant roles of hOCTs in HepG2 by comparing cationic fluorescent 4‐(4‐(dimethylamino)styryl)‐N‐methylpyridinium (ASP+) with traditional [3H]‐1‐methyl‐4‐phenylpyridinium (MPP+). The results showed ASP+ was preferably transported into HepG2 compared to [3H]‐MPP+ with high affinity and a high maximal transport rate. Selective transport of ASP+ mediated by hOCTs was influenced by extracellular pH, temperature, and membrane depolarization, corresponding to hOCT1 and hOCT3 expressions. Furthermore, transport of cationic drugs, metformin, and paclitaxel in HepG2 cells was blunted by OCT inhibitors, suggesting that hOCT1 and hOCT3 expressed in HepG2 cells exhibit notable impacts on cationic drug actions. The fluorescent ASP+‐based in vitro model may also provide a rapid and powerful analytical tool for further screening of cationic drug actions and interactions with hOCTs, particularly hOCT1 and hOCT3 in hepatocellular carcinoma.
The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase‐dihydropteroate synthase reveals the basis of sulfa resistance
Authors: Chitnumsub Penchit , Jaruwat Aritsara , Talawanich Yuwadee , Noytanom Krittikar , Liwnaree Benjamas , Poen Sinothai , Yuthavong Yongyuth
Published: December 2019

The clinical efficacy of sulfa drugs as antimalarials has declined owing to the evolution of resistance in Plasmodium falciparum (Pf) malaria parasites. In order to understand the basis of this resistance and to design more effective antimalarials, we have solved 13 structures of the bifunctional enzyme 6‐hydroxymethyl‐7,8‐dihydropterin pyrophosphokinase (HPPK)–dihydropteroate synthase (DHPS) from wild‐type (WT) P. falciparum and sulfa‐resistant mutants, both as apoenzyme and as complexes with pteroate (PTA) and sulfa derivatives. The structures of these complexes show that PTA, which effectively inhibits both the WT and mutants, stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants. Kinetic data show that the mutants have enhanced enzyme activity compared with the WT. These PfDHPS structural insights are critical for the design of novel, substrate envelope–compliant DHPS inhibitors that are less vulnerable to resistance mutations.

Databases

The data reported in this paper have been deposited in the Protein Data Bank, www.wwpdb.org. PDB ID codes: 6JWQ for apoWT; 6JWR, 6JWS, and 6JWT for PTA complexes of WT, A437G (3D7), and V1/S; 6JWU, 6JWV, and 6JWW for STZ‐DHP complexes of WT, 3D7, and V1/S; 6JWX, 6JWY, and 6JWZ for SDX‐DHP complexes of WT, 3D7, and W2; 6KCK, 6KCL, and 6KCM for Pterin/pHBA complexes of WT, TN1, and W2.
Environment outweighs the effects of fishing in regulating demersal community structure in an exploited marine ecosystem
Authors: Mérillet Laurène , Kopp Dorothée , Robert Marianne , Mouchet Maud , Pavoine Sandrine
Published: December 2019

Global climate change has already caused bottom temperatures of coastal marine ecosystems to increase worldwide. These ecosystems face many pressures, of which fishing is one of the most important. While consequences of global warming on commercial species are studied extensively, the importance of the increase in bottom temperature and of variation in fishing effort is more rarely considered together in these exploited ecosystems. Using a 17 year time series from an international bottom trawl survey, we investigated covariations of an entire demersal ecosystem (101 taxa) with the environment in the Celtic Sea. Our results showed that over the past two decades, biotic communities in the Celtic Sea were likely controlled more by environmental variables than fisheries, probably due to its long history of exploitation. At the scale of the entire zone, relations between taxa and the environment remained stable over the years, but at a local scale, in the center of the Celtic Sea, dynamics were probably driven by interannual variation in temperature. Fishing was an important factor structuring species assemblages at the beginning of the time series (2000) but decreased in importance after 2009. This was most likely caused by a change in spatial distribution of fishing effort, following a change in targeted taxa from nephrops to deeper water anglerfish that did not covary with fishing effort. Increasing bottom temperatures could induce additional changes in the coming years, notably in the cold‐water commercial species cod, hake, nephrops, and American plaice. We showed that analyzing covariation is an effective way to screen a large number of taxa and highlight those that may be most susceptible to future simultaneous increases in temperature and changes in exploitation pattern by fisheries. This information can be particularly relevant for ecosystem assessments.