bluuebunny/crossref_metadata_2025 huggingface dataset:
Semiparametric regression calibration for general hazard models in survival analysis with covariate measurement error; surprising performance under linear hazard
Authors: Wang Ching‐Yun , Song Xiao
Published: June 2020

Observational epidemiological studies often confront the problem of estimating exposure‐disease relationships when the exposure is not measured exactly. Regression calibration (RC) is a common approach to correct for bias in regression analysis with covariate measurement error. In survival analysis with covariate measurement error, it is well known that the RC estimator may be biased when the hazard is an exponential function of the covariates. In the paper, we investigate the RC estimator with general hazard functions, including exponential and linear functions of the covariates. When the hazard is a linear function of the covariates, we show that a risk set regression calibration (RRC) is consistent and robust to a working model for the calibration function. Under exponential hazard models, there is a trade‐off between bias and efficiency when comparing RC and RRC. However, one surprising finding is that the trade‐off between bias and efficiency in measurement error research is not seen under linear hazard when the unobserved covariate is from a uniform or normal distribution. Under this situation, the RRC estimator is in general slightly better than the RC estimator in terms of both bias and efficiency. The methods are applied to the Nutritional Biomarkers Study of the Women's Health Initiative.
Communication behaviours of children with cerebral palsy who are minimally verbal
Authors: Mei Cristina , Fern Bethany , Reilly Sheena , Hodgson Madeleine , Reddihough Dinah , Mensah Fiona , Morgan Angela
Published: June 2020

Background

There is a lack of population‐based studies exploring the communicative behaviours of minimally verbal children with cerebral palsy (CP), with factors associated with superior and poorer communication outcomes unknown. This study aimed to examine the communication behaviours of minimally verbal children with CP recruited from a representative community sample and to identify factors associated with communication outcomes.

Methods

Twenty minimally verbal children aged 5–6 years, recruited through the Victorian Cerebral Palsy Register, completed the Communication and Symbolic Behaviour Scales–Developmental Profile (CSBS‐DP). Linear regressions examined child‐related and environmental factors associated with communication outcomes.

Results

CSBS‐DP total raw scores ranged from 0 to 113. Strengths were the use of conventional gestures and understanding of language. Challenges were noted in using sequential action schemes during play. Communication typically served to regulate the behaviour of others. All participants demonstrated reduced functional communication (Communication Function Classification System levels III–IV). In the multivariable regression model adjusted for cognition, poorer communication skills were associated with Manual Ability Classification System levels IV–V (P = 0.004).

Conclusions

Although some children with CP who are minimally verbal use a variety of communication functions, significant functional limitations may be apparent. Severe upper limb impairment may provide an early indication of greater communication difficulties.
Vemurafenib‐related photosensitivity
Authors: Eberlein Bernadette , Biedermann Tilo , Hein Rüdiger , Posch Christian
Published: June 2020

Increased photosensitivity is a common cutaneous adverse effect associated with the BRAF inhibitor vemurafenib. Clinically, it presents as an immediate sensation of heat and edematous erythema during sun exposure, as well as a sunburn reaction in terms of a late reaction. Phototesting has shown that the UVA range (320 nm to 400 nm), triggers both the immediate and the late reaction. In terms of pathogenesis, photochemical studies have suggested that exposure of vemurafenib to UVA radiation produces an UVA‐absorbing photoproduct. In vitro studies on various cell models have also demonstrated that the phototoxic effects of vemurafenib are exclusively caused by UVA irradiation. This latter mechanism is probably responsible for the photosensitivity clinically observed in patients receiving vemurafenib.

In addition, vemurafenib is able to inhibit ferrochelatase. The resulting increase in protoporphyrin IX has also been observed in some human studies involving the drug. However, it is yet unproven whether porphyrins actually contribute to the immediate skin reactions seen in individuals on vemurafenib, even though the clinical presentation is similar to that found in erythropoietic protoporphyria with a comparable pathomechanism.

Other BRAF inhibitors, such as dabrafenib and encorafenib, are associated with significantly lower photosensitivity. It is essential that patients treated with vemurafenib are informed about immediate and delayed reactions potentially caused even by low doses of UVA. This includes counseling on photoprotective measures.
Suicidal risk with isotretinoin treatment – a never‐ending story
Authors: Gieler U. , Gieler T.
Published: June 2020

Linked article: C. Droitcourt et al. J Eur Acad Dermatol Venereol 2020; 34: 1293‐1301. https://doi.org/10.1111/jdv.16005.
The Influence of Various Cerebral and Extracerebral Pathologies on Apparent Diffusion Coefficient Values in the Fetal Brain
Authors: Schönberg Nadja , Weisstanner Christian , Wiest Roland , Bonél Harald M. , Piechowiak Eike I. , Cullmann Jennifer L. , Raio Luigi , Pastore‐Wapp Manuela , Slavova Nedelina
Published: June 2020

BACKGROUND AND PURPOSE

The changing MRI signal accompanying brain maturation in fetal brains can be quantified on apparent diffusion coefficient (ADC) maps. Deviations from the natural course of ADC values may reflect structural pathology. The purpose of this study was to determine the influence of fetal pathologies on the ADC values in different regions of the fetal brain and their evolution with increasing gestational age.

METHODS

This was a retrospective study of 291 fetuses evaluated between the 14th and the 40th week of gestation using diffusion‐weighted imaging (DWI). Fetuses with normal MRI findings but sonographically suspected pathology or fetuses with abnormalities not affecting the brain were analyzed in the control group and compared to fetuses suffering from different pathologies like hydrocephalus/ventriculomegaly, brain malformations, infections, ischemia/hemorrhage, diaphragmatic hernias, and congenital heart disease. Pairwise ADC measurements in each side of the white matter (WM) of the frontal, parietal, and occipital lobes, in the basal ganglia and the cerebellum, as well as a single measurement in the pons were performed and were plotted against gestational age.

RESULTS

In the control group, brain maturation followed a defined gradient, resulting in lower ADC values in the most mature regions. Each disorder group experienced abnormal patterns of evolution of the ADC values over time deviating from the expected course.

CONCLUSIONS

The ADC values in different regions of the fetal brain and their evolution with increasing gestational age are influenced by pathologies compromising the cerebral maturation.
Drift, selection and adaptive variation in small populations of a threatened rattlesnake
Authors: Ochoa Alexander , Broe Michael , Moriarty Lemmon Emily , Lemmon Alan R. , Rokyta Darin R. , Gibbs H. Lisle
Published: June 2020

An important goal of conservation genetics is to determine if the viability of small populations is reduced by a loss of adaptive variation due to genetic drift. Here, we assessed the impact of drift and selection on direct measures of adaptive variation (toxin loci encoding venom proteins) in the eastern massasauga rattlesnake (Sistrurus catenatus), a threatened reptile that exists in small isolated populations. We estimated levels of individual polymorphism in 46 toxin loci and 1,467 control loci across 12 populations of this species, and compared the results with patterns of selection on the same loci following speciation ofS. catenatusand its closest relative, the western massasauga (S. tergeminus). Multiple lines of evidence suggest that both drift and selection have had observable impacts on standing adaptive variation. In support of drift effects, we found little evidence for selection on toxin variation within populations and a significant positive relationship between current levels of adaptive variation and long‐ and short‐term estimates of effective population size. However, we also observed levels of directional selection on toxin loci among populations that are broadly similar to patterns predicted from interspecific selection analyses that pre‐date the effects of recent drift, and that functional variation in these loci persists despite small short‐term effective sizes. This suggests that much of the adaptive variation present in populations may represent an example of “drift debt,” a nonequilibrium state where present‐day levels of variation overestimate the amount of functional genetic diversity present in future populations.
Infant peripherally inserted central catheter insertion without general anesthesia
Authors: Laing Sarah , Burgoyne Laura L. , Muncaster Michele , Taranath Ajay , Taverner Fiona J.
Published: June 2020

Background

Avoiding anesthesia for infant peripherally inserted central catheter insertion beyond the neonatal period has been the subject of very little research despite this being a high‐risk age group. In our institution, we introduced a “Fast, Feed, and Wrap” technique, previously described for magnetic resonance imaging scans, for infants up to 6 months and weighing under 5.5 kg undergoing peripherally inserted central catheter insertion.

Aims

The aim was to report our experience using “Fast, Feed, and Wrap,” in particular the success rate and proportion of qualifying infants who were managed this way.

Methods

A retrospective study was undertaken using electronic records and case notes to determine patient age, weight, indication for procedure, anesthetic technique (general anesthesia or “Fast, Feed, and Wrap”), peripherally inserted central catheter details (site of insertion, gauge, and number of lumens), and length of procedure.

Results

Fifty‐one infants qualified for “Fast, Feed, and Wrap” over a 42‐month period, 43 were attempted this way and 40 were successful. All infants were greater than 40 weeks postconceptual age at the time of peripherally inserted central catheter insertion under “Fast, Feed, and Wrap,” though 26% were preterm. The average age of babies undergoing “Fast, Feed, and Wrap” was 35 days (IQR 18‐55), and the median weight was 3.78 kg (IQR 3.48‐4.77).

Conclusions

Infants younger than 6 months and under 5.5 kg can be managed without general anesthesia for peripherally inserted central catheter insertion using a Fast, Feed, and Wrap technique.
Factors affecting survival in children requiring intensive care after hematopoietic stem cell transplantation. A retrospective single‐center study
Authors: Szmit Zofia , Kośmider‐Żurawska Magdalena , Król Anna , Łobos Monika , Miśkiewicz‐Bujna Justyna , Zielińska Marzena , Kałwak Krzysztof , Mielcarek‐Siedziuk Monika , Salamonowicz‐Bodzioch Małgorzata , Frączkiewicz Jowita , Ussowicz Marek , Owoc‐Lempach Joanna , Gorczyńska Ewa
Published: June 2020

Allo‐HSCT is associated with life‐threatening complications. Therefore, a considerable number of patients require admission to a PICU. We evaluated the incidence and outcome of PICU admissions after allo‐HSCT in children, along with the potential factors influencing PICU survival. A retrospective chart review of 668 children who underwent first allo‐HSCT in the Department of Pediatric Hematology/Oncology and BMT in Wrocław during years 2005‐2017, particularly focusing on patients admitted to the PICU within 1‐year post‐HSCT. Fifty‐eight (8.7%) patients required 64 admissions to the PICU. Twenty‐four (41.5%) were discharged, and 34 (58.6%) patients died. Among the discharged patients, 6‐month survival was 66.7%. Compared with survivors, death cases were more likely to have required MV (31/34; 91.2% vs. 16/24; 66.7% P = .049), received more aggressive cardiac support (17/34; 50% vs. 2/24; 8.3% P = .002), and had a lower ANC on the last day of their PICU stay (P = .004). Five patients were successfully treated with NIV and survived longer than 6 months post‐discharge. The intensity of cardiac support and ANC on the last day of PICU treatment was independent factors influencing PICU survival. Children admitted to the PICU after allo‐HSCT have a high mortality rate. Mainly those who needed a more aggressive approach and had a lower ANC on the last day of treatment had a greater risk of death. While requiring MV is associated with decreased PICU survival, early implementation of NIV might be considered.
Serostatus following polio‐containing vaccination before and after liver transplantation
Authors: Funaki Takanori , Fukuda Akinari , Sakamoto Seisuke , Kasahara Mureo , Saitoh Akihiko , Miyairi Isao
Published: June 2020

Background

The strategy to eradicate polio is based on preventing infection by immunizing all children until the world is polio‐free. However, data regarding efficacy of polio‐containing vaccination in immunocompromised patients such as LT recipients are limited.

Methods

We conducted an observational study at the largest pediatric transplant center in Japan from January 2011 to January 2015. LT recipients were enrolled after transplantation, and those who had completed the Japanese polio vaccination program were eligible for the study. Patients' demographics were collected from their medical records. Antibody titers against poliovirus serotypes 1‐3 were measured using the neutralization test at the routine follow‐up visits after enrollment. Factors associated with seropositivity against each type of poliovirus were evaluated.

Results

Sixty‐four patients who had received the complete polio vaccination series were enrolled in the study. Of these, 37 patients had received all series of polio‐containing vaccination before LT. Median age of the patients was 75 months. Their underlying diseases included the following: 40 (63%) with cholestatic liver diseases and 11 (17%) with metabolic disorders. After a median interval of 43 months after LT, seropositivity rates against poliovirus 1, 2, and 3 were 93.8% (60/64), 92.2% (59/64), and 54.7% (35/64), respectively. Among 32 patients who had received only oral polio vaccine (OPV), seropositivity against poliovirus 3 was particularly low (25.0%). No factors associated with seropositivity against each type of poliovirus were identified.

Conclusions

In the LT recipients, seropositivity for poliovirus 3 was low, suggesting a need for additional inactivated polio‐containing vaccination after LT, especially for patients who had received only OPV.
Synchronous vasomotion of skin microvessels at acupoints on the twelve main meridians of beagle dogs
Authors: Zhang Tao , Liu Chun , Hu Ge , Dong Hong , Mu Xiang
Published: June 2020

Background/purpose

Synchronous microvascular vasomotion was detected at acupoints in our previous human study. This present study aimed to characterize the skin microvascular vasomotion at acupoints on the twelve meridians of beagle dogs.

Materials and methods

Two acupoints were selected on each meridian and exactly located at the rosy red spots by an electrochemical color‐appearing method, where the electrical resistance was measured. The skin blood flow at acupoints was recorded by laser Doppler flowmetry (LDF), and microvascular vasomotion was analyzed according to LDF waveforms.

Results

The skin electrical resistance at acupoints was significantly lower than that at control non‐acupoints. The LDF waveforms at acupoints were sinusoidal, which showed the synchronization of the microvascular vasomotion. The spectral analysis revealed that the vasomotion frequencies at acupoints on the same meridian were identical but not among different meridians, and the frequencies on the twelve main meridians displayed a constant order.

Conclusion

The skin microvascular vasomotion is synchronous at acupoints of beagle dogs and has a specific frequency along the meridian, and the electrochemical color‐appearing method is a feasible strategy for the precise and visual location of acupoints. The study provides evidence for the universality of synchronous vasomotion of skin microvessels at acupoints.
Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses
Authors: Wu Nicholas C. , Thompson Andrew J. , Lee Juhye M. , Su Wen , Arlian Britni M. , Xie Jia , Lerner Richard A. , Yen Hui-Ling , Bloom Jesse D. , Wilson Ian A.
Published: June 2020

Resistance to influenza antibodies

Broadly neutralizing human antibodies (bnAbs) to the stem of hemagglutinin (HA), a trimeric glycoprotein found on the surface of influenza viruses, are valuable therapeutics and can guide the development of universal influenza vaccines. For their use in therapy development, it is important to understand the extent to which HA stem variants with resistance to bnAbs can develop. Wu
et al.
used saturation mutagenesis combined with next-generation sequencing to systematically search for resistance mutations to prototypic bnAbs in two influenza subtypes, H3 and H1. They found that the genetic barrier to resistance to stem bnAbs was low for the H3 subtype but higher for the H1 subtype. The ability of H3 to develop resistance to bnAbs presents a challenge in the development of a universal influenza vaccine.

Science
, this issue p.
1335
Structural evidence for a dynamic metallocofactor during N
2
reduction by Mo-nitrogenase
Authors: Kang Wonchull , Lee Chi Chung , Jasniewski Andrew J. , Ribbe Markus W. , Hu Yilin
Published: June 2020

Delicate dance becomes a ballet

The enzyme nitrogenase uses adenosine triphosphate and several unusual iron-sulfur cofactors to pump electrons into typically inert dinitrogen (N
2
), providing protons along the way. Previous work has shown that sulfur atoms in the iron-molybdenum cofactor (FeMoCo) are labile and suggests that replacement of one of the sulfurs by N
2
is integral to the mechanism of N
2
binding and reduction. Through the elimination of excess reducing agent during preparation, Kang
et al.
determined structures of Mo-nitrogenase in a resting conformation. Unexpectedly, they found that all three sulfurs at the outer edge of FeMoCo appear to be labile, with one subunit even having two of three sulfurs replaced by light, diatomic ligands. Biochemical and spectroscopic data indicate that the protein is active, holds tightly bound N
2
, and is in the expected oxidation state. These results may prompt a reassessment of the possible mechanisms of N
2
reduction and the role of dynamic belt ligands in FeMoCo.

Science
, this issue p.
1381
Measles virus and rinderpest virus divergence dated to the sixth century BCE
Authors: Düx Ariane , Lequime Sebastian , Patrono Livia Victoria , Vrancken Bram , Boral Sengül , Gogarten Jan F. , Hilbig Antonia , Horst David , Merkel Kevin , Prepoint Baptiste , Santibanez Sabine , Schlotterbeck Jasmin , Suchard Marc A. , Ulrich Markus , Widulin Navena , Mankertz Annette , Leendertz Fabian H. , Harper Kyle , Schnalke Thomas , Lemey Philippe , Calvignac-Spencer Sébastien
Published: June 2020

Older origins of measles virus

Animal domestication by humans is thought to have given many pathogens an opportunity to invade a new host, and measles is one example of this. However, there is controversy about when measles emerged in humans, because the historical descriptions of measles are relatively recent (late ninth century CE). The controversy has persisted in part because ancient RNA is thought to be a poor target for molecular clock techniques. Düx
et al.
have overcome the ancient RNA challenge by sequencing a measles virus genome obtained from a museum specimen of the lungs of child who died in 1912 (see the Perspective by Ho and Duchêne). The authors used these and other more recent sequencing data in a Bayesian molecular clock–modeling technique, which showed that measles virus diverged from rinderpest virus in the sixth century BCE, indicating an early origin for measles possibly associated with the beginnings of urbanization.

Science
, this issue p.
1367
; see also p.
1310
Human-specific
ARHGAP11B
increases size and folding of primate neocortex in the fetal marmoset
Authors: Heide Michael , Haffner Christiane , Murayama Ayako , Kurotaki Yoko , Shinohara Haruka , Okano Hideyuki , Sasaki Erika , Huttner Wieland B.
Published: June 2020

Neocortex in the fetal brain

Along the path of human evolution, gene duplication and divergence produced a protein, ARHGAP11B, that is found in humans but not nonhuman primates or other mammals. Heide
et al.
analyzed the effects of
ARHGAP11B
gene expression, under control of its own human-specific promoter, in the fetal marmoset (see the Perspective by Dehay and Kennedy). In the early weeks of fetal growth, the gene drove greater elaboration of neural progenitors and neocortex than is evident in the normal fetal marmoset. ARHGAP11B expression may be one cause of the more robust neocortex that characterizes the human brain.

Science
, this issue p.
546
; see also p.
506
Genomic Analysis Reveals Antibiotic-Susceptible Clones and Emerging Resistance in Neisseria gonorrhoeae in Saskatchewan, Canada
Authors: Parmar Nidhi R. , Singh Reema , Martin Irene , Perera Sumudu R. , Demczuk Walter , Kusalik Anthony , Minion Jessica , Dillon Jo-Anne R.
Published: June 2020

Whole-genome sequencing was used to identify mutations in antibiotic resistance-conferring genes to compare susceptibility predictions with MICs and to ascertain strain types in 99 isolates of
Neisseria gonorrhoeae
. Genotypes associated with susceptibility, as well as MIC creep or emerging resistance, were noted. Phylogenomic analysis revealed three distinctive clades and putative gonococcal transmission linkages involving a tetracycline-resistant
N. gonorrhoeae
outbreak and the clonal spread of susceptible isolates in men.
Supplemental Material: Himalayan Miocene adakitic rocks, a case study of the Mayum pluton: Insights into geodynamic processes within the subducted Indian continental lithosphere and Himalayan mid-Miocene tectonic regime transition
Authors: Lin Chao , Zhang Jinjiang , al. et
Published: June 2020

Table S1: Bulk element geochemistry and isotopic composition of the Mayum pluton; Table S2: Zircon LA-ICP-MS U-Pb data for the Mayum pluton; Table S3: Zircon in situ Lu-Hf isotopic data for the Mayum pluton; Table S4: Data statistics for Himalayan Eocene and Miocene adakitic rocks.
Non-functioning retroperitoneal abdominal schwannoma
Authors: Sultan Sherif , Barrett Nora , Curran Stephanie , Hynes Niamh
Published: June 2020

There are less than 150 cases of non-functioning retroperitoneal abdominal schwannoma (NRS) reported. Hormonal assay is crucial in confirming the diagnosis of NRS, as manipulation of a functional retroperitoneal paraganglioma will instigate an abrupt liberation of catecholamines, resulting in devastating consequences. We report the case of 42-year-old woman who presented with headache, night sweats and abdominal discomfort. Cross-sectional imaging demonstrated a retroperitoneal mass adherent to the aorta and inferior vena cava but biochemical testing of blood and urine was negative for metanephrines and normetanephrines. She underwent successful tumour resection via laparotomy, as location increased the complexity and risk of laparoscopic resection.
Sexual violence in sport: American Medical Society for Sports Medicine Position Statement
Authors: Koontz Jennifer Scott , Mountjoy Margo , Abbott Kristin E , Aron Cindy Miller , Basile Kathleen C , Carlson Chad T , Chang Cindy J , Diamond Alex B , Dugan Sheila A , Hainline Brian , Herring Stanley A , Hopkins B Elliot , Joy Elizabeth A , Judge Janet P , LaBotz Michele , Matuszak Jason , McDavis Cody J , Myers Rebecca A , Nattiv Aurelia , Tanji Jeffrey L , Wagner Jessica , Roberts William O
Published: June 2020

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the Task Force used an iterative process and expert consensus to finalise the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.
Pattern, clinical and demographic profile of inpatient psychiatry referrals in a tertiary care teaching hospital: a descriptive study
Authors: Mudgal Varchasvi , Rastogi Pali , Niranjan Vijay , Razdan Ramghulam
Published: June 2020

Background

Consultation liaison psychiatry (CLP) as a subspecialty is defined as the area of clinical psychiatry that encompasses clinical understanding, teaching and research activities of psychiatrists and allied health professionals in the non-psychiatric divisions of a general hospital. Psychiatric comorbidity of inpatients in tertiary care hospitals is huge. However, the amount of research in India in the field of consultation liaison is strikingly low.

Aim

To investigate the sociodemographic profile and psychiatric and physical subtypes of illness in patients admitted in other departments and referred to psychiatry department.

Methods

The study population comprised all consecutive inpatients referred for psychiatric consultation from other departments of a multispecialty tertiary care teaching hospital over 3 months. In a semistructured proforma, sociodemographic profile, referring departments, reasons for referral, referral rate, psychiatric diagnosis and physical illness diagnosis were recorded and analysed using descriptive statistics.

Results

172 patients were included and assessed after referral from various departments, of which 56.4% were male and 43.6% were female. The mean age was about 33.95 years, with majority of the patients in the 21–30 years age group. The referral rate was 1.1%. The maximum referrals were from the medicine department, with abnormal behaviour (26.2%) being the most common reason for referral, followed by alleged suicide attempt or self-harm (24.4%), anxiety (10.5%), substance use (10%) and disorientation (7.6%). The most common psychiatric disorder among patients was depressive disorder (24.4%), followed by substance use disorder (19.7%), schizophrenia and psychotic disorder (9.3%), and stress and trauma-related disorder (8.1%).

Conclusion

There are very few psychiatry referrals and an alarmingly low referral rate, given the psychiatric morbidities in the medical setting. Psychiatry training should have more weightage across different medical specialties and liaison activities between psychiatry and other disciplines should be augmented, which can lead to a better understanding of psychiatric symptomatology, early symptom recognition, swift referral and ensuring follow-up, which, in turn, would be key to improving CLP services.
First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE2-receptor E-type 4 (EP4), in patients with advanced cancers
Authors: Hong David S , Parikh Aparna , Shapiro Geoffrey I , Varga Andrea , Naing Aung , Meric-Bernstam Funda , Ataman Özlem , Reyderman Larisa , Binder Terri A , Ren Min , Liu Mingjie , Dayal Satish , Siu Amy Y , Sachdev Pallavi , Xu Lucy , Bhagawati-Prasad Vijay , Tchakov Ilian , Ooi Chean Eng , Bao Xingfeng , Marabelle Aurelien
Published: June 2020

Background

E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.

Methods

This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.

Results

No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.

Conclusions

In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.

Trial registration number

NCT02540291.
HDAC9 deficiency promotes tumor progression by decreasing the CD8+dendritic cell infiltration of the tumor microenvironment
Authors: Ning Yongling , Ding Jun , Sun Xiao , Xie Yewen , Su Mingming , Ma Chenglong , Pan Jie , Chen Jie , Jiang Hua , Qi Chunjian
Published: June 2020

Background

The tumor microenvironment (TME) contains a variety of immune cells, which play critical roles during the multistep development of tumors. Histone deacetylase 9 (HDAC9) has been reported to have either proinflammatory or anti-inflammatory effects, depending on the immune environment. In this study, we investigated whether HDAC9 in the tumor stroma regulated inflammation and antitumor immunity.

Methods

Hdac9knockout mice were generated to analyze the HDAC9-associated inflammation and tumor progression. Immune cells and cytokines in TME or draining lymph nodes were quantified by flow cytometry and quantitative reverse transcription-PCR. The antigen presentation and CD8+T cell priming by tumor-infiltrating dendritic cells (DCs) were evaluated in vitro and in vivo. HDAC9-associated inflammation was investigated in a mouse model with dextran sulfate sodium–induced colitis. Correlation of HDAC9 with CD8+expression was assessed in tissue sections from patients with non-small cell lung cancer.

Results

HDAC9 deficiency promoted tumor progression by decreasing the CD8+DC infiltration of the TME. Compared with wild-type mice, the tumor-infiltrating DCs ofHdac9-/-mice displayed impaired cross-presentation of tumor antigens and cross-priming of CD8+T cells. Moreover, HDAC9 expression was significantly positively correlated with CD8+cell counts in human lung cancer stroma samples.

Conclusions

HDAC9 deficiency decreased inflammation and promoted tumor progression by decreasing CD8+DC infiltration of the TME. HDAC9 expression in the tumor stroma may represent a promising biomarker to predict the therapeutic responses of patients receiving CD8+T cell-dependent immune treatment regimens.
Reexamining the Thomas precession
Authors: Carvalho Marcelo
Published: June 2020

We review the Thomas precession exhibiting the exact form of the Thomas rotation in the axis-angle parameterization. Assuming three inertial frames S, S′, and S″ moving with arbitrary velocities and with S and S″ having their axes parallel to the axes of S′, we focus our attention on the two essential elements of the Thomas precession: (i) there is a rotation between the axes of frames S and S″ and (ii) the combination of two Lorentz transformations from S to S′ and from S′ to S″ fails to produce a pure Lorentz transformation from S to S″. The physical consequence of (i) and (ii) refers to the impossibility of arbitrary frames S, S′, and S″ moving with non-parallel relative velocities having their axes mutually parallel. Then, we reexamine the validity of (i) and (ii) under the conjecture that time depends on the state of motion of the frames and we show that the Thomas precession assumes a different form as formulated in (i) and (ii).
Extreme genetic diversity among springtails (Collembola) in subterranean calcretes of arid Australia
Authors: Guzik Michelle T. , Stevens Mark I. , Cooper Steven J.B. , Humphreys William F. , Austin Andrew D.
Published: June 2020

The subterranean islands hypothesis for calcretes of the Yilgarn region in Western Australia applies to many stygobitic (subterranean–aquatic) species that are “trapped” evolutionarily within isolated aquifers due to their aquatic lifestyles. In contrast, little is known about the distribution of terrestrial–subterranean invertebrates associated with the calcretes. We used subterranean Collembola from the Yilgarn calcretes to test the hypothesis that troglobitic species, those inhabiting the subterranean unsaturated (non-aquatic) zone of calcretes, are also restricted in their distribution and represent reciprocally monophyletic and endemic lineages. We used the barcoding fragment of the mtDNA cytochrome c oxidase subunit 1 (COI) gene from 183 individuals to reconstruct the phylogenetic history of the genus Pseudosinella Schäffer (Collembola, Lepidocyrtidae) from 10 calcretes in the Yilgarn. These calcretes represent less than 5% of the total possible calcretes in this region, yet we show that their diversity for subterranean Collembola comprises a minimum of 25 new species. Regionally, multiple levels of diversity exist in Pseudosinella, indicative of a complex evolutionary history for this genus in the Yilgarn. These species have probably been impacted by climatic oscillations, facilitating their dispersal across the landscape. The results represent a small proportion of the undiscovered diversity in Australia’s arid zone.
Multiplex and Multilayer Network EEG Analyses: A Novel Strategy in the Differential Diagnosis of Patients with Chronic Disorders of Consciousness
Authors: Naro Antonino , Maggio Maria Grazia , Leo Antonino , Calabrò Rocco Salvatore
Published: June 2020

The deterioration of specific topological network measures that quantify different features of whole-brain functional network organization can be considered a marker for awareness impairment. Such topological measures reflect the functional interactions of multiple brain structures, which support the integration of different sensorimotor information subtending awareness. However, conventional, single-layer, graph theoretical analysis (GTA)-based approaches cannot always reliably differentiate patients with Disorders of Consciousness (DoC). Using multiplex and multilayer network analyses of frequency-specific and area-specific networks, we investigated functional connectivity during resting-state EEG in 17 patients with Unresponsive Wakefulness Syndrome (UWS) and 15 with Minimally Conscious State (MCS). Multiplex and multilayer network metrics indicated the deterioration and heterogeneity of functional networks and, particularly, the frontal-parietal (FP), as the discriminant between patients with MCS and UWS. These data were not appreciable when considering each individual frequency-specific network. The distinctive properties of multiplex/multilayer network metrics and individual frequency-specific network metrics further suggest the value of integrating the networks as opposed to analyzing frequency-specific network metrics one at a time. The hub vulnerability of these regions was positively correlated with the behavioral responsiveness, thus strengthening the clinically-based differential diagnosis. Therefore, it may be beneficial to adopt both multiplex and multilayer network analyses when expanding the conventional GTA-based analyses in the differential diagnosis of patients with DoC. Multiplex analysis differentiated patients at a group level, whereas the multilayer analysis offered complementary information to differentiate patients with DoC individually. Although further studies are necessary to confirm our preliminary findings, these results contribute to the issue of DoC differential diagnosis and may help in guiding patient-tailored management.
A Cap-less Voltage Spike Detection and Correction Circuit for Low Dropout Regulator
Authors: Manikandan P. , Bindu B.
Published: June 2020

A cap-less voltage spike detection and correction circuit for flipped voltage follower (FVF)-based low dropout regulator (LDO) is proposed in this paper. The transients in the output voltage are controlled by the pull-up currents [Formula: see text] and [Formula: see text] and pull-down currents [Formula: see text] and [Formula: see text]. These currents are dynamic current sources which are activated only during transient period and noise contributed by these current sources at steady state is zero. These currents increase/decrease based on the intermediate FVF node voltage [Formula: see text]. The proposed circuit detects the output voltage via [Formula: see text] and controls the power MOSFET gate and output capacitances by changing the pull-up and pull-down currents whenever the load changes. The proposed circuit consumes small additional bias current in the steady state and achieves less settling time and output spike voltage. This LDO is simulated using 180[Formula: see text]nm technology and the simulation result shows that the LDO has good load transient response with 190[Formula: see text]ns settling time and 170[Formula: see text]mV voltage spike over 1[Formula: see text]mA to 100[Formula: see text]mA load current range.
Gelfand–Tsetlin varieties for 𝔤𝔩n
Authors: Benitez Germán
Published: June 2020

Sergei Ovsienko proved that the Gelfand–Tsetlin variety for [Formula: see text] is equidimensional and the dimension of all irreducible components equals [Formula: see text]. This implies in particular the equidimensionality of the nilfiber of the (partial) Kostant–Wallach map. We generalize this result for the [Formula: see text]-partial Kostant–Wallach map and prove that all its fibers are equidimensional of dimension [Formula: see text]. Also, we study certain subvarieties of the Gelfand–Tsetlin variety and show their equidimensionality which gives a new proof of Ovsienko’s theorem for [Formula: see text] and [Formula: see text].
Limit theorems for numbers of returns in arrays under ϕ-mixing
Authors: Kifer Yuri
Published: June 2020

We consider a [Formula: see text]-mixing shift [Formula: see text] on a sequence space [Formula: see text] and study the number [Formula: see text] of returns [Formula: see text] at times [Formula: see text] to a cylinder [Formula: see text] constructed by a sequence [Formula: see text] where [Formula: see text] runs either until a fixed integer [Formula: see text] or until a time [Formula: see text] of the first return [Formula: see text] to another cylinder [Formula: see text] constructed by [Formula: see text]. Here, [Formula: see text] are certain functions of [Formula: see text] taking on nonnegative integer values when [Formula: see text] runs from 0 to [Formula: see text] and the dependence on [Formula: see text] is the main generalization here in comparison to [20]. Still, the dependence on [Formula: see text] requires certain conditions under which we obtain Poisson distributions limits of [Formula: see text] when counting is until [Formula: see text] as [Formula: see text] and geometric distributions limits when counting is until [Formula: see text] as [Formula: see text]. The results and the setup are similar to [17] where multiple returns are considered but under the stronger [Formula: see text]-mixing assumption.
Cyclic p-group actions on ℝℙ3
Authors: Kalliongis John , Ohashi Ryo
Published: June 2020

In this paper, we classify the smooth orientation preserving cyclic [Formula: see text]-group actions on the real projective space [Formula: see text] up equivalence, where two actions are equivalent if their images are conjugate in the group of self-diffeomorphisms. We view [Formula: see text] as the lens space [Formula: see text]. We show that any such action on [Formula: see text] is conjugate to a standard action explicitly defined, and we identify the quotient spaces of these actions. In addition, we enumerate the equivalence classes.
On ϕ-ideals and the structure of Lie algebras
Authors: Goudarzi Leila , Riyahi Zahra
Published: June 2020

This paper aims to study the concept of [Formula: see text]-ideals of a finite-dimensional Lie algebra which is analogous to the concept of [Formula: see text]-ideal and [Formula: see text]-normal subgroup. We compile some basic properties of [Formula: see text]-ideals and consider the influence of this concept on the structure of a finite-dimensional Lie algebra, especially its solvability and supersolvability. We also show that the counterpart of some results for [Formula: see text]-ideals of Lie algebras and [Formula: see text]-normal subgroups are not valid here.
Analytical solutions of citrate–phosphate coupled model of rice (Oryza sativaL.) roots
Authors: Zhang Huiping , Wang Shuyue , Ou Zhonghui
Published: June 2020

The citrate secreted by the rice (Oryza sativa L.) roots will promote the absorption of phosphate, and this process is described by the Kirk model. In our work, the Kirk model is divided into citrate sub-model and phosphate sub-model. In the citrate sub-model, we obtain the analytical solution of citrate with the Laplace transform, inverse Laplace transform and convolution theorem. The citrate solution is substituted into the phosphate sub-model, and the analytical solution of phosphate is obtained by the separation variable method. The existence of the solutions can be proved by the comparison test, the Weierstrass M-test and the Abel discriminating method.
Analysis of a mathematical model for the transmission dynamics of human melioidosis
Authors: Terefe Yibeltal Adane , Kassa Semu Mitiku
Published: June 2020

A deterministic model for the transmission dynamics of melioidosis disease in human population is designed and analyzed. The model is shown to exhibit the phenomenon of backward bifurcation, where a stable disease-free equilibrium co-exists with a stable endemic equilibrium when the basic reproduction number [Formula: see text] is less than one. It is further shown that the backward bifurcation dynamics is caused by the reinfection of individuals who recovered from the disease and relapse. The existence of backward bifurcation implies that bringing down [Formula: see text] to less than unity is not enough for disease eradication. In the absence of backward bifurcation, the global asymptotic stability of the disease-free equilibrium is shown whenever [Formula: see text]. For [Formula: see text], the existence of at least one locally asymptotically stable endemic equilibrium is shown. Sensitivity analysis of the model, using the parameters relevant to the transmission dynamics of the melioidosis disease, is discussed. Numerical experiments are presented to support the theoretical analysis of the model. In the numerical experimentations, it has been observed that screening and treating individuals in the exposed class has a significant impact on the disease dynamics.
The data science life cycle
Authors: Stodden Victoria
Published: June 2020

A cycle that traces ways to define the landscape of data science.
Hypergames and Cyber-Physical Security for Control Systems
Authors: Bakker Craig , Bhattacharya Arnab , Chatterjee Samrat , Vrabie Draguna L.
Published: June 2020

The identification of the Stuxnet worm in 2010 provided a highly publicized example of a cyber attack that physically damaged an industrial control system. This raised public awareness about the possibility of similar attacks against other industrial targets—including critical infrastructure. In this article, we use hypergames to analyze how strategic perturbations of sensor readings and calibrated parameters can be used to manipulate a system that employs optimal control. Hypergames form an extension of game theory that enables us to model strategic interactions where the players may have significantly different perceptions of the game(s) they are playing. Past work with hypergames has focused on relatively simple interactions consisting of a small set of discrete choices for each player. Here, we apply single-stage hypergames to larger systems with continuous variables. We find that manipulating constraints can be a more effective attacker strategy than manipulating objective function parameters. Moreover, the attacker need not change the underlying system to carry out a successful attack—it may be sufficient to deceive the defender controlling the system. It is possible to scale our approach up to even larger systems, but this will depend on the characteristics of the system in question, and we identify several characteristics that will make those systems amenable to hypergame analysis.
Breaking the Accessibility Barrier in Non-Visual Interaction with PDF Forms
Authors: Uckun Utku , Aydin Ali Selman , Ashok Vikas , Ramakrishnan IV
Published: June 2020

PDF forms are ubiquitous. Businesses big and small, government agencies, health and educational institutions and many others have all embraced PDF forms. People use PDF forms for providing information to these entities. But people who are blind frequently find it very difficult to fill out PDF forms with screen readers, the standard assistive software that they use for interacting with computer applications. Firstly, many of the them are not even accessible as they are non-interactive and hence not editable on a computer. Secondly, even if they are interactive, it is not always easy to associate the correct labels with the form fields, either because the labels are not meaningful or the sequential reading order of the screen reader misses the visual cues that associate the correct labels with the fields. In this paper we present a solution to the accessibility problem of PDF forms. We leverage the fact that many people with visual impairments are familiar with web browsing and are proficient at filling out web forms. Thus, we create a web form layer over the PDF form via a high fidelity transformation process that attempts to preserve all the spatial relationships of the PDF elements including forms, their labels and the textual content. Blind people only interact with the web forms, and the filled out web form fields are transparently transferred to the corresponding fields in the PDF form. An optimization algorithm automatically adjusts the length and width of the PDF fields to accommodate arbitrary size field data. This ensures that the filled out PDF document does not have any truncated form-field values, and additionally, it is readable. A user study with fourteen users with visual impairments revealed that they were able to populate more form fields than the status quo and the self-reported user experience with the proposed interface was superior compared to the status quo.
The Impact of Thinking-Aloud on Usability Inspection
Authors: McDonald Sharon , Cockton Gilbert , Irons Alastair
Published: June 2020

This study compared the results of a usability inspection conducted under two separate conditions: An explicit concurrent think-aloud that required explanations and silent working. 12 student analysts inspected two travel websites thinking-aloud and working in silence to produce a set of problem predictions. Overall, the silent working condition produced more initial predictions, but the think-aloud condition yielded a greater proportion of accurate predictions as revealed by falsification testing. The analysts used a range of problem discovery methods with system searching being favoured by the silent working condition and the more active, goal playing discovery method in the think-aloud condition. Thinking-aloud was also associated with a broader spread of knowledge resources.
Your wish is my CMD
Authors: Savage Neil
Published: June 2020

Artificial intelligence could automate software coding.