bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of LCL161, a novel oral pan‐inhibitor of apoptosis protein (IAP) antagonist, in Japanese patients with advanced solid tumors
Authors: Morita Sachi , Minami Hironobu , Mitsuma Ayako , Toyoda Masanori , Kiyota Naomi , Ando Yuichi 
Published: January 2022

AbstractIntroductionLCL161 is a novel oral pan‐inhibitor of apoptosis protein (IAP) antagonist. LCL161 enhances paclitaxel activity in cell lines and xenograft models. A phase I study of LCL161 combined with paclitaxel for the treatment of Japanese patients with advanced solid tumors was conducted.MethodsEach patient received oral LCL161 in a single weekly dose on days 1, 8, and 15 of a 21‐day treatment cycle. In the second cycle, patients received a combination treatment with weekly paclitaxel (80 mg/m2) whenever possible. A Bayesian logistic regression model by escalation with the overdose control principle was used.ResultsNine patients were treated with LCL161 at a dose of 600 mg (five patients) or 1200 mg (four patients). Seven patients were treated with LCL161 plus paclitaxel, and two patients received only LCL161 monotherapy. Because this study was terminated early due to a change in the LCL161 development strategy, the maximum tolerated dose (MTD) was not determined. One patient treated with LCL161 monotherapy at a dose of 1200 mg experienced dose limitind toxicity (grade 3 maculopapular rash). Another patient died on day 86 of bacterial pneumonia, which was suspected to be related to the study treatment. The most common serious adverse events were infections and infestations (n = 3).ConclusionThe present study suggests that the risk of infection may increase when LCL161 is combined with paclitaxel, but other conclusions about the MTD, pharmacokinetic profile, and preliminary activity of the combination of LCL161 plus paclitaxel were not drawn.
Successful treatment of vulvovaginal lichen planus with tildrakizumab: A case series of 24 patients
Authors: Kherlopian Ashod , Fischer Gayle 
Published: January 2022

ABSTRACTVulvovaginal lichen planus (VLP) is a chronic inflammatory dermatosis affecting the genital skin and mucosa that can have a profound negative impact on patient quality of life. Up to 43% of women with VLP require systemic immunosuppression to achieve disease remission, and some individuals prove to be highly treatment resistant. We present a case series of 24 women with severe VLP who successfully achieved remission using off‐label treatment with the interleukin‐23 (IL‐23) monoclonal antibody blocker tildrakizumab, and highlight tildrakizumab as a treatment for women with recalcitrant VLP who have failed more conservative treatments.
Nightmares of a Dying World and the Dream of a Counter‐Apocalypse
Authors: Keller Catherine 
Published: January 2022

AbstractIn common parlance, an apocalypse refers to a calamity that signals the end. It represents a closure. But the original meaning in the biblical Greek is the opposite. Apocalypse means “revelation” or disclosure. It offers hope, not despair. For the early Christians facing persecution by the Roman Empire, hope was disclosed in a coded narrative that showed the hidden weakness of their tormentors. The “beast” of imperial power and the “great whore” of its global economy crash in mutual destruction. For us, the revelation we most need is reflexive: signs that will enable us to see clearly how our current civilization is self‐destructive. If the new Rome is the Pax Americana, the empire that the United States has imposed on much of the world in the name of democracy and freedom, the “whore of Babylon” is the global economy. Once again, what appears on the surface to be an unstoppable force of progress is the engine of its own destruction. Right‐wing Christians have inverted the vision, seeing, by analogy, the emperor as the one being persecuted. Rather than abandoning the apocalypse to reactionary literalizations or liberal paralysis, we may read it in terms of a counter‐apocalypse. Not a mere anti‐apocalypse, this symbolic strategy helps us to address such cataclysmic threats as climate change in the spirit of an honest hope, beyond panic or evasion.
Q fever prevention: Perspectives from university animal science and veterinary students and livestock farmers
Authors: Rahaman Md Rezanur , Burgess Teresa , Marshall Helen , Milazzo Adriana , Chaber Anne‐Lise , Crabb Deane , Bi Peng 
Published: January 2022

AbstractObjectiveTo explore animal science and veterinary students’ and livestock farmers’ perceptions concerning Q fever prevention.DesignAn online survey with an open‐ended question seeking knowledge and perceptions about Q fever prevention was distributed among participants during March‐September 2019. We applied thematic analysis to identify emerging themes.SettingAnimal science and veterinary students enrolled at the University of Adelaide and members of Livestock South Australia representing cattle, sheep and goat farmers in South Australia.ParticipantsA total of56 animal science and veterinary students and 154 livestock farmers responded to the open‐ended question.InterventionsNot applicable.Main outcome measuresPerceived challenges and opportunities for a coordinated Q fever prevention approach including human vaccination reported by the participants.ResultsTwo major themes arose in each group. Students and farmers viewed Q fever vaccination as important. However, excessive cost for students was a barrier and for farmers, it was general practitioners' lack of knowledge of Q fever and access to an accredited immunisation provider. Similarly, both groups highlighted the need for education and increasing public and community awareness of Q fever.ConclusionOur findings underscore that a sector‐wide approach involving community awareness programmes, education and training for general practitioners, and subsidised vaccination as well as commitment from government and industry partners may contribute to reducing the burden of Q fever among at‐risk populations.
Systematic review with meta‐analysis: artificial intelligence in the diagnosis of oesophageal diseases
Authors: Visaggi Pierfrancesco , Barberio Brigida , Gregori Dario , Azzolina Danila , Martinato Matteo , Hassan Cesare , Sharma Prateek , Savarino Edoardo , de Bortoli Nicola 
Published: January 2022

SummaryBackgroundArtificial intelligence (AI) has recently been applied to endoscopy and questionnaires for the evaluation of oesophageal diseases (ODs).AimWe performed a systematic review with meta‐analysis to evaluate the performance of AI in the diagnosis of malignant and benign OD.MethodsWe searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane Library. A bivariate random‐effect model was used to calculate pooled diagnostic efficacy of AI models and endoscopists. The reference tests were histology for neoplasms and the clinical and instrumental diagnosis for gastro‐oesophageal reflux disease (GERD). The pooled area under the summary receiver operating characteristic (AUROC), sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR) and diagnostic odds ratio (DOR) were estimated.ResultsFor the diagnosis of Barrett's neoplasia, AI had AUROC of 0.90, sensitivity 0.89, specificity 0.86, PLR 6.50, NLR 0.13 and DOR 50.53. AI models’ performance was comparable with that of endoscopists (P = 0.35). For the diagnosis of oesophageal squamous cell carcinoma, the AUROC, sensitivity, specificity, PLR, NLR and DOR were 0.97, 0.95, 0.92, 12.65, 0.05 and DOR 258.36, respectively. In this task, AI performed better than endoscopists although without statistically significant differences. In the detection of abnormal intrapapillary capillary loops, the performance of AI was: AUROC 0.98, sensitivity 0.94, specificity 0.94, PLR 14.75, NLR 0.07 and DOR 225.83. For the diagnosis of GERD based on questionnaires, the AUROC, sensitivity, specificity, PLR, NLR and DOR were 0.99, 0.97, 0.97, 38.26, 0.03 and 1159.6, respectively.ConclusionsAI demonstrated high performance in the clinical and endoscopic diagnosis of OD.
Understanding the evolution of viviparity using intraspecific variation in reproductive mode and transitional forms of pregnancy
Authors: Whittington Camilla M. , Van Dyke James U. , Liang Stephanie Q. T. , Edwards Scott V. , Shine Richard , Thompson Michael B. , Grueber Catherine E. 
Published: January 2022

ABSTRACTHow innovations such as vision, flight and pregnancy evolve is a central question in evolutionary biology. Examination of transitional (intermediate) forms of these traits can help address this question, but these intermediate phenotypes are very rare in extant species. Here we explore the biology and evolution of transitional forms of pregnancy that are midway between the ancestral state of oviparity (egg‐laying) and the derived state, viviparity (live birth). Transitional forms of pregnancy occur in only three vertebrates, all of which are lizard species that also display intraspecific variation in reproductive phenotype. In these lizards (Lerista bougainvillii, Saiphos equalis, and Zootoca vivipara), geographic variation of three reproductive forms occurs within a single species: oviparity, viviparity, and a transitional form of pregnancy. This phenomenon offers the valuable prospect of watching ‘evolution in action’. In these species, it is possible to conduct comparative research using different reproductive forms that are not confounded by speciation, and are of relatively recent origin. We identify major proximate and ultimate questions that can be addressed in these species, and the genetic and genomic tools that can help us understand how transitional forms of pregnancy are produced, despite predicted fitness costs. We argue that these taxa represent an excellent prospect for understanding the major evolutionary shift between egg‐laying and live birth, which is a fundamental innovation in the history of animals.
Inhibition of adult T‐cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis
Authors: Ichikawa Tomonaga , Sugamoto Kazuhiro , Matsuura Yasushi , Kunitake Hisato , Shimoda Kazuya , Morishita Kazuhiro 
Published: January 2022

AbstractWe have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB‐PAC) inhibits the proliferation of HTLV‐1‐infected adult T‐cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the structure of BB‐PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV‐1‐infected and ATL cells. After hot water extraction with fractionation with methanol‐acetone, BB‐PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB‐PAC polymerization degree of 14. The basic structure of BB‐PAC is mainly B‐type bonds, with A‐type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome‐dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome‐dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB‐PAC treatment. Therefore, BB‐PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV‐1‐infected and ATL cells.
Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes
Authors: Sukhbaatar Ariunbuyan , Mori Shiro , Kodama Tetsuya 
Published: January 2022

AbstractDelivery of chemotherapeutic agents into metastatic lymph nodes (LNs) is challenging as they are unevenly distributed in the body. They are difficult to access via traditional systemic routes of drug administration, which produce significant adverse effects and result in low accumulation of drugs into the cancerous LN. To improve the survival rate of patients with LN metastasis, a lymphatic drug delivery system (LDDS) has been developed to target metastatic LN by delivering chemotherapy agents into sentinel LN (SLN) under ultrasound guidance. The LDDS is an advanced method that can be applied in the early stage of the progression of tumor cells in the SLN before tumor mass formation has occurred. Here we investigated the optimal physicochemical ranges of chemotherapeutic agents’ solvents with the aim of increasing treatment efficacy using the LDDS. We found that an appropriate osmotic pressure range for drug administration was 700–3,000 kPa, with a viscosity < 40 mPa⋅s. In these physicochemical ranges, expansion of lymphatic vessels and sinuses, drug retention, and subsequent antitumor effects could be more precisely controlled. Furthermore, the antitumor effects depended on the tumor progression stage in the SLN, the injection rate, and the volumes of administered drugs. We anticipate these optimal ranges to be a starting point for developing more effective drug regimens to treat metastatic LN with the LDDS.
Homeschooling: What do we know and what do we need to learn?
Authors: Valiente Carlos , Spinrad Tracy L. , Ray Brian D. , Eisenberg Nancy , Ruof Ariana 
Published: January 2022

AbstractIn this article, we identify approaches for understanding more thoroughly the academic and social experiences of homeschooled students. The growth of the homeschooling movement in the United States, questions about the need for additional regulation, and the importance of high‐quality education for children motivate this scholarly effort. We begin by defining homeschooling and outlining why it is a topic worthy of study. Next, we describe who is homeschooled, motivations for homeschooling, and ways parents engage in homeschooling. Preliminary evidence suggests that homeschoolers perform equal to or better than their conventionally schooled peers on measures of achievement and socioemotional functioning, but methodological limitations, especially selection effects, make it premature to draw definitive conclusions. Throughout the article, we offer suggestions for advancing knowledge on homeschooling.
European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC
Authors: Uter Wolfgang , Wilkinson S. Mark , Aerts Olivier , Bauer Andrea , Borrego Leopoldo , Buhl Timo , Cooper Susan M. , Dickel Heinrich , Gallo Rosella , Giménez‐Arnau Ana M. , John Swen M. , Navarini Alexander A. , Pesonen Maria , Pónyai Györgyi , Rustemeyer Thomas , Schliemann Sibylle , Schubert Steffen , Schuttelaar Marie‐Louise A. , Valiukevičienė Skaidra , Wagner Nicola , Weisshaar Elke , Gonçalo Margarida ,   for the ESSCA and EBS ESCD working groups, and the GEIDAC
Published: January 2022

AbstractBackgroundIn 2019, a number of allergens (haptens), henceforth, “the audit allergens,” were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2‐bromo‐2‐nitropropane‐1,3‐diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin‐OOH), limonene hydroperoxides (lim‐OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well.ObjectivesTo collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe.MethodsPatch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered.ResultsAltogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin‐OOH 1% pet. (8.74% [95%CI: 8.14–9.37%]), followed by lin‐OOH 0.5% pet., and lim‐OOH 0.3% pet (5.41% [95% CI: 4.95–5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2–5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32–4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84–2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain.ConclusionsDespite many positive patch test reactions, it remains controversial whether lin‐ and lim‐OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.
Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy
Authors: Juliá‐Palacios Natalia , Molina‐Anguita Cristina , Sigatulina Bondarenko María , Cortès‐Saladelafont Elisenda , Aparicio Javier , Cuadras Daniel , Horvath Gabriella , Fons Carmen , Artuch Rafael , García‐Cazorla Àngels ,   Institut de Recerca Sant Joan de Déu Working Group
Published: January 2022

AimTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.MethodTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.ResultsAbnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.InterpretationA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.What this paper adds

5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy.

Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.
Repetitive transcranial magnetic stimulation for patients with functional paralysis: a randomized controlled study
Authors: Chastan Nathalie , Etard Olivier , Parain Dominique , Gerardin Priscille , Fouldrin Gaël , Derambure Philippe , Tard Céline , Gillibert André , Nathou Clément , Delval Arnaud , Welter Marie‐Laure , Guillin Olivier 
Published: January 2022

AbstractBackground and purposeRepetitive transcranial magnetic stimulation (rTMS) has been proposed to treat functional neurological disorders. Here, the aim was to assess the efficacy of rTMS to treat functional paralysis in a controlled randomized trial.MethodsPatients received two sessions of active or sham 0.25 Hz rTMS (60 stimuli each), with a 1‐day interval, applied over the motor cortex contralateral to the paralysis. The primary outcome was the number of patients with an increase in motor score between baseline and after the second rTMS session, rated by two investigators blinded to the treatment allocation. Secondary outcomes were changes in global and fine motor scores between groups after rTMS, and the occurrence of adverse events.ResultsSixty‐two patients (46 female; mean [SD] age, 35.2 [13.9] years) were enrolled and randomized. Thirteen out of 32 (41%) and 11/30 (37%) patients had increased motor strength after active or sham rTMS, respectively (p = 0.80). Changes in both global and fine motor scores after rTMS relative to baseline were also not significantly different between treatment groups (median difference in the global motor score 0.62 [0.83] and 0.37 [0.61], and in the fine motor scores 0.12 [0.18] and 0.08 [0.11], in active and sham rTMS groups, respectively; p = 0.14). Six serious adverse events, consisting of three cephalalgia in the active group and two cephalalgia and one asthenia in the sham group, were observed.ConclusionsTwo sessions of sham or active low frequency rTMS were effective to improve functional paralysis, suggesting a placebo effect of this non‐invasive brain stimulation technique.
Fruit fly phylogeny imprints bacterial gut microbiota
Authors: Ravigné Virginie , Becker Nathalie , Massol François , Guichoux Erwan , Boury Christophe , Mahé Frédéric , Facon Benoit 
Published: January 2022

AbstractOne promising avenue for reconciling the goals of crop production and ecosystem preservation consists in the manipulation of beneficial biotic interactions, such as between insects and microbes. Insect gut microbiota can affect host fitness by contributing to development, host immunity, nutrition, or behavior. However, the determinants of gut microbiota composition and structure, including host phylogeny and host ecology, remain poorly known. Here, we used a well‐studied community of eight sympatric fruit fly species to test the contributions of fly phylogeny, fly specialization, and fly sampling environment on the composition and structure of bacterial gut microbiota. Comprising both specialists and generalists, these species belong to five genera from to two tribes of the Tephritidae family. For each fly species, one field and one laboratory samples were studied. Bacterial inventories to the genus level were produced using 16S metabarcoding with the Oxford Nanopore Technology. Sample bacterial compositions were analyzed with recent network‐based clustering techniques. Whereas gut microbiota were dominated by the Enterobacteriaceae family in all samples, microbial profiles varied across samples, mainly in relation to fly identity and sampling environment. Alpha diversity varied across samples and was higher in the Dacinae tribe than in the Ceratitinae tribe. Network analyses allowed grouping samples according to their microbial profiles. The resulting groups were very congruent with fly phylogeny, with a significant modulation of sampling environment, and with a very low impact of fly specialization. Such a strong imprint of host phylogeny in sympatric fly species, some of which share much of their host plants, suggests important control of fruit flies on their gut microbiota through vertical transmission and/or intense filtering of environmental bacteria.