bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor-associated nonmyelinating Schwann cell–expressed
PVT1
promotes pancreatic cancer kynurenine pathway and tumor immune exclusion
Authors: Sun Chengcao , Ye Youqiong , Tan Zhi , Liu Yuan , Li Yajuan , Hu Wei , Liang Ke , Egranov Sergey D. , Huang Lisa Angela , Zhang Zhao , Zhang Yaohua , Yao Jun , Nguyen Tina K. , Zhao Zilong , Wu Andrew , Marks Jeffrey R. , Caudle Abigail S. , Sahin Aysegul A. , Gao Jianjun , Gammon Seth T. , Piwnica-Worms David , Hu Jian , Chiao Paul J. , Yu Dihua , Hung Mien-Chie , Curran Michael A. , Calin George A. , Ying Haoqiang , Han Leng , Lin Chunru , Yang Liuqing
Published: February 2023

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (
PVT1
) was triggered by the tumor cell–produced interleukin-6. Mechanistically,
PVT1
modulated RAF proto-oncogene serine/threonine protein kinase–mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed
PVT1
suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.
Hunting and processing of straight-tusked elephants 125.000 years ago: Implications for Neanderthal behavior
Authors: Gaudzinski-Windheuser Sabine , Kindler Lutz , MacDonald Katharine , Roebroeks Wil
Published: February 2023

Straight-tusked elephants (
Palaeoloxodon antiquus
) were the largest terrestrial mammals of the Pleistocene, present in Eurasian landscapes between 800,000 and 100,000 years ago. The occasional co-occurrence of their skeletal remains with stone tools has generated rich speculation about the nature of interactions between these elephants and Pleistocene humans: Did hominins scavenge on elephants that died a natural death or maybe even hunt some individuals? Our archaeozoological study of the largest
P. antiquus
assemblage known, excavated from 125,000-year-old lake deposits in Germany, shows that hunting of elephants weighing up to 13 metric tons was part of the cultural repertoire of Last Interglacial Neanderthals there, over >2000 years, many dozens of generations. The intensity and nutritional yields of these well-documented butchering activities, combined with previously reported data from this Neumark-Nord site complex, suggest that Neanderthals were less mobile and operated within social units substantially larger than commonly envisaged.
Big data mining, rational modification, and ancestral sequence reconstruction inferred multiple xylose isomerases for biorefinery
Authors: Chen Sitong , Xu Zhaoxian , Ding Boning , Zhang Yuwei , Liu Shuangmei , Cai Chenggu , Li Muzi , Dale Bruce E. , Jin Mingjie
Published: February 2023

The isomerization of xylose to xylulose is considered the most promising approach to initiate xylose bioconversion. Here, phylogeny-guided big data mining, rational modification, and ancestral sequence reconstruction strategies were implemented to explore new active xylose isomerases (XIs) for
Saccharomyces cerevisiae
. Significantly, 13 new active XIs for
S. cerevisiae
were mined or artificially created. Moreover, the importance of the amino-terminal fragment for maintaining basic XI activity was demonstrated. With the mined XIs, four efficient xylose-utilizing
S. cerevisiae
were constructed and evolved, among which the strain
S. cerevisiae
CRD5HS contributed to ethanol titers as high as 85.95 and 94.76 g/liter from pretreated corn stover and corn cob, respectively, without detoxifying or washing pretreated biomass. Potential genetic targets obtained from adaptive laboratory evolution were further analyzed by sequencing the high-performance strains. The combined XI mining methods described here provide practical references for mining other scarce and valuable enzymes.
NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8
Authors: Anandhan Annadurai , Dodson Matthew , Shakya Aryatara , Chen Jinjing , Liu Pengfei , Wei Yongyi , Tan Hui , Wang Qian , Jiang Ziyan , Yang Kevin , Garcia Joe GN , Chambers Setsuko K. , Chapman Eli , Ooi Aikseng , Yang-Hartwich Yang , Stockwell Brent R. , Zhang Donna D.
Published: February 2023

Enhancing the intracellular labile iron pool (LIP) represents a powerful, yet untapped strategy for driving ferroptotic death of cancer cells. Here, we show that NRF2 maintains iron homeostasis by controlling HERC2 (E3 ubiquitin ligase for NCOA4 and FBXL5) and VAMP8 (mediates autophagosome-lysosome fusion).
NFE2L2/NRF2
knockout cells have low
HERC2
expression, leading to a simultaneous increase in ferritin and NCOA4 and recruitment of apoferritin into the autophagosome.
NFE2L2/NRF2
knockout cells also have low
VAMP8
expression, which leads to ferritinophagy blockage. Therefore, deletion of
NFE2L2/NRF2
results in apoferritin accumulation in the autophagosome, an elevated LIP, and enhanced sensitivity to ferroptosis. Concordantly, NRF2 levels correlate with HERC2 and VAMP8 in human ovarian cancer tissues, as well as ferroptosis resistance in a panel of ovarian cancer cell lines. Last, the feasibility of inhibiting NRF2 to increase the LIP and kill cancer cells via ferroptosis was demonstrated in preclinical models, signifying the impact of NRF2 inhibition in cancer treatment.
Covalent organic frameworks with Ni-Bis(dithiolene) and Co-porphyrin units as bifunctional catalysts for Li-O
2
batteries
Authors: Ke Si-Wen , Li Wei , Gu Yuming , Su Jian , Liu Yifan , Yuan Shuai , Zuo Jing-Lin , Ma Jing , He Ping
Published: February 2023

The rational design of efficient and stable catalysts for the oxygen reduction reaction and oxygen evolution reaction (ORR/OER) is the key to improving Li-O
2
battery performance. Here, we report the construction of ORR/OER bifunctional cathode catalysts in a covalent organic framework (COF) platform by simultaneously incorporating Ni-bis(dithiolene) and Co-porphyrin units. The resulting bimetallic Ni/Co-COF exhibits high surface area, fairly good electrical conductivity, and excellent chemical stability. Li-O
2
batteries with the Ni/Co-COF–based cathode show a low discharge/charge potential gap (1.0 V) and stable cycling (200 cycles) at a current density of 500 mA g
−1
, rivaling that of PtAu nanocrystals. Density functional theory computations and control experiments using nonmetal or single metal–based isostructural COFs reveal the critical role of Ni and Co sites in reducing the discharge/charge overpotentials and regulating the Li
2
O
2
deposition. This work highlights the advantage of bimetallic COFs in the rational design of efficient and stable Li-O
2
batteries.
The ion transporter Na
+
-K
+
-ATPase enables pathological B cell survival in the kidney microenvironment of lupus nephritis
Authors: Chernova Irene , Song Wenzhi , Steach Holly , Hafez Omeed , Al Souz Jafar , Chen Ping-Min , Chandra Nisha , Cantley Lloyd , Veselits Margaret , Clark Marcus R. , Craft Joe
Published: February 2023

The kidney is a comparatively hostile microenvironment characterized by highsodium concentrations; however, lymphocytes infiltrate and survive therein in autoimmune diseases such as lupus. The effects of sodium-lymphocyte interactions on tissue injury in autoimmune diseases and the mechanisms used by infiltrating lymphocytes to survive the highsodium environment of the kidney are not known. Here, we show that kidney-infiltrating B cells in lupus adapt to elevated sodium concentrations and that expression of sodium potassium adenosine triphosphatase (Na
+
-K
+
-ATPase) correlates with the ability of infiltrating cells to survive. Pharmacological inhibition of Na
+
-K
+
-ATPase and genetic knockout of Na
+
-K
+
-ATPase γ subunit resulted in reduced B cell infiltration into kidneys and amelioration of proteinuria. B cells in human lupus nephritis biopsies also had high expression of Na
+
-K
+
-ATPase. Our study reveals that kidney-infiltrating B cells in lupus initiate a tissue adaption program in response to sodium stress and identifies Na
+
-K
+
-ATPase as an organ-specific therapeutic target.
Perception versus reality: Implications of elephant hunting by Neanderthals
Authors: Starkovich Britt M.
Published: February 2023

Neanderthals hunted elephants at Neumark-Nord 1 (Germany), a finding that has major implications for our understanding of social and cultural aspects of Neanderthal behavior.
Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events
Authors: Karle Anette C. , Wrobel Matthias B. , Koepke Stephan , Gutknecht Michael , Gottlieb Sascha , Christen Brigitte , Rubic-Schneider Tina , Pruimboom-Brees Ingrid , Leber Xavier Charles , Scharenberg Meike , Maciejewski Benjamin , Turner Oliver , Saravanan Chandra , Huet Francois , Littlewood-Evans Amanda , Clemens Andreas , Grosskreutz Cynthia L. , Kearns Jeffrey D. , Mehan Pawan , Schmouder Robert L. , Sasseville Vito , Brees Dominique
Published: February 2023

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.
Virulence Protein Pgp3 Is Insufficient To Mediate Plasmid-Dependent Infectivity of Chlamydia trachomatis
Authors: Turman Breanna J. , Alzhanov Damir , Nagarajan Uma M. , Darville Toni , O’Connell Catherine M.
Published: February 2023

Chlamydia trachomatis
is the most common cause of infectious blindness and sexually transmitted bacterial infection globally.
C. trachomatis
contains a conserved chlamydial plasmid with eight coding sequences. Plasmid-cured
Chlamydia
strains are attenuated and display reduced infectivity in cell culture and
in vivo
genital infection of female mice.
Building Radical Listening and Empathy through an Implementation Lab in an Undergraduate Microbiology Course
Authors: Mills Jessie Lee , Chandrangsu Pete
Published: February 2023

With rapid advances in science and technology, individuals are faced with the challenging process of making decisions based on sound and accurate information. As a result, to promote scientific literacy, scientists must be able to engage with a wide range of audiences in an inclusive and engaging manner.
SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3
Authors: Schindewolf Craig , Lokugamage Kumari , Vu Michelle N. , Johnson Bryan A. , Scharton Dionna , Plante Jessica A. , Kalveram Birte , Crocquet-Valdes Patricia A. , Sotcheff Stephanea , Jaworski Elizabeth , Alvarado Rojelio E. , Debbink Kari , Daugherty Matthew D. , Weaver Scott C. , Routh Andrew L. , Walker David H. , Plante Kenneth S. , Menachery Vineet D.
Published: February 2023

Similar to other coronaviruses, disruption of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP16 function attenuates viral replication in a type I interferon-dependent manner.
In vivo
, our results show reduced disease and viral replication at late times in the hamster lung, but an earlier titer deficit for the NSP16 mutant (dNSP16) in the upper airway. In addition, our results confirm a role for IFIT1 but also demonstrate the necessity of IFIT3 in mediating dNSP16 attenuation.
CP204L Is a Multifunctional Protein of African Swine Fever Virus That Interacts with the VPS39 Subunit of the Homotypic Fusion and Vacuole Protein Sorting Complex and Promotes Lysosome Clustering
Authors: Dolata Katarzyna Magdalena , Fuchs Walter , Caignard Grégory , Dupré Juliette , Pannhorst Katrin , Blome Sandra , Mettenleiter Thomas C. , Karger Axel
Published: February 2023

African swine fever virus (ASFV) was first identified over a hundred years ago. Since then, much effort has been made to understand the pathogenesis of ASFV.
Apical Secretory Glycoprotein Complex Contributes to Cell Attachment and Entry by Cryptosporidium parvum
Authors: Akey Marianna E. , Xu Rui , Ravindran Soumya , Funkhouser-Jones Lisa , Sibley L. David
Published: February 2023

Although
Cryptosporidium
is extremely efficient at penetrating mucus and invading epithelial cells in the intestine, the mechanism of cell attachment is poorly understood. To expand our understanding of this process, we characterized the antigens recognized by a monoclonal antibody that stains the apical end of invasive stages called sporozoites and merozoites.
High-Quality Draft Genome Sequence of Streptomyces albidoflavus CCOS 2040, Isolated from a Swiss Soil Sample
Authors: Pothier Joël F. , Bolt Valentin , Arn Fabienne , Frasson David , Rhyner Nicola , Sievers Martin
Published: February 2023

Here, we report the high-quality draft genome sequence of the actinomycete
Streptomyces albidoflavus
CCOS 2040, isolated from a Swiss soil sample. The genome contains 7,136,301 bp with 73.35% GC content. In total, 22 biosynthetic gene clusters, including polyketides and terpenes, were predicted within the sequenced genome.
Complete Genome Sequences of Caldicellulosiruptor acetigenus DSM 7040, Caldicellulosiruptor morganii DSM 8990 (RT8.B8), and Caldicellulosiruptor naganoensis DSM 8991 (NA10)
Authors: Bing Ryan G. , Willard Daniel J. , Manesh Mohamad J. H. , Laemthong Tunyaboon , Crosby James R. , Adams Michael W. W. , Kelly Robert M.
Published: February 2023

The genome sequences of three extremely thermophilic, lignocellulolytic
Caldicellulosiruptor
species were closed, improving previously reported multiple-contig assemblies. All 14 classified
Caldicellulosiruptor
spp. now have closed genomes. Genome closure will enhance bioinformatic analysis of the species, including identification of carbohydrate-active enzymes (CAZymes) and comparison against other
Caldicellulosiruptor
species and lignocellulolytic microorganisms.
Prevalence of Viral Frequency-Dependent Infection in Coastal Marine Prokaryotes Revealed Using Monthly Time Series Virome Analysis
Authors: Tominaga Kento , Ogawa-Haruki Nana , Nishimura Yosuke , Watai Hiroyasu , Yamamoto Keigo , Ogata Hiroyuki , Yoshida Takashi
Published: February 2023

There is little room for doubt that viral infection is prevalent among abundant marine prokaryotes regardless of their taxa or growth strategy. However, comprehensive evaluations of viral infections in natural prokaryotic communities are still technically difficult.
Tracking the Emergence and Dissemination of a
bla
NDM-23
Gene in a Multidrug Resistance Plasmid of Klebsiella pneumoniae
Authors: García-González Neris , Beamud Beatriz , Fuster Begoña , Giner Salvador , Domínguez Maria Victoria , Sánchez Antonia , Sevilla Jordi , Coque Teresa M. , Gimeno Concepción , González-Candelas Fernando , García-González Neris , González-Candelas Fernando , Fuster Begoña , Tormo Nuria , Salvador Carme , Gimeno Concepción , Domínguez Victoria , Giner Salvador , Colomina Javier , Navarro David , Martínez Llúcia , Burgos Antonio , Martínez Olalla , Gomila-Sard Barbara , Moreno Rosario , Vidal Inmaculada , Sánchez Antonia , Rodriguez Juan Carlos , Sánchez-Hellín Victoria
Published: February 2023

At a time when antimicrobial resistance has become one of the biggest concerns worldwide, the emergence of novel alleles and extremely drug-resistant plasmids is a threat to public health worldwide, especially when they produce carbapenem resistance in one of the most problematic pathogens, such as
Klebsiella pneumoniae
. We used genomic epidemiology to describe the emergence of a novel NDM-23 allele and identify it in a MDR plasmid that has disseminated through a
K. pneumoniae
ST437 clone in several hospitals in Spain.
Respiratory Virus Infections during the COVID-19 Pandemic Revealed by Multiplex PCR Testing in Japan
Authors: Yamashita Sho , Ikegame Satoshi , Nakatomi Keita , Sakurai Yuko , Shuto Hiroe , Sato Noriko , Mizoguchi Yoshihiro , Uehara Maki , Nakashima Nobutaka , Okamoto Isamu , Koto Hiroshi
Published: February 2023

Influenza virus, RSV, adenovirus, and rhino/enterovirus were the major respiratory viruses before COVID-19 pandemic. Circulating respiratory viruses may have been affected by our strong quarantine policy during the COVID-19 pandemic.
Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews
Authors: Ferreira Giovanni E , Abdel-Shaheed Christina , Underwood Martin , Finnerup Nanna B , Day Richard O , McLachlan Andrew , Eldabe Sam , Zadro Joshua R , Maher Christopher G
Published: February 2023

Objective

To provide a comprehensive overview of the efficacy, safety, and tolerability of antidepressants for pain according to condition.

Design

Overview of systematic reviews.

Data sources

PubMed, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to 20 June 2022.

Eligibility criteria for selecting studies

Systematic reviews comparing any antidepressant with placebo for any pain condition in adults.

Data extraction and synthesis

Two reviewers independently extracted data. The main outcome measure was pain; for headache disorders it was frequency of headaches. Continuous pain outcomes were converted into a scale of 0 (no pain) to 100 (worst pain) and were presented as mean differences (95% confidence intervals). Dichotomous outcomes were presented as risk ratios (95% confidence intervals). Data were extracted from the time point closest to the end of treatment. When end of treatment was too variable across trials in a review, data were extracted from the outcome or time point with the largest number of trials and participants. Secondary outcomes were safety and tolerability (withdrawals because of adverse events). Findings were classified from each comparison as efficacious, not efficacious, or inconclusive. Certainty of evidence was assessed with the grading of recommendations assessment, development, and evaluation framework.

Results

26 reviews (156 unique trials and >25 000 participants) were included. These reviews reported on the efficacy of eight antidepressant classes covering 22 pain conditions (42 distinct comparisons). No review provided high certainty evidence on the efficacy of antidepressants for pain for any condition. 11 comparisons (nine conditions) were found where antidepressants were efficacious, four with moderate certainty evidence: serotonin-norepinephrine reuptake inhibitors (SNRIs) for back pain (mean difference −5.3, 95% confidence interval −7.3 to −3.3), postoperative pain (−7.3, −12.9 to −1.7), neuropathic pain (−6.8, −8.7 to −4.8), and fibromyalgia (risk ratio 1.4, 95% confidence interval 1.3 to 1.6). For the other 31 comparisons, antidepressants were either not efficacious (five comparisons) or the evidence was inconclusive (26 comparisons).

Conclusions

Evidence of efficacy of antidepressants was found in 11 of the 42 comparisons included in this overview of systematic reviews—seven of the 11 comparisons investigated the efficacy of SNRIs. For the other 31 comparisons, antidepressants were either inefficacious or evidence on efficacy was inconclusive. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain conditions.

Systematic review registration

PROSPERO CRD42022311073.
Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study
Authors: Husby Anders , Gulseth Hanne Løvdal , Hovi Petteri , Hansen Jørgen Vinsløv , Pihlström Nicklas , Gunnes Nina , Härkänen Tommi , Dahl Jesper , Karlstad Øystein , Heliö Tiina , Køber Lars , Ljung Rickard , Hviid Anders
Published: February 2023

Objective

To investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis.

Design

Population based cohort study.

Setting

Nationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022.

Participants

The Nordic myocarditis cohort; 7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden.

Main outcome measures

Heart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared.

Results

In 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis; the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20).

Conclusions

Compared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.
Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn’s disease (CD): protocol of a pilot study
Authors: Verburgt Charlotte M , Dunn Katherine A , Otley Anthony , Heyman Melvin B , Verstraete Sofia , Sunseri Withney , Sylvester Francisco , de Meij Tim , Comeau Andre , Langille Morgan , de Jonge Wouter J , Benninga Marc A , Van Limbergen Johan E
Published: February 2023

Introduction

Early relapse in Crohn’s disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles.

Methods and analysis

This is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10<PCDAI≤37.5; PCDAI, Pediatric Crohn’s Disease Activity Index). SOC induction treatment will be Crohn’s Disease Exclusion Diet+Partial Enteral Nutrition (CDED+PEN). Relapse-associated microbiome signatures will be evaluated using 16S rRNA gene sequencing and a previously generated Bayesian predictive model (BioMiCo) based on baseline stool. At week 4, patients in remission with relapse-associated signatures (group A) will be randomised to CDED+antibiotics (A2) or CDED+PEN alone (A1). Patients in remission without this signature will continue CDED+PEN alone (B). Patients not in remission will receive CDED+antibiotics regardless of their microbiome signature (C). Subjects in group A2 or C will receive a combination of azithromycin 7.5 mg/kg (weeks 4–8: 5 days/week; weeks 9–12: 3 days/week) with metronidazole 20 mg/kg/day (weeks 4–12). Primary outcomes will assess feasibility of treatment allocation and possible efficacy to sustain remission (PCDAI≤10, no need for reinduction). Exploratory outcomes will include changes in PCDAI, inflammatory markers and patient-reported outcomes. We will additionally explore changes in faecal microbiome taxonomic composition between groups.

Ethics and dissemination

This study was approved by METC-AMC and CCMO (Netherlands) and IWK Health Centre (Canada). The first version of this protocol was approved by North Carolina Children’s Hospital (USA), Wolfson Medical Centre (Israel). The FDA (USA), Health Canada and Ministry of Health (Israel) have reviewed and approved the protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders and participants.

Trial registration number

NCT04186247.
Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study
Authors: Reilev Mette , Jensen Peter Bjødstrup , Ranch Lise Skov , Egeberg Alexander , Furu Kari , Gembert Karin , Hagg David , Haug Ulrike , Karlstad Øystein , Reutfors Johan , Schäfer Wiebke , Schwartz Sarina , Smits Elisabeth , Holthius Emily , Herings Ron , Trifirò Gianluca , Kirchmayer Ursula , Rosa Alessandro Cesare , Belleudi Valeria , Gini Rosa , Støvring Henrik , Hallas Jesper
Published: February 2023

Introduction

Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.

Methods and analysis

BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.

Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.

In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.

In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.

Ethics and dissemination

The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.

Trial registration number

EUPAS30280.
Diagnostic delay in children with neurodevelopmental conditions attending a publicly funded developmental assessment service: findings from the Sydney Child Neurodevelopment Research Registry
Authors: Boulton Kelsie A , Hodge Marie-Antoinette , Jewell Ailsa , Ong Natalie , Silove Natalie , Guastella Adam J
Published: February 2023

Objectives

Early developmental assessment is crucial for effective support and intervention. This study examined factors that contribute to (a) older child age when caregivers first became concerned about their child’s development and (b) older child age at the point of entry into developmental and diagnostic assessment. We also quantified how factors contributed to risk of children not receiving an assessment by 5 years and considered the acceptability of electronic data capture for families.

Design

This cross-sectional study collected information about caregiver developmental concerns, family history and child characteristics.

Setting

Children and families entered a large, publicly funded hospital-based paediatric developmental assessment service.

Participants

Consecutively enrolled children (N=916) aged 6 months to 17 years with neurodevelopmental concerns and their caregivers.

Main outcomes and measures

A developmental history questionnaire completed by caregivers.

Results

The average age that caregivers identified developmental concerns was 3.0 years of age but the average age of a receiving a developmental assessment was 6.6 years. Only 46.4% of children received a diagnostic assessment by 5 years of age, even though 88.0% of caregivers were concerned about their child’s development by that age. Parental age, relationship status, education level, prior use of support services and being from a culturally and linguistically diverse background contributed to age at identification of concern, age at diagnostic assessment and the likelihood of receiving a diagnostic assessment by 5 years. Electronic data capture had high acceptability, with 88.2% of caregivers reporting a preference for electronic completion of questionnaires.

Conclusions

The study shows a substantial delay in diagnostic assessments that leaves most vulnerable children without an assessment by school age and highlights contributors to delays. These delays highlight the complexity of delivering early intervention and support policies that rely on swift and appropriate developmental assessment to vulnerable families.
Correlates of early initiation of breast feeding and prelacteal feeding: a cross-sectional study in Sindh province of Pakistan
Authors: Kumar Ramesh , Amir-ud-Din Rafi , Ahmed Jamil , Asim Muhammad , Rashid Fozia , Khan Shahzad Ali , Ali Shaukat , Pongpanich Sathirakorn
Published: February 2023

Objectives

The objective of this study was to determine the prevalence and correlates of early initiation of breast feeding and prelacteal feeding in highly disadvantaged districts in Pakistan.

Design

This cross-sectional study design.

Settings

This study was carried out in twelve districts of the Sindh province of Pakistan.

Participants

A total of 4800 mothers with children under 2 years, selected through a multistage random sampling method.

Data analysis

Bivariate association, survival analysis (Kaplan-Meier and Cox proportional hazard techniques), multivariate linear regression and the ordinary least square model were used.

Results

The results show that the prevalence of early initiation of breast feeding was 68% and prelacteal feeding was 32%. Adequate treatment, proper guidance at antenatal care visits, postpartum health check, normal birth with skilled birth attendants, institutional birth, skin-to-skin contact at birth and birth size were all associated with early breastfeeding initiation (p<0.001). The odds of early initiation of breast feeding after birth are higher if the respondents received proper guidance (OR 2.05; 95% CI 1.02 to 4.11) or made skin-to-skin contact (OR 10.65; 95% CI 6.82 to 16.65). Bivariate association between the prelacteal feeding and a set of correlates suggests that all variables under study were significantly associated with the outcome variable of interest at a 95% or higher significance level. The factors which significantly reduced the odds of prelacteal feeding were adequate treatment (OR 0.29; 95% CI 0.23 to 0.37) and postpartum health check (OR 0.65; 95% CI 0.53 to 0.80).

Conclusion

Sudy concludes that the correlates like adequate treatment of mothers during labour, postpartum health check-up, normal birth with skilled birth attendants, institutional births and skin-to-skin contact between mother and the baby determine the early initiation of breast feeding and prelecteal feeding. Early initiation of breast feeding needs to be encouraged, and communities must be educated against the use of prelacteal feeding.
Single-cell spatial landscape of immunotherapy response reveals mechanisms of CXCL13 enhanced antitumor immunity
Authors: Sorin Mark , Karimi Elham , Rezanejad Morteza , Yu Miranda W , Desharnais Lysanne , McDowell Sheri A C , Doré Samuel , Arabzadeh Azadeh , Breton Valerie , Fiset Benoit , Wei Yuhong , Rayes Roni , Orain Michele , Coulombe Francois , Manem Venkata S K , Gagne Andreanne , Quail Daniela F , Joubert Philippe , Spicer Jonathan D , Walsh Logan A
Published: February 2023

Background

Immunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI.

Methods

Here, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade.

Results

We resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2+ monocytes.

Discussion

Our results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.
First pass effect of mechanical thrombectomy for acute vertebrobasilar artery occlusion: data from the ANGEL-ACT registry
Authors: Sun Dapeng , Huo Xiaochuan , Raynald  , Jia BaiXue , Tong Xu , Wang Anxin , Ma Ning , Gao Feng , Mo Dapeng , Miao Zhongrong
Published: February 2023

Background

To explore the incidence, predictors, and association of first pass effect (FPE) on clinical outcomes of mechanical thrombectomy (MT) for acute vertebrobasilar artery occlusion (VBAO) in the Asian population.

Methods

We selected patients from the ANGEL-ACT registry. We defined FPE as complete recanalization after one MT attempt without rescue treatment, multiple pass effect (MPE) as complete recanalization after >1 MT attempt or after one MT attempt with rescue treatment, and incomplete recanalization (ICR) as a modified Thrombolysis in Cerebral Ischemia score of 2b, independent of the number of MT attempts. We conducted multivariable logistic analyses to identify the independent predictors of FPE and to compare the outcomes, including favorable outcome, mortality within 90 days, and intracranial hemorrhage (ICH) among the FPE, MPE, and ICR groups.

Results

Two hundred and seventy-nine patients, 68 with FPE (24.4%), 114 with MPE (40.9%), and 83 with ICR (29.7%), were included. Underlying intracranial atherosclerosis disease (ICAD) (adjusted OR (aOR) 0.16, 95% CI 0.08 to 0.34, P<0.001) was independently associated with a low chance of FPE. Furthermore, FPE was associated with a favorable outcome compared with MPE and ICR (MPE vs FPE, aOR 0.49, 95% CI 0.25 to 0.97, P=0.040; ICR vs FPE, aOR 0.38, 95% CI 0.18 to 0.81, P=0.012), and decreased mortality (MPE vs FPE, aOR 2.57, 95% CI 1.04 to 6.36, P=0.041) compared with MPE but similar mortality to ICR (P=0.374). No difference was found for ICH among the three groups (P>0.05).

Conclusions

FPE occurred in 24.4% of patients with VBAO in our cohort, which was associated with improved clinical outcomes compared with MPE and ICR. VBAO with underlying ICAD was less likely to achieve FPE.

Trial registration number

NCT03370939.
Understanding occipital pressure sores in UK military casualties: a pilot study in healthy military personnel
Authors: Chatzistergos Panagiotis , E Scott T , Thorburn M , Chockalingam N
Published: February 2023

Introduction

The high prevalence of occipital ulcers in UK military casualties observed during the conflict in Afghanistan is a multifactorial phenomenon. However, the consensus is that ulceration is triggered by excessive pressure that is maintained for too long during the use of the general service military stretcher. Thresholds for capillary occlusion are accepted benchmarks to define excessive pressure, but similar thresholds for safe/excessive duration of pressure application do not exist. To address this gap in knowledge, we propose to use the time it takes for a healthy person to feel pain at the back of the head as an initial indication of safe exposure to pressure.

Methods

Healthy military personnel (16 male/10 female) were asked to lie motionless on a typical general service stretcher until they felt pain. Time-to-pain and the location of pain were recorded. To support the interpretation of results, baseline sensitivity to pain and pressure distribution at the back of the head were also measured. Independent samples t-test was used to assess differences between genders.

Results

Twenty participants felt pressure-induced soft-tissue pain at the back of the head. The remaining six participants terminated the test due to musculoskeletal pain caused by poor ergonomic positioning. On average, pain at the occiput developed after 31 min (±14 min). Female participants were significantly more sensitive to pain (t(24)=3.038,p=0.006), but time-to-pain did not differ significantly between genders (p>0.05).

Conclusions

When people lie motionless on a typical military stretcher, the back of the head is the first area of the body that becomes painful due to pressure. The fact that pain develops in ≈30 min can help healthcare providers decide how frequently to reposition their patients who are unable to do this on their own. More research is still needed to directly link time-to-pain with time-to-injury.
Enhanced estimate of fracture network dimensions by injection of non-Newtonian fluids
Authors: Jaffal Hamza A. , El Mohtar Chadi S.
Published: February 2023

Lugeon tests, also known as water pressure tests, are widely used to estimate the transmissivity of rock-fracture networks and are considered standard testing for grouting of dam foundations. The Lugeon test consists of injecting water into an isolated borehole section intersecting several fractures and monitoring water pressure and flow rate over time to estimate the rock fractures’ transmissivity. An average fracture aperture for the whole section is then estimated from the transmissivity value, which is used for selecting the appropriate grout mix. However, the current procedure does not provide any information on the variability in aperture sizes within the investigated rock interval. This paper presents a new approach for performing Lugeon testing that allows for providing a probabilistic distribution of fracture apertures by injecting bio-degradable non-Newtonian fluids at different pressures/flow rates. The theoretical framework demonstrating the ability to estimate the dimensions of multiple fractures, in parallel and in series, from non-Newtonian fluid injection tests is presented. Then, experimental results on different combinations of simple fractures, made of parallel plates, are used to validate the derived model and evaluate its performance.
Synthesis of ZnO/Ag-doped C/N heterostructure for photocatalytic application
Authors: Rahmah Muntadher I. , Majdi Hasan Sh. , Al-Azzawi Waleed Khaild , Rasn Moayad Jabbar , Jasim Hadi Hassan , Jabir Majid S. , Alkareem Roonak Abdul Salam A. , Rashid Taha M.
Published: February 2023

A zinc oxide–silver doped with graphite and nitrogen (ZnO/Ag doped with C/N) heterostructure was prepared by a simple method with a study of the photodegradation of methylene blue (MB) dye under sunlight irradiation. Results from X-ray diffraction (XRD) experiments show the presence of sharp peaks for ZnO, Ag, and C, with the wurtzite phase of ZnO. Energy-dispersive X-ray spectroscopy (EDX) results match the results of XRD and confirm the presence of Ag, Zn, C, O, and N. Field emission scanning electron microscope (FESEM) images confirm the presence of clusters of spherical nanoparticles (NPs). The optical properties results confirm the high-absorption ability in the visible area with an energy gap of 2.95[Formula: see text]eV. After 140[Formula: see text]min of exposure to sunlight radiation, the photocatalysis results show that the MB dye can be broken down very well by light.
Flexural vibration bandgaps in one-dimensional periodic rods with tri-wing rhombus ligament resonators
Authors: Feng Yang , Zhao Hao-Jiang , Li Wei , Xue Chuang
Published: February 2023

Structural stiffness of phononic crystals (PnCs) can affect their bandgap properties. It thus needs to consider stiffness in the design of the unit cell of a PnC. In this paper, a local resonant (LR) rod composed of tri-wing rhombus ligament (TRL) resonators arranged periodically within a common hollow rod is proposed to create a low-frequency flexural vibration bandgap. The dispersion relations, mode of resonances and vibration transfer function are studied using a finite element method. Low-frequency forbidden bands can be effectively shifted by changing the resonator geometries. In addition, both numerical simulations and sample test are conducted to verify the low-frequency bandgap. The results show that the hollow rod with TRL resonators can create a low-frequency flexural vibration bandgap as well as have high support structure stiffness.
Bottleneck Convex Subsets: Finding k Large Convex Sets in a Point Set
Authors: Durocher Stephane , Keil J. Mark , Mehrabi Saeed , Mondal Debajyoti
Published: February 2023

Chvátal and Klincsek (1980) gave an [Formula: see text]-time algorithm for the problem of finding a maximum-cardinality convex subset of an arbitrary given set [Formula: see text] of [Formula: see text] points in the plane. This paper examines a generalization of the problem, the Bottleneck Convex Subsets problem: given a set [Formula: see text] of [Formula: see text] points in the plane and a positive integer [Formula: see text], select [Formula: see text] pairwise disjoint convex subsets of [Formula: see text] such that the cardinality of the smallest subset is maximized. Equivalently, a solution maximizes the cardinality of [Formula: see text] mutually disjoint convex subsets of [Formula: see text] of equal cardinality. We give an algorithm that solves the problem exactly, with running time polynomial in [Formula: see text] when [Formula: see text] is fixed. We then show the problem to be NP-hard when [Formula: see text] is an arbitrary input parameter, even for points in general position. Finally, we give a fixed-parameter tractable algorithm parameterized in terms of the number of points strictly interior to the convex hull.
DO CARBON TAXES KILL JOBS? FIRM-LEVEL EVIDENCE FROM BRITISH COLUMBIA
Authors: AZEVEDO DEVEN , WOLFF HENDRIK , YAMAZAKI AKIO
Published: February 2023

This paper investigates the employment impacts of British Columbia’s revenue neutral carbon tax. Using the synthetic control method with firm-level data, we find considerable heterogeneity in employment responses to the policy. We show that firm size matters. In particular, the carbon tax had a negative impact on large emission-intensive firms, but simultaneous tax cuts and transfers increased the purchasing power of low income households, substantially benefiting small businesses in the service sector and food/clothing manufacturing. Furthermore, we find that aggregate employment was not adversely affected by the policy. Our results provide additional insight for the “job-shifting hypothesis” of revenue neutral carbon taxes.