bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilayer metal etch mask strategy for deep diamond etching
Authors: Zheng Yixiong , Muehle Matthias , Lai Junyu , Albrecht John D. , Seo Jung-Hun
Published: March 2022

In this study, we demonstrate a tolerant and durable Cr/Ni bilayer metal etch mask that allows us to realize approximately 150:1 etch selectivity to diamond. This result is achieved through the use of a very thin initial Cr layer of <10 nm thickness as part of the bilayer metal mask, which results in five to ten times improved selectivity than thick single metal layer masks or bilayer masks with thicker combinations. A finite element analysis was employed to design and understand the physics and working mechanism of the bilayer metal masks with different thicknesses. Raman spectroscopy and energy-dispersive x-ray spectroscopy on the diamond surface were also performed to investigate the changes in diamond quality before and after the deep diamond etching and found that no noticeable etch damage or defects were formed. Overall, this mask strategy offers a viable way to realize deep diamond etching using a high heat and chemistry tolerant and durable bilayer metal etching mask. It also offers several technological benefits and advantages, including various deposition method options, such as sputtering and physical vapor deposition, that can be used and the total thinness of the bilayer metal mask required given the higher selectivity allows us to realize fine diamond etching or high-aspect ratio etching, which is a critical fabrication process for future power, RF, MEMS, and quantum device applications.
Single Ascending-Dose Study To Evaluate the Safety, Tolerability, and Pharmacokinetics of Sutezolid in Healthy Adult Subjects
Authors: Bruinenberg Paul , Nedelman Jerry , Yang Tian J. , Pappas Fran , Everitt Dan
Published: March 2022

The primary objective of the study was to evaluate the safety and tolerability of single oral doses of sutezolid tablets administered under fasting conditions in healthy adult subjects. The secondary objective was to determine the pharmacokinetics (PK) of sutezolid and two metabolites, PNU-101603 and PNU-101244.
Mechanistic Insight into the Fragmentation of Type I Collagen Fibers into Peptides and Amino Acids by a
Vibrio
Collagenase
Authors: Wang Yan , Su Hai-Nan , Cao Hai-Yan , Liu Si-Min , Liu Shi-Cheng , Zhang Xia , Wang Peng , Li Chun-Yang , Zhang Yu-Zhong , Zhang Xi-Ying , Chen Xiu-Lan
Published: March 2022

Many
Vibrio
species are pathogens and cause serious diseases in humans and aquatic animals. The collagenases produced by pathogenic
Vibrio
species have been regarded as important virulence factors, which occasionally exhibit direct pathogenicity to the infected host or facilitate other toxins’ diffusion through the digestion of host collagen.
Genetic Characteristics of the Transmissible Locus of Stress Tolerance (tLST) and tLST Harboring Escherichia coli as Revealed by Large-Scale Genomic Analysis
Authors: Zhang Peipei , Yang Xianqin
Published: March 2022

This study, through a large-scale genomic analysis, demonstrated that the genomic island tLST related to multiple stress resistance (such as extreme heat resistance and oxidative stress tolerance) in
E. coli
is differentially present in subgroups of
E. coli
and is strongly associated with certain phylogenetic background of the host strain. The study also shows the transmission mechanisms of tLST in
E. coli
and other bacterial species.
Design of SARS-CoV-2 Variant-Specific PCR Assays Considering Regional and Temporal Characteristics
Authors: Oh Chamteut , Sashittal Palash , Zhou Aijia , Wang Leyi , El-Kebir Mohammed , Nguyen Thanh H.
Published: March 2022

Monitoring the introduction and prevalence of variants of concern (VOCs) and variants of interest (VOIs) in a community can help the local authorities make informed public health decisions. PCR assays can be designed to keep track of SARS-CoV-2 variants by measuring unique mutation markers that are exclusive to the target variants.
Data on Transfer of Human Coronavirus SARS-CoV-2 from Foods and Packaging Materials to Gloves Indicate That Fomite Transmission Is of Minor Importance
Authors: Butot S. , Zuber S. , Moser M. , Baert L.
Published: March 2022

The observation of SARS-CoV-2 RNA in swab samples from frozen fish packages in China, confirmed only once by cell culture, led to the hypothesis that food contaminated with SARS-CoV-2 virus particles could be the source of an outbreak. Epidemiological evidence for fomites as infection source is scarce, but it is important for the food industry to evaluate this infection path with quantitative microbial risk assessment (QMRA), using measured viral transfer rates from surfaces to hands and face.
Nitrogen Metabolism in Pseudomonas putida: Functional Analysis Using Random Barcode Transposon Sequencing
Authors: Schmidt Matthias , Pearson Allison N. , Incha Matthew R. , Thompson Mitchell G. , Baidoo Edward E. K. , Kakumanu Ramu , Mukhopadhyay Aindrila , Shih Patrick M. , Deutschbauer Adam M. , Blank Lars M. , Keasling Jay D.
Published: March 2022

Understanding the genetic basis of
P. putida
’s diverse metabolism is imperative for us to reach its full potential as a host for metabolic engineering. Many target molecules of the bioeconomy and their precursors contain nitrogen.
Convergent Evolution of Antibiotic Tolerance in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia
Authors: Elgrail Mitra M. , Chen Edwin , Shaffer Marla G. , Srinivasa Vatsala , Griffith Marissa P. , Mustapha Mustapha M. , Shields Ryan K. , Van Tyne Daria , Culyba Matthew J.
Published: March 2022

Severe infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA) are often complicated by persistent bacteremia (PB) despite active antibiotic therapy. Antibiotic resistance rarely contributes to MRSA-PB, suggesting an important role for antibiotic tolerance pathways.
Genome-Wide Identification of Novel sRNAs in Streptococcus mutans
Authors: Krieger Madeline C. , Merritt Justin , Raghavan Rahul
Published: March 2022

Small RNAs (sRNAs) are important gene regulators in bacteria, but the identities and functions of sRNAs in
Streptococcus mutans
, the principal bacterium involved in the formation of dental caries, are unknown. In this study, we identified 15 putative sRNAs in
S. mutans
and show that they respond to four common stress-inducing conditions present in human mouth: sugar-phosphate stress, hydrogen peroxide exposure, high temperature, and low pH.
Diverse Subclade Differentiation Attributed to the Ubiquity of
Prochlorococcus
High-Light-Adapted Clade II
Authors: Yan Wei , Feng Xuejin , Lin Ta-Hui , Huang Xingyu , Xie Le , Wei Shuzhen , Zhou Kun , Chen Yi-Lung , Luo Weicheng , Xu Wenqian , Zhang Wei , Nawaz Muhammad Zohaib , Luo Ya-Wei , Zeng Qinglu , Zhang Rui , Jiao Nianzhi
Published: March 2022

Prochlorococcus
is the most abundant oxygenic photosynthetic microorganism on Earth, and high-light-adapted clade II (HLII) is the dominant ecotype. However, the factors behind the dominance of HLII in the vast oligotrophic oceans are still unknown.
Molecular Mechanism of Porcine Epidemic Diarrhea Virus Cell Tropism
Authors: Li Zhiwei , Ma Zhiqian , Dong Linfang , Yang Ting , Li Yang , Jiao Dian , Han Weiguo , Zheng Haixue , Xiao Shuqi
Published: March 2022

CoVs can spill from an animal reservoir into a naive host to cause diseases in humans or domestic animals. PEDV results in high mortality in piglets, which has caused immense economic losses in the pork industry.
Genome Sequence of Sclerotinia sclerotiorum Hypovirulence-Associated DNA Virus 1 Found in the Fungus Penicillium olsonii Isolated from Washington State, USA
Authors: Fu Min , Pappu Hanu R. , Vandemark George J. , Chen Weidong
Published: March 2022

We report the discovery of a
Sclerotinia sclerotiorum
hypovirulence-associated DNA virus 1 (SsHADV-1) isolate, named SsHADV1_PO, from the fungus
Penicillium olsonii
isolated from Washington state, USA. The genome of SsHADV1_PO is 2,166 bp and contains two open reading frames, with more than 98% nucleotide identity with respect to reported SsHADV-1 isolates.
Genome Sequence of Rotavirus A from a Florida Racing Pigeon (
Columba livia domestica
)
Authors: Basham Rowan A. , Dill-Okubo Jennifer , Subramaniam Kuttichantran , Waltzek Thomas B. , Viadanna Pedro H. O.
Published: March 2022

The complete coding sequence of a rotavirus A strain was determined from a dead racing pigeon in Florida. It was found to be most closely related to a rotavirus A strain isolated from a dead racing pigeon in California.
Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir
Authors: Ortiz-Gracia Alba , Ríos María , Tobías Ester , Noguera-Julian Antoni , García-García Francesc Josep , Cantó-Santos Judith , Valls-Roca Laura , Garrabou Glòria , Grau Josep Maria , Cardellach Francesc , Sánchez Emilia , Morén Constanza , Fortuny Clàudia
Published: March 2022

Background

Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV.

Objective

To determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls).

Design

Longitudinal, observational and controlled study.

Setting and patients

Subjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up.

Methods

Mitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3–6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied.

Results

Complex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases).

Conclusions

No evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.
Crossing the line? Ethics of parenteral nutrition in paediatric neurodisability complicated by intestinal failure
Authors: McCallum Zoe , Delany Clare , Gillam Lynn
Published: March 2022

Children with severe neurological impairment (such as cerebral palsy or congenital anomalies) are living longer, although medically complex, lives. Feeding intolerance is an increasing problem that is emerging as a new end-of-life issue. Long-term parenteral nutrition (LTPN) is technically feasible in these children. However, clinicians are concerned about whether it is appropriate in these circumstances or whether it constitutes a treatment ‘too far’. This narrative review of the literature identifies, categorises and explores the ethical foundations and reasons for clinician hesitancy about the use of LTPN in this population. The categories of reasons are: lack of clear diagnostic criteria for feeding failure; risks of LTPN to the child; burden of LTPN to the family/caregivers; burden of LTPN to the child; difficulty in cessation of LTPN; and the concept that feeding failure may be a preterminal sign. These reasons are all ultimately about risks and burden outweighing the benefits. We argue that the risks of LTPN have decreased over time, the burden for individual children and their parents may be less than imagined, and the benefit is a realistic prospect. Case-by-case consideration, giving due weight to child and parental perspectives, can show that LTPN is ethically justified for some children with severe neurological impairment.
A Low rectal GIST
Authors: Connelly Tara M , Clancy Cillian , Hu Shaomin , Steele Scott R , Kessler Hermann
Published: March 2022

A man in his 70s presented with narrowing of his stool calibre and a palpable mass on rectal examination. Colonoscopy revealed a submucosal bulge without a mucosal lesion. CT and MRI demonstrated an 8×5.4×7 cm mass in lower rectum. Biopsy of the mass confirmed a rectal gastrointestinal stromal tumour (GIST). It was moderately sensitive to neoadjuvant imatinib and radiotherapy, which slightly downsized the tumour. He required abdominal perineal resection with curative intent. Uncommonly found in the rectum, when located here, GISTs are typically aggressive and are a rare cause of stool calibre narrowing. Rectal GISTs should be considered in patients presenting with this symptom.
Quantitative analysis of optical coherence tomography imaging in patients with different severities of hydroxychloroquine toxicity
Authors: Membreno Raul F , De Silva Tharindu , Agrón Elvira , Keenan Tiarnan DL , Cukras Catherine A
Published: March 2022

Purpose

To determine the diagnostic validity of quantitative measures derived from optical coherence tomography (OCT) images in their ability to discriminate between cohorts of eyes unaffected by hydroxychloroquine (HCQ) and those with a range of toxicity severities, including mild toxicity.

Methods

Prospective, single-centre, case–control study conducted between August 2010 and May 2017. Participants were exposed to HCQ for at least 5 years (mean±SD =14±7.2 years) and classified into affected and unaffected cohorts based on the American Academy of Ophthalmology’s 2016 recommendations. For affected eyes, severity (groups 1–4) was assigned based on the extent of ellipsoid zone loss. For all eyes, spectral domain-OCT scans were analysed quantitatively to compute inner retinal thickness (IRT), outer retinal thickness (ORT), and minimum signal intensity (MI) and compared across toxicity groups.

Results

Of the 85 participants (mean age 59±12 years, 93% female), 30 had retinal toxicity. Significant differences in ORT and MI were observed between each affected severity group and unaffected eyes. Significant differences in IRT were observed for groups 3–4 but not groups 1–2. ORT and MI were each able to discriminate between unaffected and group 1 eyes with the highest discrimination at the inner subfields (areas under the curve, AUC=0.96 for ORT and AUC=0.93 for MI).

Conclusions

Quantitative analysis of OCT scans revealed significant differences between eyes with and without toxicity in two different measures. Each individual metric could discriminate between the unaffected and the lowest severity category, suggesting their potential utility in screening for HCQ toxicity in patients at risk.
Associations of long-term physical activity trajectories with coronary artery calcium progression and cardiovascular disease events: results from the CARDIA study
Authors: Gao Jing-Wei , Hao Qing-Yun , Lu Liu-Yi , Han Jia-Jin , Huang Fei-Fei , Vuitton Dominique A. , Wang Jing-Feng , Zhang Shao-Ling , Liu Pin-Ming
Published: March 2022

Objective

The study aimed to assess the associations of physical activity (PA) trajectories across a 25-year span with coronary artery calcium (CAC) progression, and subsequent risk of cardiovascular disease (CVD) events.

Methods

We included 2497 participants from the Coronary Artery Disease Risk Development in Young Adults study who had computed tomography-assessment of CAC at baseline (year 15: 2000–2001) and follow-up (year 20 or 25) and at least three measures of PA from year 0 to year 25. Long-term PA trajectories were determined by latent class modelling using a validated questionnaire.

Results

Among the included participants, 1120 (44.9%) were men, 1418 (56.8%) were white, and the mean (SD) age was 40.4 (3.6) years. We identified three distinct PA trajectories based on PA average levels and change patterns: low (below PA guidelines, n=1332; 53.3%); moderate (meeting and slightly over PA guidelines, n=919; 36.8%) and high (about three times PA guidelines or more, n=246; 9.9%). During a mean (SD) follow-up of 8.9 (2.1) years, 640 (25.6%) participants had CAC progression. Participants in the high PA trajectory group had a higher risk of CAC progression than those in the low PA trajectory group after adjustment for traditional cardiovascular risk factors (HR 1.51; 95% CI 1.18 to 1.94). However, high PA trajectory was not associated with an increased risk of incident CVD events (HR 1.01; 95% CI 0.44 to 2.31) and the incidence of CVD events in participants with CAC progression was similar across all three PA trajectory groups (p=0.736).

Conclusion

Long-term PA about three times the guidelines or more is independently associated with CAC progression; however, no additional risk of incident CVD events could be detected.
Comparison of diabetic and idiopathic sensory polyneuropathies with respect to nerve fibre affection and risk factors
Authors: Itani Mustapha , Gylfadottir Sif , Krøigård Thomas , Gaist Laura , Holbech Jakob Vormstrup , Kristensen Alexander Gramm , Karlsson Pall , Möller Sören , Tankisi Hatice , Gaist David , Jensen Troels S , Finnerup Nanna Brix , Sindrup Søren Hein
Published: March 2022

Background and purpose

Chronic distal sensory or sensorimotor polyneuropathy is the most common pattern of polyneuropathy. The cause of this pattern is most often diabetes or unknown. This cross-sectional study is one of the first studies to compare the demographics, cardiovascular risk factors and clinical characteristics of diabetic polyneuropathy (DPN) with idiopathic polyneuropathy (IPN).

Methods

Patients with DPN were included from a sample of 389 patients with type 2 diabetes mellitus (T2DM) enrolled from a national cohort of patients with recently diagnosed T2DM (Danish Centre for Strategic Research in Type 2 Diabetes cohort). Patients with IPN were included from a regional cohort of patients with symptoms of polyneuropathy referred for workup at a combined secondary and tertiary neurological centre (database cohort).

Results

A total of 214 patients with DPN were compared with a total of 88 patients with IPN. Patients with DPN were older (67.4 vs 59 years) and had a longer duration of neuropathy symptoms. Patients with DPN had greater body mass index (32 vs 27.4 kg/m2) and waist circumference (110 cm vs 97 cm); higher frequency of hypertension diagnosis (72.9% vs 30.7%); lower total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels; and a higher prevalence of use of statins (81.8% vs 19.3%). DPN was associated with a slightly higher autonomic score and total score on the Neuropathy Symptom Score; lower frequency of hyperalgesia, allodynia and decreased vibration on quantitative sensory testing; lower intraepidermal nerve fibre density count and higher frequency of small-fibre neuropathy.

Conclusion

DPN and IPN showed clear differences in neuropathy characteristics, indicating that these two entities are to be regarded as aetiologically and pathogenetically distinct.
Impact of ‘4+7’ volume-based drug procurement on the use of policy-related original and generic drugs: a natural experimental study in China
Authors: Wang Jing , Yang Ying , Xu Luxinyi , Shen Yuan , Wen Xiaotong , Mao Lining , Wang Quan , Cui Dan , Mao Zongfu
Published: March 2022

Objective

To evaluate the impact of the first round of the National Centralized Drug Procurement pilot (so-called ‘4+7’ policy) on the use of policy-related original and generic drugs.

Methods

A retrospective natural experimental design was adopted. Drug procurement data from the China Drug Supply Information Platform database were used, involving 9 ‘4+7’ pilot cities in intervention group and 12 non-pilot provinces in control group. ‘4+7’ policy-related drugs were selected as study samples, including 25 drugs in the ‘4+7’ procurement list and their alternative drugs that have not yet been covered by the policy. ‘4+7’ List drugs were divided into bid-winning and non-winning products according to the bidding results. Included drugs were sorted into original and generic products. Difference-in-difference method was employed to estimate the net effect of policy impact.

Results

After policy intervention, the DDDs (defined daily doses) of ‘4+7’ List original drugs significantly reduced (β=−39.10, p<0.001), while generic drugs increased (β=40.43, p<0.01). 17.08% of the original drugs in DDDs were substituted by generic drugs. Prominent reduction was observed in the monthly expenditure of ‘4+7’ List drugs (¥726.40 million) and overall policy-related drugs (¥654.47 million). The defined daily drug cost (DDDc) of bid-winning original and generic drugs, as well as non-winning original drugs, decreased by 44.44%, 79.00% and 15.10% (all p<0.01), while the DDDc of non-winning generic drugs increased by 64.81% (p<0.001). The use proportion of higher-quality drugs raised prominently from 39.66% to 91.93%.

Conclusions

‘4+7’ policy is conducive to generic substitution, drug price reduction and pharmaceutical cost-containment in China. The overall quality level of drug use of the Chinese population increased after policy intervention, especially in primary healthcare settings. However, the increased DDDc of non-winning generic drugs and alternative drugs should draw the importance of further policy monitoring.
Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO)
Authors: Hayes Wesley , Laing Emma , Foley Claire , Pankhurst Laura , Thomas Helen , Hume-Smith Helen , Marks Stephen , Kessaris Nicos , Bryant William A , Spiridou Anastassia , Wray Jo , Peters Mark J
Published: March 2022

Introduction

Acute electrolyte and acid–base imbalance is experienced by many children following kidney transplantation. When severe, this can lead to complications including seizures, cerebral oedema and death. Relatively large volumes of intravenous fluid are administered to children perioperatively in order to establish perfusion to the donor kidney, the majority of which are from living and deceased adult donors. Hypotonic intravenous fluid is commonly used in the post-transplant period due to clinicians’ concerns about the sodium, chloride and potassium content of isotonic alternatives when administered in large volumes.

Plasma-Lyte 148 is an isotonic, balanced intravenous fluid that contains sodium, chloride, potassium and magnesium with concentrations equivalent to those of plasma. There is a physiological basis to expect that Plasma-Lyte 148 will reduce the incidence of clinically significant electrolyte and acid–base abnormalities in children following kidney transplantation compared with current practice.

The aim of the PLUTO trial is to determine whether the incidence of clinically significantly abnormal plasma electrolyte levels in paediatric kidney transplant recipients will be different with the use of Plasma-Lyte-148 compared to intravenous fluid currently administered.

Methods and analysis

PLUTO is a pragmatic, open-label, randomised controlled trial comparing Plasma-Lyte 148 to current care in paediatric kidney transplant recipients, conducted in nine UK paediatric kidney transplant centres.

A total of 144 children receiving kidney transplants will be randomised to receive either Plasma-Lyte 148 (the intervention) intraoperatively and postoperatively, or current fluid. Apart from intravenous fluid composition, all participants will receive standard clinical transplant care.

The primary outcome measure is acute hyponatraemia in the first 72 hours post-transplant, defined as laboratory plasma sodium concentration of <135 mmol/L. Secondary outcomes include symptoms of acute hyponatraemia, other electrolyte and acid–base imbalances and transplant kidney function.

The primary outcome will be analysed using a logistic regression model adjusting for donor type (living vs deceased donor), patient weight (<20 kg vs ≥20 kg pretransplant) and transplant centre as a random effect.

Ethics and dissemination

The trial received Health Research Authority approval on 20 January 2020. Findings will be presented to academic groups via national and international conferences and peer-reviewed journals. The patient and public involvement group will play an important part in disseminating the study findings to the public domain.

Trial registration numbers

2019-003025-22 and 16586164.
AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors
Authors: Matsushita Tadashi , Suzuki Nobuaki , Nagao Azusa , Nagae Chiai , Yamaguchi-Suita Haruko , Kyogoku Yui , Ioka Akiko , Nogami Keiji
Published: March 2022

Introduction

For persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol.

Methods and analysis

AKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment.

Conclusions

AKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI.

Ethics and dissemination

The results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp).

Trial registration number

jRCTs041200037.
Association between sustained opioid prescription and frequent emergency department use: a cohort study
Authors: Racine-Hemmings François , Vanasse Alain , Lacasse Anaïs , Chiu Yohann , Courteau Josiane , Dépelteau Andréa , Hudon Catherine
Published: March 2022

Background

Chronic non-cancer pain (CNCP) is common among frequent emergency department (ED) users, although factors underlying this association are unclear. This study estimated the association between sustained opioid use and frequent ED use among patients with CNCP.

Methods

Retrospective cohort study using a Canadian provincial health insurer database (Régie d’Assurance Maladie du Québec). The database included adults with both ≥1 chronic condition and ≥ 1 ED visit in 2012 or 2013. Inclusion in the study further required a CNCP diagnosis, public drug insurance coverage and 1-year survival after the first ED visit in 2012 or 2013 (index visit). Multivariable logistic regression was used to derive ORs of frequent ED use (≥5 visits in the year following the index visit) subsequent to sustained opioid use (≥60 days opioids prescription within 90 days preceding the index visit), adjusting for important covariables.

Results

From 576 688 patients in the database, 58 237 were included in the study. Of these, 4109 (7.1%) had received a sustained opioid prescription and 4735 (8.1%) were frequent ED users in the follow-up year. Sustained opioid use was not associated with frequent ED use in the multivariable model (OR: 1.06, 95% CI 0.94 to 1.19). Novel associated covariables were benzodiazepine prescription (OR: 1.21, 95% CI 1.12 to 1.30) and polypharmacy (OR: 1.23, 95% CI 1.13 to 1.34).

Conclusions

Due to confounding by social and medical vulnerability, patients with CNCP with sustained opioid use appear to have a higher propensity for frequent ED use in unadjusted models. However, sustained opioid use was not associated with frequent ED use in these patients after adjustment.
Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer
Authors: Wang Yumeng , Wang Congwen , Qiu Junjun , Qu Xinyu , Peng Jing , Lu Chong , Zhang Meng , Zhang Mingxing , Qi Xingling , Li Guiling , Hua Keqin
Published: March 2022

Background

Novel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy.

Methods

Blood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo.

Results

We found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96−CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models.

Conclusions

Our findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.
T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion
Authors: Morton Laura T , Wachsmann Tassilo L A , Meeuwsen Miranda H , Wouters Anne K , Remst Dennis F G , van Loenen Marleen M , Falkenburg J H Frederik , Heemskerk Mirjam H M
Published: March 2022

Background

T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an ‘off the shelf’ cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance.

Methods

BOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B*07:02 restricted BOB1-specifc TCR in peripheral blood–derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B*07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo.

Results

Firstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing.

Conclusion

NK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic.
PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+T cell-dependent antitumor immunity and abscopal effect after local irradiation
Authors: Yoon Yi Na , Lee Eunju , Kwon Young-Ju , Gim Jeong-An , Kim Tae-Jin , Kim Jae-Sung
Published: March 2022

Background

Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.

Methods

We used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.

Results

This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.

Conclusions

Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.
High-precision Q-value measurement and nuclear matrix element calculations for the double-$$\beta $$ decay of $$^{98}$$Mo
Authors: Nesterenko D. A. , Jokiniemi L. , Kotila J. , Kankainen A. , Ge Z. , Eronen T. , Rinta-Antila S. , Suhonen J.
Published: March 2022

The $$^{98}$$

98

Mo double-beta decay Q-value has been measured, and the corresponding nuclear matrix elements of neutrinoless double-beta ($$0\nu \beta \beta $$

0
ν
β
β

) decay and the standard two-neutrino double-beta ($$2\nu \beta \beta $$

2
ν
β
β

) decay have been provided by nuclear theory. The double-beta decay Q-value has been determined as $$Q_{\beta \beta }=113.668(68)$$

Q

β
β

=
113.668

(
68
)

 keV using the JYFLTRAP Penning trap mass spectrometer. It is in agreement with the literature value, $$Q_{\beta \beta }=109(6)$$

Q

β
β

=
109

(
6
)

 keV, but almost 90 times more precise. Based on the measured Q-value, precise phase-space factors for $$2\nu \beta \beta $$

2
ν
β
β

decay and $$0\nu \beta \beta $$

0
ν
β
β

decay, needed in the half-life predictions, have been calculated. Furthermore, the involved nuclear matrix elements have been computed in the proton–neutron quasiparticle random-phase approximation (pnQRPA) and the microscopic interacting boson model (IBM-2) frameworks. Finally, predictions for the $$2\nu \beta \beta $$

2
ν
β
β

decay are given, suggesting a much longer half-life than for the currently observed cases.
Therapeutic Effect and Mechanism of Acupuncture in Autoimmune Diseases
Authors: Wang Jing , Zhu Fangyi , Huang Wei , Chen Zhengyi , Zhao Ping , Lei Yanting , Liu Yumei , Liu Xijun , Sun Bo , Li Hulun
Published: March 2022

Autoimmune diseases (AIDs) are conditions arising from abnormal immune reactions to autoantigens, which can be defined as the loss of immune tolerance to autoantigens, causing the production of autoantibodies and subsequent inflammation and tissue injury. The etiology of AIDs remains elusive, which may involve both genetic and environmental factors, such as diet, drugs, and infections. Despite rapid progress in the treatment of autoimmune diseases over the past few decades, there is still no approach that can cure AIDs. As an alternative approach, traditional Chinese medicine (TCM) such as acupuncture has been used in an attempt to treat AIDs including multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), and the results have proven to be quite promising, despite the fact that its mechanism is still not fully understood. In this review, the present knowledge regarding mechanisms of acupuncture in the treatment of AIDs has been summarized, and deeper insights will be provided in order to better understand how acupuncture may regulate immune responses during AIDs.
The Changing Global Landscape in the Development of Artemisinin-Based Treatments: A Clinical Trial Perspective
Authors: Kong Xiang-Jun , Liu Kun-Meng , Zuo Hua-Li , Huang Hsien-Da , Hu Yuan-Jia
Published: March 2022

Artemisinin and its derivatives (ARTs), due to their potent antimalarial activities, are widely used as frontline antimalarials across the world. Although the large-scale deployment of ARTs has significantly contributed to a substantial decline in malaria deaths, the global malaria burden is still high. New antimalarial treatments need to be developed to manage the growing artemisinin resistance. Understanding the status of ART development is crucial for developing strategies for new alternatives and identifying opportunities to develop ART-based treatments. This study sampled ART clinical trials from the past two decades to gain an overview of the global ART-development landscape. A total of 768 trials were collected to analyze the disease focuses, activity trends, development status, geographic distribution, and combination treatment profiles of ART trials. The findings highlighted the constant focus of ARTs on malaria, the evolving combination research focus, the distinctions between ART development preferences across global regions, the urgent demands for treatments for artemisinin-resistant malaria, and the unavoidable need to consider ART combinations in the development of new antimalarials.
Cordyceps Improves Obesity and its Related Inflammation via Modulation of Enterococcus cecorum Abundance and Bile Acid Metabolism
Authors: Wu Guo-Dong , Pan An , Zhang Xu , Cai Yuan-Yuan , Wang Qi , Huang Feng-Qing , Alolga Raphael N. , Li Jing , Qi Lian-Wen , Liu Qun
Published: March 2022

Abstract: Dysbiotic gut microbiota has been identified as a primary mediator of inherent inflammation that underlies the pathogenesis of obesity. Cordyceps comprises the larval body and the stroma of Cordyceps sinensis (BerK.) Sacc. parasiting on Hepialidae larvae of moths (H. pialusoberthur) with potent metabolic regulation functions. The underlying anti-obesity mechanisms, however, remain largely unknown. Here, we demonstrate that the water extract of Cordyceps attenuates glucose and lipid metabolism disorders and its associated inflammation in high-fat diet (HFD)-fed mice. 16S rRNA gene sequencing and microbiomic analysis showed that Cordyceps reduced the amounts of Enterococcus cecorum, a bile-salt hydrolase-producing microbe to regulate the metabolism of bile acids in the gut. Importantly, E. cecorum transplantation or liver-specific knockdown of farnesoid X receptor (FXR), a bile acid receptor, diminished the protective effect of Cordyceps against HFD-induced obesity. Together, our results shed light on the mechanisms that underlie the glucose- and lipid-lowering effects of Cordyceps and suggest that targeting intestinalE. cecorum or hepatic FXR are potential anti-obesity and anti-inflammation therapeutic avenues.
Ameliorative Effects of Malonyl Ginsenoside fromPanax ginsengon Glucose-Lipid Metabolism and Insulin Resistance via IRS1/PI3K/Akt and AMPK Signaling Pathways in Type 2 Diabetic Mice
Authors: Wang Dong-Sheng , Wang Jia-Mei , Zhang Fu-Rui , Lei Feng-Jie , Wen Xin , Song Jia , Sun Guang-Zhi , Liu Zhi
Published: March 2022

Abstract: Our previous study has revealed that malonyl-ginsenosides from Panax ginseng (PG-MGR) play a crucial role in the treatment of T2DM. However, its potential mechanism was still unclear. In this study, we investigated the anti-diabetic mechanisms of action of PG-MGR in high fat diet-fed (HFD) and streptozotocin-induced diabetic mice and determined the main constituents of PG-MGR responsible for its anti-diabetic effects. Our results showed that 16 malonyl ginsenosides were identified in PG-MGR by HPLC-ESI-MS/MS. PG-MGR treatment significantly reduced fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels and improved insulin resistance and glucose tolerance. Simultaneously, PG-MGR treatment improved liver injury by decreasing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) expression. Furthermore, Western blot analysis demonstrated that the protein expression levels of p-PI3K/PI3K, p-AKT/AKT, p-AMPK/AMPK, p-ACC/ACC and GLUT4 in liver and skeletal muscle were significantly up-regulated after PG-MGR treatment, and the protein expression levels of p-IRS-1/IRS-1, Fas and SREBP-1c were significantly reduced. These findings revealed that PG-MGR has the potential to improve glucose and lipid metabolism and insulin resistance by activating the IRS-1/PI3K/AKT and AMPK signal pathways.
Harvesting quantum coherence from axion dark matter
Authors: Kanno Sugumi , Matsumura Akira , Soda Jiro
Published: March 2022

Quantum coherence is one of the most striking features of quantum mechanics rooted in the superposition principle. Recently, it has been demonstrated that it is possible to harvest the quantum coherence from a coherent scalar field. In order to explore a new method of detecting axion dark matter, we consider a point-like Unruh–DeWitt detector coupled to the axion field and quantify a coherent measure of the detector. We show that the detector can harvest the quantum coherence from the axion dark matter. To be more precise, we consider a two-level electron system in an atom as the detector. In this case, we obtain the coherence measure [Formula: see text] where [Formula: see text] and [Formula: see text] are an observation time and the Lorentz factor. At the same time, the axion mass [Formula: see text] we can probe is determined by the energy gap of the detector.
Influence of working pressure on the structure and magnetic properties of polycrystalline iron films
Authors: Zhou C. X. , Yu Y. , Wei X. S. , Yan B.
Published: March 2022

In this work, we aimed to evaluate the influence of working pressure on the structure and magnetic properties of the iron film. Iron films were deposited on Si (100) substrates by direct current (DC) magnetron sputtering at different working pressures. The X-ray diffraction (XRD) results indicated that all iron films were polycrystalline BCC structures with the obvious (110) orientation. When the working pressure increased, the (110) peak became weaker and wider, indicating that the crystallinity and the particle size decreased. Particle size gradually decreased, easily seen from the surface morphology. The (100) peak shifted toward the smaller angle with the increase of working pressure, displaying the production of compressive strain. The increase of the working pressure raised the density of defects, which was the origin of the strain. It was the main reason that the Hc dramatically increased. The atomic force microscope (AFM) results exhibited that low working pressure was conducive to obtaining uniform and smooth surface morphology. This is why the iron film at low working pressure can achieve better magnetic properties. The iron film deposited at 0.6 Pa had the largest saturation magnetization (Ms) and squareness ratio (Mr/Ms), the smallest coercivity (Hc), reaching 1573 emu/cm3, 0.86, 102 Oe, respectively.
Structure and morphology of graphite nanoparticles treated by fiber laser irradiation
Authors: Luo Fang , Jiang Rongjie , Wang Weibin , Lu Yuanhang , Shen Yizhou
Published: March 2022

The graphite nanoparticles (GNPs) were prepared on the surface of monocrystalline Si by laser irradiation under different laser energy densities (3.3–8.33 kJ/cm2). The effects of laser energy density on structure and surface morphology were systematically investigated. The results show that the morphology of GNPs remained polycrystalline structure under laser irradiation with an energy density of 2.22 kJ/cm2. When the laser energy density was 2.78 kJ/cm2, the GNPs can induce the preset GNPs to transform into amorphous graphite nanofibers. The GNPs under the laser density of 3.33 kJ/cm2 showed a more amorphous structure. With the further increase of the laser energy density to 5.55 kJ/cm2, the main phase composition turned to SiC and Si.