bluuebunny/crossref_metadata_2025 huggingface dataset:
Sputtering produced by vacuum electrospray droplet ions with different sizes and charges
Authors: Ninomiya Satoshi , Chen Lee Chuin , Hiraoka Kenzo
Published: April 2023

We have been developing a vacuum electrospray droplet ion (V-EDI) beam technique that uses water droplet ions generated by electrospraying aqueous solutions under vacuum. The V-EDI beam is one of the massive cluster ion beams that have the potential to significantly improve the performance of surface analysis. In order to utilize the V-EDI beams effectively as ionization and sputtering probes in secondary ion mass spectrometry and x-ray photoelectron spectroscopy, it is necessary to optimize the sizes and charge states of the droplet ions included in the V-EDI beams. However, the droplet ions themselves in the V-EDI beams are not well understood. In this study, the V-EDI beams generated from the capillaries with different inner diameters were irradiated on polystyrene film samples under constant electrospray and accelerating voltage conditions, and then their surfaces were analyzed with atomic force microscopy and spectroscopic ellipsometer. The impact trace distributions produced by the droplet ions and the sputtered volumes produced by each droplet ion impact were investigated.
“Living High-Training Low” for Olympic Medal Performance: What Have We Learned 25 Years After Implementation?
Authors: Girard Olivier , Levine Benjamin D. , Chapman Robert F. , Wilber Randall
Published: April 2023

Background: Altitude training is often regarded as an indispensable tool for the success of elite endurance athletes. Historically, altitude training emerged as a key strategy to prepare for the 1968 Olympics, held at 2300 m in Mexico City, and was limited to the “Live High-Train High” method for endurance athletes aiming for performance gains through improved oxygen transport. This “classical” intervention was modified in 1997 by the “Live High-Train Low” (LHTL) model wherein athletes supplemented acclimatization to chronic hypoxia with high-intensity training at low altitude. Purpose: This review discusses important considerations for successful implementation of LHTL camps in elite athletes based on experiences, both published and unpublished, of the authors. Approach: The originality of our approach is to discuss 10 key “lessons learned,” since the seminal work by Levine and Stray-Gundersen was published in 1997, and focusing on (1) optimal dose, (2) individual responses, (3) iron status, (4) training-load monitoring, (5) wellness and well-being monitoring, (6) timing of the intervention, (7) use of natural versus simulated hypoxia, (8) robustness of adaptative mechanisms versus performance benefits, (9) application for a broad range of athletes, and (10) combination of methods. Successful LHTL strategies implemented by Team USA athletes for podium performance at Olympic Games and/or World Championships are presented. Conclusions: The evolution of the LHTL model represents an essential framework for sport science, in which field-driven questions about performance led to critical scientific investigation and subsequent practical implementation of a unique approach to altitude training.
Mercury isotopes show vascular plants had colonized land extensively by the early Silurian
Authors: Yuan Wei , Liu Mu , Chen Daizhao , Xing Yao-Wu , Spicer Robert A. , Chen Jitao , Them Theodore R. , Wang Xun , Li Shizhen , Guo Chuan , Zhang Gongjing , Zhang Liyu , Zhang Hui , Feng Xinbin
Published: April 2023

The colonization and expansion of plants on land is considered one of the most profound ecological revolutions, yet the precise timing remains controversial. Because land vegetation can enhance weathering intensity and affect terrigenous input to the ocean, changes in terrestrial plant biomass with distinct negative Δ
199
Hg and Δ
200
Hg signatures may overwrite the positive Hg isotope signatures commonly found in marine sediments. By investigating secular Hg isotopic variations in the Paleozoic marine sediments from South China and peripheral paleocontinents, we highlight distinct negative excursions in both Δ
199
Hg and Δ
200
Hg at Stage level starting in the early Silurian and again in the Carboniferous. These geochemical signatures were driven by increased terrestrial contribution of Hg due to the rapid expansion of vascular plants. These excursions broadly coincide with rising atmospheric oxygen concentrations and global cooling. Therefore, vascular plants were widely distributed on land during the Ordovician-Silurian transition (~444 million years), long before the earliest reported vascular plant fossil,
Cooksonia
(~430 million years).
Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8
+
T cells
Authors: Helm Eric Y. , Zelenka Tomas , Cismasiu Valeriu B. , Islam Shamima , Silvane Leonardo , Zitti Beatrice , Holmes Tim D. , Drashansky Theodore T. , Kwiatkowski Alexander J. , Tao Christine , Dean Joseph , Obermayer Alyssa N. , Chen Xianghong , Keselowsky Benjamin G. , Zhang Weizhou , Huo Zhiguang , Zhou Liang , Sheridan Brian S. , Conejo-Garcia Jose R. , Shaw Timothy I. , Bryceson Yenan T. , Avram Dorina
Published: April 2023

The networks of transcription factors (TFs) that control intestinal-resident memory CD8
+
T (T
RM
) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in T
RM
cells during infection with
Listeria monocytogenes
using mice with post-activation, conditional deletion of Bcl11b in CD8
+
T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal T
RM
cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of

Bcl11b
−/−

circulating precursors, with no major alterations in their programs.

Bcl11b
−/−

T
RM
cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including
Tcf7
, and up-regulation of the effector program genes, including
Prdm1.
Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8
+
T
RM
cell differentiation. Deregulation of T
RM
programs translated into a poor recall response despite T
RM
cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b
−/−
T
RM
cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.
Effect of exercise therapy versus surgery on mechanical symptoms in young patients with a meniscal tear: a secondary analysis of the DREAM trial
Authors: Damsted Camma , Thorlund Jonas Bloch , Hölmich Per , Lind Martin , Varnum Claus , Villumsen Martin Dalgaard , Hansen Mogens Strange , Skou Søren T
Published: April 2023

Objective

To compare the effect of early surgery versus exercise and education on mechanical symptoms and other patient-reported outcomes in patients aged 18–40 years with a meniscal tear and self-reported mechanical knee symptoms.

Methods

In a randomised controlled trial, 121 patients aged 18–40 years with a MRI-verified meniscal tear were randomised to surgery or 12-week supervised exercise and education. For this study, 63 patients (33 and 30 patients in the surgery and in the exercise group, respectively) reporting baseline mechanical symptoms were included. The main outcome was self-reported mechanical symptoms (yes/no) at 3, 6 and 12 months assessed using a single item from the Knee Injury and Osteoarthritis Outcome Score (KOOS). Secondary outcomes were KOOS4and the 5 KOOS-subscales and the Western Ontario Meniscal Evaluation Tool (WOMET).

Results

In total, 55/63 patients completed the 12-month follow-up. At 12 months, 9/26 (35%) in the surgery group and 20/29 (69%) in the exercise group reported mechanical symptoms. The risk difference and relative risk at any time point was 28.7% (95% CI 8.6% to 48.8%) and 1.83 (95% CI 0.98 to 2.70) of reporting mechanical symptoms in the exercise group compared with the surgery group. We did not detect any between-group differences in the secondary outcomes.

Conclusion

The results from this secondary analysis suggest that early surgery is more effective than exercise and education for relieving self-reported mechanical knee symptoms, but not for improving pain, function and quality of life in young patients with a meniscal tear and mechanical symptoms.

Trial registration number

NCT02995551.
Effect of a moderately carbohydrate-restricted diet on liver enzymes, steatosis and fibrosis in normal-weight individuals with non-alcoholic fatty liver disease: study protocol for a parallel randomised controlled clinical trial
Authors: Dashti Fatemeh , Alavian Seyed Moayed , Sohrabpour Amir Ali , Mousavi Sara Ebrahimi , Keshavarz Seyed-Ali , Esmaillzadeh Ahmad
Published: April 2023

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a hepatic condition that is considerably prevalent across the world. Dietary intakes, in which macronutrient composition is precisely planned, might be able to reduce inflammation, steatosis and fibrosis among patients with NAFLD. A moderately carbohydrate restricted diet with weight loss has been demonstrated to improve liver fat content among overweight or obese patients. However, there is no information about the appropriateness of such a restriction, without weight loss, in normal-weight patients. This randomised clinical trial will be aimed at assessing the effect of moderate carbohydrate restriction on liver enzymes, liver steatosis and fibrosis in normal-weight patients with NAFLD.

Methods and analysis

This randomised controlled clinical trial will be conducted to evaluate the impact of a moderately carbohydrate restricted diet on liver enzymes, steatosis and fibrosis in 52 eligible normal-weight individuals with NAFLD. Transient elastography and controlled attenuation parameter with FibroScan will be applied to diagnose NAFLD. After individual matching based on body mass index, age and sex, patients will be randomly assigned to receive a moderately carbohydrate restricted diet or an isocaloric diet without carbohydrate restriction for 12 weeks. The primary and secondary outcomes in this study will be liver function indices, including liver steatosis and fibrosis, metabolic parameters and anthropometric measures. All these variables will be assessed at study baseline and postintervention.

Ethics and dissemination

The present clinical trial study was accepted by the ethics committee of TUMS (Tehran University of Medical Sciences) (code: IR.TUMS.MEDICINE.REC.1400.116).

Trial registration number

IRCT20210119050086N1.
Protocol for a bandit-based response adaptive trial to evaluate the effectiveness of brief self-guided digital interventions for reducing psychological distress in university students: the Vibe Up study
Authors: Huckvale Kit , Hoon Leonard , Stech Eileen , Newby Jill M , Zheng Wu Yi , Han Jin , Vasa Rajesh , Gupta Sunil , Barnett Scott , Senadeera Manisha , Cameron Stuart , Kurniawan Stefanus , Agarwal Akash , Kupper Joost Funke , Asbury Joshua , Willie David , Grant Alasdair , Cutler Henry , Parkinson Bonny , Ahumada-Canale Antonio , Beames Joanne R , Logothetis Rena , Bautista Marya , Rosenberg Jodie , Shvetcov Artur , Quinn Thomas , Mackinnon Andrew , Rana Santu , Tran Truyen , Rosenbaum Simon , Mouzakis Kon , Werner-Seidler Aliza , Whitton Alexis , Venkatesh Svetha , Christensen Helen
Published: April 2023

Introduction

Meta-analytical evidence confirms a range of interventions, including mindfulness, physical activity and sleep hygiene, can reduce psychological distress in university students. However, it is unclear which intervention is most effective. Artificial intelligence (AI)-driven adaptive trials may be an efficient method to determine what works best and for whom. The primary purpose of the study is to rank the effectiveness of mindfulness, physical activity, sleep hygiene and an active control on reducing distress, using a multiarm contextual bandit-based AI-adaptive trial method. Furthermore, the study will explore which interventions have the largest effect for students with different levels of baseline distress severity.

Methods and analysis

The Vibe Up study is a pragmatically oriented, decentralised AI-adaptive group sequential randomised controlled trial comparing the effectiveness of one of three brief, 2-week digital self-guided interventions (mindfulness, physical activity or sleep hygiene) or active control (ecological momentary assessment) in reducing self-reported psychological distress in Australian university students. The adaptive trial methodology involves up to 12 sequential mini-trials that allow for the optimisation of allocation ratios. The primary outcome is change in psychological distress (Depression, Anxiety and Stress Scale, 21-item version, DASS-21 total score) from preintervention to postintervention. Secondary outcomes include change in physical activity, sleep quality and mindfulness from preintervention to postintervention. Planned contrasts will compare the four groups (ie, the three intervention and control) using self-reported psychological distress at prespecified time points for interim analyses. The study aims to determine the best performing intervention, as well as ranking of other interventions.

Ethics and dissemination

Ethical approval was sought and obtained from the UNSW Sydney Human Research Ethics Committee (HREC A, HC200466). A trial protocol adhering to the requirements of the Guideline for Good Clinical Practice was prepared for and approved by the Sponsor, UNSW Sydney (Protocol number: HC200466_CTP).

Trial registration number

ACTRN12621001223820.
History of heart failure and chronic kidney disease and risk of all-cause death after COVID-19 during the first three waves of the pandemic in comparison with influenza outbreaks in Sweden: a registry-based, retrospective, case–control study
Authors: Ritsinger Viveca , Bodegård Johan , Kristofi Robin , Thuresson Marcus , Nathanson David , Nyström Thomas , Eriksson Jan , Norhammar Anna
Published: April 2023

Objectives

To explore how cardiorenal disease (CRD; heart failure and/or chronic kidney disease) impacted mortality in men and women hospitalised for COVID-19 during the first three waves of the pandemic in Sweden in comparison to previous influenza outbreaks.

Design

A registry-based, retrospective, case–control study.

Setting

Hospital care in Sweden.

Participants

All patients in Sweden with a main hospital diagnosis of COVID‐19 (January 2020–September 2021) or influenza (January 2015–December 2019) with previous CRD were identified in registries and compared with a reference group free from CRD but with COVID-19 or influenza.

Primary outcome measure

Associated risk of all-cause death during the first year was analysed using adjusted Cox proportional hazards models.

Results

In COVID-19 patients with and without prior history of CRD (n=44 866), mean age was 79.8 years (SD 11.8) and 43% were women. In influenza patients (n=8897), mean age was 80.6 years (SD 11.5) and 45% were women. COVID-19 versus influenza was associated with higher mortality risk during the first two COVID-19 waves (HR 1.53; 95% CI 1.45 to 1.62, p<0.001 and HR 1.52; 95% CI 1.44 to 1.61, p<0.001), but not in the third wave (HR 1.07; 95% CI 0.99 to 1.14, p=0.072). CRD was an independent risk factor for all-cause death after COVID-19 in men and women (men: 1.37; 95% CI 1.31 to 1.44, p<0.001; women: 1.46; 95% CI 1.38 to 1.54, p<0.001). At ages <70 years, women with CRD had a similar mortality rate to men with CRD, while at ages ≥70 years, the mortality rate was higher in men.

Conclusions

Outcome after COVID-19 is worse if CRD is present. In women at ages <70 years, the presence of CRD attenuates the protective effect of female sex. COVID-19 was associated with higher mortality risk than influenza during the first two pandemic waves.
UK physiotherapists delivering physical activity advice: what are the challenges and possible solutions? A qualitative study
Authors: Stead Alexandra , Vishnubala Dane , Marino Katherine Rose , Iqbal Adil , Pringle Andy , Nykjaer Camilla
Published: April 2023

Objectives

Despite the known health benefits of physical activity (PA), PA levels are in decline. Healthcare professionals, including physiotherapists, have been identified as ideal conduits to promote PA, yet their knowledge and awareness of PA guidelines are poor. The aims of this study were to explore current knowledge of PA guidelines among UK physiotherapists and identify barriers and possible solutions to delivering PA advice.

Design

A qualitative approach using semistructured interviews that took place between March and May 2021. Data were analysed with a thematic approach using Braun and Clarke’s six steps.

Setting

Various inpatient and outpatient clinical settings across six UK regions.

Participants

Eighteen UK-based physiotherapists managing National Health Service patients were recruited through volunteer sampling in March 2021.

Results

Five themes and 16 subthemes (shown in parenthesis) were identified as barriers and solutions to delivering PA advice: physiotherapist intrinsic barriers (knowledge, fear/confidence); a lack of emphasis and priority given to PA (time constraints, minimal educational and staff training); patient barriers (compliance, expectations and fear of doing PA); increasing awareness of the PA guidelines (staff training, signposting awareness, use of social media and television campaigns); and optimising delivery (use of visual resources, good communication and approaches involving being individualised and gradual for patients with chronic conditions).

Conclusions

In this study, physiotherapist participants seemed to have limited awareness of the PA guidelines despite recent updates and were faced with similar barriers to those previously reported in the literature. The solutions suggested could guide strategies to support physiotherapists being able to deliver PA advice. Further research is needed to evaluate the efficiency of any implemented solutions supporting the delivery of PA advice.
Resting heart rate and risk of atrial fibrillation in Chinese general population: Kailuan prospective cohort study
Authors: Hou Ziwei , Zhao Mao Xiang , Sun Yizhen , Zhang Sijing , Yao Siyu , Wang Chi , Wang Miao , Yun Cuijuan , Xue Hao , Wu Shouling
Published: April 2023

Objective

Previous research has shown an association of higher heart rate with an increased risk of atrial fibrillation (AF). However, the relationship between resting heart rate (RHR) and AF is unknown. The aim of this study was to investigate the association between RHR and AF in the general population of China.

Design

Prospective observational cohort study.

Setting

Community based.

Participants

A total of 46 126 individuals from the Kailuan study who participated in the first three surveys (2006/2007, 2008/2009 and 2010/2011) and were followed up at 2-year intervals were enrolled.

Primary outcome measures

The association between RHR and risk of incident AF was evaluated using Cox proportional hazards regression and restricted cubic spline models.

Results

Two hundred and forty-one individuals (0.52%) developed AF during 7.5 years of follow-up. After adjustment for age, sex, low-density and high-density lipoprotein, physical activity, alcohol consumption, smoking status, body mass index, mean systolic blood pressure, and history of diabetes and hypertension, the HRs were 2.32 (95% CI 1.45 to 3.72) for an RHR <60 beats/min and 2.80 (1.13 to 6.94) for an RHR ≥100 beats/min in comparison with an RHR of 70–80 beats/min. Restricted cubic spline models revealed a U-shaped relationship between RHR and incident AF.

Conclusion

These findings indicate that RHR and incident AF have a U-shaped relationship in the Chinese general population. Both lower and higher RHRs were associated with an increased risk of AF.
Group cognitive stimulation therapy versus usual care for people with intellectual disabilities and dementia (CST-IDD) in the UK: protocol for a mixed-methods feasibility randomised controlled trial
Authors: Ali Afia , Aguirre Elisa , Carter Joanna , Hoare Sarah , Brackley Kate , Goulden Nia , Hoare Zoe , Clarke Caroline S , Charlesworth Georgina , Acton Danny , Spector Aimee
Published: April 2023

Introduction

The prevalence of dementia is almost five times higher in people with intellectual disabilities compared with the general population. However, evidence-based treatments for this population are lacking, as most randomised controlled trials for dementia interventions have not included people with intellectual disabilities. Cognitive stimulation therapy (CST) has a robust evidence base in the general dementia population, consistently showing benefits to cognition, quality of life and being cost-effective. We are conducting a mixed-methods feasibility trial of group CST for people with intellectual disabilities and dementia, to determine if a future definitive randomised controlled trial is feasible.

Methods and analysis

Fifty individuals with intellectual disabilities and dementia will be randomised to either the intervention arm (14 sessions of group CST plus treatment as usual) or the control arm (treatment as usual). Randomisation will occur after informed consent has been obtained and baseline assessments completed. Each arm will have 25 participants, with the intervention arm divided into five or more CST groups with three to five participants in each. The outcomes will be feasibility of recruitment, acceptability and adherence of the intervention, suitability of study outcome measures and feasibility of collecting resource use data. Quantitative and qualitative approaches, including semistructured interviews with group participants, carers and group facilitators, will be employed to assess these outcomes.

Ethics and dissemination

This study has been approved by Essex REC (Ref: 21/EE/027) and the HRA ethical approval process through the Integrated Research Application System (IRAS ID: 306 756). We plan to publish the results in peer-reviewed journals and conferences as well as provide feedback to funders, sponsors and study participants.

Trial registration number

ISRCTN88614460.
Survey of exercise testing and training in cystic fibrosis clinics in the UK: a decade of progress
Authors: Tomlinson Owen William , Saynor Zoe L , Stevens Daniel , Antoun Joe , Urquhart Don S , Williams Craig Anthony
Published: April 2023

Objectives

Regular exercise testing is recommended for people with cystic fibrosis (pwCF), as is the provision and regular review of exercise training programmes. A previous survey on exercise testing and training for pwCF in the UK was conducted over a decade ago. With the landscape of CF changing considerably during this time, this survey aimed to evaluate UK-based exercise testing and training practices for pwCF a decade on.

Design

Cross-sectional, online survey.

Participants

A survey was distributed electronically to UK CF clinics and completed by the individual primarily responsible for exercise services. Descriptive statistics and qualitative analyses were undertaken.

Results

In total, 31 CF centres participated, representing ~50% of UK specialist clinics. Of these, 94% reported using exercise testing, 48% of which primarily use cardiopulmonary exercise testing. Exercise testing mostly occurs at annual review (93%) and is most often conducted by physiotherapists (62%). A wide variation in protocols, exercise modalities, normative reference values and cut-offs for exercise-induced desaturation are currently used. All centres reportedly discuss exercise training with pwCF; 94% at every clinic appointment. However, only 52% of centres reportedly use exercise testing to inform individualised exercise training. Physiotherapists typically lead discussions around exercise training (74%).

Conclusions

These data demonstrate that the majority of respondent centres in the UK now offer some exercise testing and training advice for pwCF, representing a marked improvement over the past decade. However, continued efforts are now needed to standardise exercise practices, particularly regarding field testing practices and the translation of test results into personalised training programmes for pwCF.
Morpho-mechanistic screening criteria for the echocardiographic detection of rheumatic heart disease
Authors: Hunter Luke David , Doubell Anton Frans , Pecoraro Alfonso Jan Kemp , Monaghan Mark , Lloyd Guy , Lombard Carl , Herbst Philipus George
Published: April 2023

Introduction

Screening echocardiography, guided by the current World Heart Federation (WHF) criteria, has important limitations that impede the establishment of large-scale rheumatic heart disease (RHD) control programmes in endemic regions. The criteria misclassify a significant number of normal cases as borderline RHD. Prior attempts to simplify them are limited by incorporation bias due to the lack of an externally validated, accurate diagnostic test for RHD. We set out to assess novel screening criteria designed to avoid incorporation bias and to compare this against the performance of the current WHF criteria.

Methods

The performance of the WHF and the morpho-mechanistic (MM) RHD screening criteria (a novel set of screening criteria that evaluate leaflet morphology, motion and mechanism of regurgitation) as well as a simplified RHD MM ‘rule-out’ test (based on identifying a predefined sign of anterior mitral valve leaflet restriction for the mitral valve and any aortic regurgitation for the aortic valve) were assessed in two contrasting cohorts: first, a low-risk RHD cohort consisting of children with a very low-risk RHD profile. and second, a composite reference standard (CRS) RHD-positive cohort that was created using a composite of two criteria to ensure a cohort with the highest possible likelihood of RHD. Subjects included in this group required (1) proven, prior acute rheumatic fever and (2) current evidence of predefined valvular regurgitation on echocardiography.

Results

In the low-risk RHD cohort (n=364), the screening specificities for detecting RHD of the MM and WHF criteria were 99.7% and 95.9%, respectively (p=0.0002). The MM rule-out test excluded 359/364 cases (98.6%). In the CRS RHD-positive cohort (n=65), the screening sensitivities for the detection of definite RHD by MM and WHF criteria were 92.4% and 89.2%, respectively (p=0.2231). The MM RHD rule-out test did not exclude any cases from the CRS RHD-positive cohort.

Conclusion

Our proposed MM approach showed an equal sensitivity to the WHF criteria but with significantly improved specificity. The MM RHD rule-out test excluded RHD-negative cases while identifying all cases within the CRS RHD-positive cohort. This holds promise for the development of a two-step RHD screening algorithm to enable task shifting in RHD endemic regions.
Vector Aided Microenvironment programming (VAMP): reprogramming the TME with MVA virus expressing IL-12 for effective antitumor activity
Authors: Seclì Laura , Infante Luigia , Nocchi Linda , De Lucia Maria , Cotugno Gabriella , Leoni Guido , Micarelli Elisa , Garzia Irene , Avalle Lidia , Sdruscia Giulia , Troise Fulvia , Allocca Simona , Romano Giuseppina , Scarselli Elisa , D'Alise Anna Morena
Published: April 2023

Background

Tumor microenvironment (TME) represents a critical hurdle in cancer immunotherapy, given its ability to suppress antitumor immunity. Several efforts are made to overcome this hostile TME with the development of new therapeutic strategies modifying TME to boost antitumor immunity. Among these, cytokine-based approaches have been pursued for their known immunomodulatory effects on different cell populations within the TME. IL-12 is a potent pro-inflammatory cytokine that demonstrates striking immune activation and tumor control but causes severe adverse effects when systemically administered. Thus, local administration is considered a potential strategy to achieve high cytokine concentrations at the tumor site while sparing systemic adverse effects.

Methods

Modified Vaccinia Ankara (MVA) vector is a potent inducer of pro-inflammatory response. Here, we cloned IL-12 into the genome of MVA for intratumoral immunotherapy, combining the immunomodulatory properties of both the vector and the cargo. The antitumor activity of MVA-IL-12 and its effect on TME reprogramming were investigated in preclinical tumor models. RNA sequencing (RNA-Seq) analysis was performed to assess changes in the TME in treated and distal tumors and the effect on the intratumoral T-cell receptor repertoire.

Results

Intratumoral injection of MVA-IL-12 resulted in strong antitumor activity with the complete remission of established tumors in multiple murine models, including those resistant to checkpoint inhibitors. The therapeutic activity of MVA-IL-12 was associated with very low levels of circulating cytokine. Effective TME reprogramming was demonstrated on treatment, with the reduction of immunosuppressive M2 macrophages while increasing pro-inflammatory M1, and recruitment of dendritic cells. TME switch from immunosuppressive into immunostimulatory environment allowed for CD8 T cells priming and expansion leading to tumor attack.

Conclusions

Intratumoral administration of MVA-IL-12 turns immunologically ‘cold’ tumors ‘hot’ and overcomes resistance to programmed cell death protein-1 blockade.
What is the best target in a treat-to-target strategy in rheumatoid arthritis? Results from a systematic review and meta-regression analysis
Authors: Messelink Marianne A , den Broeder Alfons A , Marinelli Florine E , Michgels Edwin , Verschueren P , Aletaha Daniel , Tekstra Janneke , Welsing Paco M J
Published: April 2023

Objectives

A treat-to-target (T2T) strategy has been shown to be superior to usual care in rheumatoid arthritis (RA), but the optimal target remains unknown. Targets are based on a disease activity measure (eg, Disease Activity Score-28 (DAS28), Simplified Disease Activity Indices/Clinical Disease Activity Indices (SDAI/CDAI), and a cut-off such as remission or low disease activity (LDA). Our aim was to compare the effect of different targets on clinical and radiographic outcomes.

Methods

Cochrane, Embase and (pre)MEDLINE databases were searched (1 June 2022) for randomised controlled trials and cohort studies after 2003 that applied T2T in RA patients for ≥12 months. Data were extracted from individual T2T study arms; risk of bias was assessed with the Cochrane Collaboration tool. Using meta-regression, we evaluated the effect of the target used on clinical and radiographic outcomes, correcting for heterogeneity between and within studies.

Results

115 treatment arms were used in the meta-regression analyses. Aiming for SDAI/CDAI-LDA was statistically superior to targeting DAS-LDA regarding DAS-remission and SDAI/CDAI/Boolean-remission outcomes over 1–3 years. Aiming for SDAI/CDAI-LDA was also significantly superior to DAS-remission regarding both SDAI/CDAI/Boolean-remission (over 1–3 years) and mean SDAI/CDAI (over 1 year). Targeting DAS-remission rather than DAS-LDA only improved the percentage of patients in DAS-remission, and only statistically significantly after 2–3 years of T2T. No differences were observed in Health Assessment Questionnaire and radiographic progression.

Conclusions

Targeting SDAI/CDAI-LDA, and to a lesser extent DAS-remission, may be superior to targeting DAS-LDA regarding several clinical outcomes. However, due to the risk of residual confounding and the lack of data on (over)treatment and safety, future studies should aim to directly and comprehensively compare targets.

PROSPERO registration number

CRD42021249015.
Weaving together Inuit knowledge and western science: a mixed-methods case study of qilalugaq (beluga whale) in Quaqtaq, Nunavik
Authors: Little Matthew , Winters Nicole , Achouba Adel , Magesky Adriano , Ayotte Pierre , Palliser Tommy , Naylor Angus , Jararuse Willie , Lemire Mélanie
Published: April 2023

The harvest and consumption of country food is a cornerstone of Inuit culture, sovereignty, food security, and nutrition. Qilalugaq (beluga whales) ( Delphinapterus leucas (Pallas, 1776)) are hunted across the Canadian Arctic and are an especially important food source for Inuit communities in Nunavik, northern Québec, Canada. The presence of environmental contaminants and nutrients in beluga has been the subject of recent research interest, including the role of selenoneine and its interactions with methylmercury. Using interviews conducted in Quaqtaq and analyses of beluga tissue samples harvested by hunters, this study aimed to bridge Inuit knowledge and scientific knowledge to understand how beluga hunting, preparation, and consumption practices may explain the different levels of selenoneine found in Nunavimmiut (Inuit from Nunavik). It also sought to characterize the health, social, and cultural importance of beluga and factors influencing its consumption. Research findings confirmed the important role of beluga in Nunavimmiut culture, food security, and nutrition. Findings documented gender-based consumption practices, including consumption of the selenoneine-rich beluga tail exclusively by women, which may explain previously documented gender differences in blood selenoneine levels. This study demonstrates the utility of weaving Inuit knowledge and scientific knowledge to inform future environmental health research, public health communications, and wildlife comanagement.
Hypernuclei production with a modified coalescence model in BUU transport calculations
Authors: Balassa Gábor , Wolf György
Published: April 2023

In this paper, the usual momentum- and coordinate-space distance criteria for creating nuclear clusters in transport simulations are readdressed by using a dynamical, covariant description in an off-shell Boltzmann-Uehling-Uhlenbeck transport approach. The free parameter of this clustering scheme is the cluster formation time, which is fitted through the FOPI data of low energy charged cluster multiplicities in Au+Au collisions at 150 A MeV, and 400 A MeV incident energies. The coalescence model is used to estimate the yields of the $$^3$$

3

H$$_\Lambda $$

Λ

, $$^5$$

5

H$$_{\Lambda \Lambda }$$

Λ
Λ

, $$^6$$

6

He$$_{\Lambda \Lambda }$$

Λ
Λ

single and double strange hypernuclei in central Au+Au collisions between 2, and 20 A GeV incident energies, giving comparable results to estimations from other methods.
Analysis of localized CP asymmetry in $${\bar{B}}_{s}^{0} \rightarrow \pi ^+\pi ^-\pi ^{0}(K^{0})$$
Authors: Shi De-Sen , Lü Gang , Zhao Yan-Lin , Na-Wang  , Guo Xin-Heng
Published: April 2023

An investigation about localized CP asymmetries for the processes of $${\bar{B}}_{s}^{0} \rightarrow \pi ^{+}\pi ^{-}\pi ^{0} (K^{0})$$

B

¯

s

0

→

π
+

π
-

π
0

(

K
0

)

is presented in this paper. The innovation of this paper is that there is a consideration of three-particle $$\rho ^0(770)$$

ρ
0

(
770
)

, $$\omega (782)$$

ω
(
782
)

and $$\phi (1020)$$

ϕ
(
1020
)

interferences effect. Generally, $$\omega (782)$$

ω
(
782
)

and $$\phi (1020)$$

ϕ
(
1020
)

both can decay into $$\pi ^+\pi ^-$$

π
+

π
-

pair where can cause extremely small contribution from isospin symmetry breaking. Nevertheless, our analysis shows that $${\bar{B}}_{s}^{0} \rightarrow \pi ^+\pi ^-\pi ^{0}(K^{0})$$

B

¯

s

0

→

π
+

π
-

π
0

(

K
0

)

decay process can bring differential CP asymmetry about $$65\%$$

65
%

($$36\%$$

36
%

) because of isospin symmetry breaking. To be better compared with the data from experimental in the future, we integrate CP asymmetry over the invariant mass and obtain localized CP asymmetry value for the decay $${\bar{B}}_{s}^{0} \rightarrow \pi ^+\pi ^-\pi ^{0} (K^{0})$$

B

¯

s

0

→

π
+

π
-

π
0

(

K
0

)

. We find that there is an evident signal about CP asymmetry at invariant mass value $$m(\pi ^{+}\pi ^{-})$$

m
(

π
+

π
-

)

below the mass of $$\rho ^{0}(770)$$

ρ
0

(
770
)

with the decay $${\bar{B}}_{s}^{0} \rightarrow \pi ^+\pi ^{-}\pi ^{0}$$

B

¯

s

0

→

π
+

π
-

π
0

.
Replica wormhole as a vacuum-to-vacuum transition
Authors: An Yang , Cheng Peng
Published: April 2023

The recent developments related to the black hole information paradox have brought us a confusing object: the replica wormhole. We are trying to better understand the object from the viewpoint of the thermo-mixed double and spontaneous symmetry breaking. In this paper, we show that the replica wormhole can be regarded as a transition between different degenerate vacua, and the corresponding gravitational partition function should be controlled by the manifold of the degenerate vacua. We also check the wormhole partition function in two-dimensional Jackiw–Teitelboim gravity and show that the wormhole saddle is indeed controlled by the dimension of the degenerate vacua. Moreover, it is suggested that the replica wormhole geometries connecting different vacua can be related to the measurement process of soft hair that compares different vacuum configurations.
Working of Expectations Channel of Monetary Policy Transmission in India
Authors: Goyal Ashima , Parab Prashant
Published: April 2023

In this paper, we examine the working of the expectations channel of monetary policy transmission for India, first by investigating the role of inflation expectations in an aggregate supply-demand (AS-AD) adapted to the Indian economy. Second, formulating an inflation function determining convergence of core inflation to its expected value in a fixed point arising through interactions between central bank (CB) expected inflation and expectations of different agents. Finally, we estimate SVARs with variables derived from the above exercises. We first estimate how expectations shocks affect macroeconomic aggregates. Second, we identify the shocks affecting expectations of households and professional forecasters (PFs). In addition, we estimate shocks influencing core inflation. Results suggest the expectation channel worked through interactions between PF forecasts and CB projections, with causality from CB projections to core and from core to household expectations. Supply shocks had short-run effects but core inflation dominated in the longer run. Expectations converged. The expectations channel of transmission to inflation was more effective through communication than through the policy rate, since the rate had low and sometimes even perverse effects. The relatively low impact of demand variables on inflation supports the hypothesized AS-AD structure.
A Reliability-Aware Splitting Duty-Cycle Physical Unclonable Function Based on Trade-off Process, Voltage, and Temperature Variations
Authors: Bian Jingchang , Huang Zhengfeng , Ye Peng , Yang Zhao , Liang Huaguo
Published: April 2023

The
physical unclonable function (PUF)
is a hardware security primitive that can be used to prevent malicious attacks aimed at obtaining device information at the hardware level. The
ring oscillator (RO)
PUF has attracted considerable research attention. To improve the reliability of the RO PUF under voltage and temperature changes, the response of the
duty-cycle (DC)
PUF was obtained by comparing the duty cycle of the RO rather than the period. However, this method reduces the effective utilization of process variations, which limits its implementation in mature advanced manufacturing processes. In this study, a
splitting duty-cycle (SDC)
PUF was proposed to balance the effective extraction of process variations and robustness under voltage and temperature changes. The sensibility formula between the performance of SDC PUF and process, voltage, and temperature was established through a circuit model and statistical methodology, and the comprehensive characteristics of SDC PUF were analyzed theoretically. Next, 16 SDC PUFs with 128-bit responses were implemented and measured on a Xilinx Virtex-7 device. The experimental results revealed that the average native reliability of SDC PUF was 98.97%, and the reliability was 97.32% under various voltage and temperature conditions. This result revealed advantages over the DC PUF implemented in the same device. The uniqueness of the SDC PUF was 50.42%, and it passed the NIST SP 800-22 randomness and autocorrelation function tests.
HMT: A Hardware-centric Hybrid Bonsai Merkle Tree Algorithm for High-performance Authentication
Authors: Shadab Rakin Muhammad , Zou Yu , Gandham Sanjay , Awad Amro , Lin Mingjie
Published: April 2023

The Bonsai Merkle tree (BMT) is a widely used tree structure for authentication of metadata such as encryption counters in a secure computing system. Common BMT algorithms were designed for traditional Von Neumann architectures with a software-centric implementation in mind and as such, they are predominantly recursive and sequential in nature. However, the modern heterogeneous computing platforms employing Field-Programmable Gate Array (FPGA) devices require concurrency-focused algorithms to fully utilize the versatility and parallel nature of such systems. The recursive nature of traditional BMT algorithms makes them challenging to implement in such hardware-based setups.

Our goal for this work is to introduce HMT, a hardware-friendly BMT algorithm that enables the verification and update processes to function independently and provides the benefits of relaxed update while being comparable to the eager update in terms of update complexity. The methodology of HMT contributes both novel algorithmic revisions and innovative hardware techniques to implementing BMT. We mathematically demonstrate the challenges of potentially unbounded recursions in relaxed BMT updates. To solve this problem, we use a partitioned BMT caching scheme that allocates a separate write-back cache for each BMT level—thus allowing for low and fixed upper bounds for dirty evictions compared to the traditional BMT caches. Then we introduce the aforementioned hybrid BMT algorithm that is hardware-targeted, parallel, and relaxes the update depending on BMT cache hit but makes the update conditions more flexible compared to lazy update to save additional write-backs.

Deploying this new algorithm, we have designed a new BMT controller with a dataflow architecture including speculative buffers and parallel write-back engines to facilitate performance-enhancing mechanisms (like multiple concurrent authentication and independent updates) that were not possible with the conventional lazy algorithm. Our empirical performance measurements on a Xilinx U200 accelerator FPGA have demonstrated that HMT can achieve up to 7× improvement in bandwidth and 4.5× reduction in latency over lazy-update BMT baseline and up to 14% faster execution in standard benchmarks compared to a state-of-the-art, eager-update BMT solution.
Hybrid Cathodic/Anodic Electrosynthesis of Phase Pure Ag4V2O7 Thin Films
Authors: Vali Abbas , Kim Soo Yeon , Danladi Fahad , Rawat Abhishek , Zhang Chuzhong , Toth Peter S. , Janáky Csaba , Myung Noseung , Meletis Efstathios I. , Rajeshwar Krishnan
Published: April 2023

Here, we demonstrate a two-step electrosynthesis approach for the preparation of silver pyrovanadate, Ag4V2O7 in thin-film form. In the first, cathodic step, polycrystalline Ag was deposited on fluorine doped tin oxide (FTO) substrate from a non-aqueous bath. Aqueous pyrovanadate species were then generated by aging of a CO2-infused sodium orthovanadate (Na3VO4) solution for three weeks. Silver ions were subsequently generated in situ in this medium using anodic stripping of the Ag/ITO films from the first step. Interfacial precipitation of the Ag+ ions with the pyrovanadate species afforded the targeted product in phase pure form. The various stages of the electrosynthesis were monitored in situ via the combined use of voltammetry, electrochemical quartz crystal nanogravimetry (EQCN), and coulometry. The Ag4V2O7 thin films were characterized by a variety of experimental techniques, including X-ray diffraction, laser Raman spectroscopy, diffuse reflectance spectroscopy, scanning electron microscopy, and high-resolution transmission electron microscopy. Surface photovoltage spectroscopy, ambient-pressure photoemission spectroscopy, and Kelvin probe contact potential difference (work function) measurements afforded information on the energy band structure of the p-type Ag4V2O7 semiconductor. Finally, the electrochemical and photoelectrochemical properties of the electrosynthesized Ag4V2O7 thin films were studied in both aqueous and non-aqueous electrolytes.
Female C57BL/6N mice are a viable model of aortic aging in women
Authors: Longtine Abigail G. , Venkatasubramanian Ravinandan , Zigler Melanie C. , Lindquist Alexandra J. , Mahoney Sophia A. , Greenberg Nathan T. , VanDongen Nicholas S. , Ludwig Katelyn R. , Moreau Kerrie L. , Seals Douglas R. , Clayton Zachary S.
Published: April 2023

Our study demonstrates that with aging, female C57BL/6N mice exhibit higher in vivo aortic stiffness, reduced modulus of elasticity, aortic wall structural and extracellular matrix remodeling, and elevations in systemic inflammation. These changes are largely reflective of those that occur with aging in women. Thus, female C57BL/6N mice are a viable model of human aortic aging and the utility of these animals should be considered in future biomedical investigations.
Qualitative Study on Solutions of Piecewise Nonlocal Implicit Fractional Differential Equations
Authors: Abdo Mohammed S. , Idris Sahar Ahmed , Albalawi Wedad , Abdel-Aty Abdel-Haleem , Zakarya Mohammed , Mahmoud Emad E.
Published: April 2023

In this paper, we investigate new types of nonlocal implicit problems involving piecewise Caputo fractional operators. The existence and uniqueness results are proved by using some fixed point theorems. Furthermore, we present analogous results involving piecewise Caputo-Fabrizio and Atangana–Baleanu fractional operators. The ensuring of the existence of solutions is shown by Ulam-Hyer’s stability. At last, two examples are given to show and approve our outcomes.
Evaluating Bicycling Environments with Trajectory Data on Shared Bikes: A Case Study of Beijing
Authors: Hu Ying , Shao Chunfu , Wang Shuling , Sun Hairui , Sun Pengfei , Chu Zhongfu
Published: April 2023

A detailed evaluation of the riding environment can help the government master the urban riding environment, identify problematic road sections, and improve riding quality. However, the current evaluation of riding environment is mainly subjective, lacking big data (e.g., shared bicycle trajectory data) as a data-driven objective evaluation system. The emergence of shared bicycle data has provided data support for data-driven riding environment evaluation, but there are few studies using shared bicycle data for riding evaluation at present. First, according to the characteristics of the data and the riding environment, a boxplot method and Bayesian probabilistic network model are used to exclude abnormal data and to match trajectories to road sections. Second, this paper proposes a data-driven evaluation framework based on riding influencing factors. An evaluation framework, which is composed of node-, link-, and block-level evaluation indicators, was constructed, using an evaluation model combining TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) and KNN (K-Nearest Neighbors). The evaluation results can identify parking issues, intersection difficulties, and lane occupancy issues on bicycle sections, and visually reflect the riding environment. The significance of this article is to create an objective evaluation system based on a data-driven technology to accurately identify sections and causes of riding quality problems. The research results can be applied in the future to evaluate the cycling environment around the railway stations for bicycle parking planning and determine the foothold for traffic management.