bluuebunny/crossref_metadata_2025_split huggingface dataset:
An observational study of patient experiences with a direct-to-patient telehealth abortion model in Australia
Authors: Thompson Terri-ann , Seymour Jane W , Melville Catriona , Khan Zara , Mazza Danielle , Grossman Daniel 
Published: September 2021

BackgroundWhile abortion care is widely legal in Australia, access to care is often poor. Many Australians must travel long distances or interstate to access abortion care, while others face stigma when seeking care. Telehealth-at-home medical abortion is a potential solution to these challenges. In this study, we compared the experience of accessing an abortion via telehealth-at-home to accessing care in-clinic.MethodsOver a 20-month period, we surveyed patients who received medical abortion services at Marie Stopes Australia via the telehealth-at-home service or in-clinic. We conducted bivariate analyses to assess differences in reported acceptability and accessibility by delivery model.ResultsIn total, 389 patients were included in the study: 216 who received medical abortion services in-clinic and 173 through the telehealth-at-home service. Telehealth-at-home and in-clinic patients reported similarly high levels of acceptability: satisfaction with the service (82% vs 82%), provider interaction (93% vs 84%), and recommending the service to a friend (73% vs 72%). Only 1% of telehealth-at-home patients reported that they would have preferred to be in the same room as the provider. While median time between discovering the pregnancy to first contact with a clinic was similar between groups, median time from first contact to taking the first abortion medication was 7 days longer for telehealth-at-home patients versus in-clinic patients (14 days (IQR 9–21) vs 7 days (IQR 4–14); p<0.01).ConclusionThe telehealth-at-home medical abortion service has the potential to address some of the challenges with provision of abortion care in Australia.
Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
Authors: Anfray Clément , Mainini Francesco , Digifico Elisabeth , Maeda Akihiro , Sironi Marina , Erreni Marco , Anselmo Achille , Ummarino Aldo , Gandoy Sara , Expósito Francisco , Redrado Miriam , Serrano Diego , Calvo Alfonso , Martens Marvin , Bravo Susana , Mantovani Alberto , Allavena Paola , Andón Fernando Torres 
Published: September 2021

BackgroundTumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments.MethodsTLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein–protein interaction analysis.ResultsResults demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4+ and CD8+ T cells, accompanied by a reduction of immunosuppressive CD206+ TAMs and FOXP3+/CD4+ T cells. The depletion of both CD4+ and CD8+ T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein–protein-interaction network analysis reveal the key activation of the STAT1 pathway.DiscussionThese findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
Simple and effective bacterial-based intratumoral cancer immunotherapy
Authors: Carroll Christina S E , Andrew Erin R , Malik Laeeq , Elliott Kathryn F , Brennan Moira , Meyer James , Hintze Alexander , Almonte Andrew A , Lappin Cassandra , MacPherson Philip , Schulte Klaus-Martin , Dahlstrom Jane E , Tamhane Rohit , Neeman Teresa , Herbert Elizabeth W , Orange Maurice , Yip Desmond , Allavena Rachel , Fahrer Aude M 
Published: September 2021

BackgroundWe describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.MethodsEfficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.ResultsSignificantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.ConclusionOur data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.
Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes
Authors: Nishida Mikako , Yamashita Nahoko , Ogawa Taisaku , Koseki Keita , Warabi Eiji , Ohue Tomoyuki , Komatsu Masaaki , Matsushita Hirokazu , Kakimi Kazuhiro , Kawakami Eiryo , Shiroguchi Katsuyuki , Udono Heiichiro 
Published: September 2021

BackgroundMetformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.MethodsMitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.ResultsMet administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.ConclusionsWe found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.
Effect of moderate potassium-elevating treatment in long QT syndrome: the TriQarr Potassium Study
Authors: Marstrand Peter , Almatlouh Kasim , Kanters Jørgen K , Graff Claus , Christensen Alex Hørby , Bundgaard Henning , Theilade Juliane 
Published: September 2021

BackgroundIn long QT syndrome (LQTS), beta blockers prevent arrhythmias. As a supplement, means to increase potassium has been suggested. We set to investigate the effect of moderate potassium elevation on cardiac repolarisation.MethodsPatients with LQTS with a disease-causingKCNQ1orKCNH2variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone (low dose) or (2) 100 mg spironolactone and 3 g potassium chloride per day (high dose+). Electrocardiographic measures were obtained at baseline and after 7 days of treatment.ResultsTwenty patients were enrolled (10 low dose and 10 high dose+). One patient was excluded due to severe influenza-like symptoms, and 5 of 19 patients completing the study had mild side effects. Plasma potassium in low dose did not increase in response to treatment (4.26±0.22 to 4.05±0.19 mmol/L, p=0.07). Also, no change was observed in resting QTcF (QT interval corrected using Fridericia's formula) before versus after treatment (478±7 vs 479±7 ms, p=0.9). In high dose+, potassium increased significantly from 4.08±0.29 to 4.48±0.54 mmol/L (p=0.001). However, no difference in QTcF was observed comparing before (472±8 ms) versus after (469±8 ms) (p=0.66) high dose+treatment. No patients developed hyperkalaemia.ConclusionIn patients with LQTS, high dose+treatment increased plasma potassium by 0.4 mmol/L without cases of hyperkalaemia. However, the potassium increase did not shorten the QT interval and several patients had side effects. Considering the QT interval as a proxy for arrhythmic risk, our data do not support that potassium-elevating treatment has a role as antiarrhythmic prophylaxis in patients with LQTS with normal-range potassium levels.Trial registration numberNCT03291145.
Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison
Authors: Brunner Hermine I , Abud-Mendoza Carlos , Mori Masaaki , Pilkington Clarissa A , Syed Reema , Takei Syuji , Viola Diego O , Furie Richard A , Navarra Sandra , Zhang Fengchun , Bass Damon L , Eriksson Gina , Hammer Anne E , Ji Beulah N , Okily Mohamed , Roth David A , Quasny Holly , Ruperto Nicolino 
Published: September 2021

ObjectiveTo assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).MethodsWe performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III).ResultsSRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies.ConclusionsThese analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE.Trial registration numbersPLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).
DFT modeling of polyaniline: a computational investigation into the structure and band gap of polyaniline
Authors: Scotland Kevin M. , Strong Oliver K.L. , Parnis J. Mark , Vreugdenhil Andrew J. 
Published: September 2021

The band gaps of three forms of polyaniline (PANI) are calculated using the DFT method with the B3LYP functional and SV(P) basis set. This marks the first time that the band gap for this polymer has been calculated using this DFT method. The calculations include an investigation of the effect of varying the benzoid–quinoid structural units, the effect of increasing oligomer length, and the inclusion of Michael’s addition structures, which could be residual in the polymer depending on the chosen synthetic method. All results were compared with the experimentally determined band gap of 1.5 eV as typically reported in the literature. A commonly used structural motif of alternating benzoid–quinoid units and a ratio of 0.5:0.5 benzoid–quinoid resulted in a computed band gap of 1.9 eV. Inclusion of one extra quinoid unit gave rise to a band gap of 1.3 eV. Incorporation of a Michael’s addition structure was found to dominate the band gap calculation, yielding a localized LUMO and a band gap of 1.3 eV that was insensitive to the polymer chain length and composition.
Simulated winter warming has negligible effects on germination success of Acadian Forest tree species
Authors: Vaughn William R. , Taylor Anthony R. , MacLean David A. , D’Orangeville Loïc 
Published: September 2021

Dormant seeds that require long periods of cold stratification to become germinable may be most sensitive to increases in winter temperatures caused by anthropogenic climate change. In this study, we used outdoor plots with infrared heaters to simulate the effects of projected winter warming (+6 °C) for Canada’s Acadian Forest Region and compared seed germination success of tree species with varying stratification requirements. We evaluated four seedlots each of balsam fir (Abies balsamea (L.) Mill.), red spruce (Picea rubens Sarg.), white pine (Pinus strobus L.), red maple (Acer rubrum L.), sugar maple (Acer saccharum Marshall), and yellow birch (Betula alleghaniensis Britton). Three central findings emerged from this study: (i) none of the tested species were significantly affected by warming; (ii) the random effect of seedlot explained more variation in germination success of deciduous species than it did for conifers; and (iii) balsam fir seedlots exhibited considerable differences in their response to warming, implying intraspecific variation in depth of dormancy. These results suggest seed germination success of the tested tree species may not be impeded by their individual seed characteristics under the magnitude of winter warming projected over the coming century in our study area.
Prompt production of the hidden charm pentaquarks in the LHC
Authors: Ling Pan , Dai Xiao-Hu , Du Meng-Lin , Wang Qian 
Published: September 2021

AbstractMotivated by the observation of the first hidden charm pentaquarks by the LHCb collaboration in 2015 and the updated analysis with an order-of-magnitude larger data set in 2019, we estimate their cross sections for the prompt production as well as their heavy quark spin partners, in the $$\Sigma _c^{(*)}\bar{D}^{(*)}$$

Σ
c

(

∗
)

D

¯

(

∗
)

hadronic molecular picture, at the center-of-mass energy $$7~\text {TeV}$$

7

TeV

in the pp collision. Their cross sections are several $${\mathrm {nb}}$$
nb
and we would expect several tens hidden charm pentaquark events in the LHC based on its current integrated luminosity. The cross sections show a sizable deviation of the cross sections for hidden charm pentaquarks with the third isospin component $$I_z=+\frac{1}{2}$$

I
z

=
+

1
2

($$P_c^+$$

P
c
+

) from those with $$I_z=-\frac{1}{2}$$

I
z

=
-

1
2

($$P_c^0$$

P
c
0

). The cross sections decrease dramatically with the increasing transverse momentum. Our study can also tell where to search for the missing hidden charm pentaquarks. The confirmation of the complete hidden charm pentaquarks in the heavy quark symmetry would further verify their $$\Sigma _c^{(*)}\bar{D}^{(*)}$$

Σ
c

(

∗
)

D

¯

(

∗
)

molecular interpretation. In addition, the relative strength among these cross sections for pentaquarks can help us to identify the quantum numbers of the $$P_c(4440)$$

P
c

(
4440
)

and $$P_c(4457)$$

P
c

(
4457
)

.
On the 3-Extra Connectivity of Enhanced Hypercubes
Authors: Zhai Liyang , Xu Liqiong , Yin Shanshan 
Published: September 2021

Reliability evaluation of interconnection networks is of significant importance to the design and maintenance of interconnection networks. The extra connectivity is an important parameter for the reliability evaluation of interconnection networks. Given a graph [Formula: see text] and a positive integer [Formula: see text], the [Formula: see text]-extra connectivity, denoted by [Formula: see text], is the minimum cardinality of a set of vertices in [Formula: see text], if exists, whose deletion disconnects [Formula: see text] and leaves each remaining component with at least [Formula: see text] vertices. In this paper, we show that the 3-extra connectivity of the [Formula: see text]-enhanced hypercube is [Formula: see text] for [Formula: see text] and [Formula: see text]. Some previous results in [IEEE Trans. Comput. 63 (2014) 1594–1600] and [Theor. Comput. Sci. 799 (2019) 22–31] are extended.
Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project
Authors: Kim Helen , Flemming Kelly D. , Nelson Jeffrey A. , Lui Avery , Majersik Jennifer J. , Cruz Michael Dela , Zabramski Joseph , Trevizo Odilette , Lanzino Giuseppe , Zafar Atif , Torbey Michel , Mabray Marc C. , Robinson Myranda , Narvid Jared , Lupo Janine , Thompson Richard E. , Hanley Daniel F. , McBee Nichol , Treine Kevin , Ostapkovich Noeleen , Stadnik Agnieszka , Piedad Kristina , Hobson Nicholas , Carroll Timothy , Shkoukani Abdallah , Carrión-Penagos Julián , Mendoza-Puccini Carolina , Koenig James I. , Awad Issam 
Published: September 2021

Background and Purpose:
Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH.

Methods:

This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample
t
test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion.

Results:

As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (
P
=0.007), but better depression (
P
=0.002) and social satisfaction scores (
P
=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites.

Conclusions:
These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.