bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the burden of aortic stenosis by sex in the province of Quebec between 2006 and 2018
Authors: Frieden Philipp , Blais Claudia , Hamel Denis , Gamache Philippe , Pibarot Philippe , Clavel Marie-Annick 
Published: March 2022

ObjectivesTo evaluate the evolution of the burden of aortic stenosis (AS) by sex in the province of Quebec from 2006–2007 to 2018–2019 and compare the percentage of mortality between people who underwent aortic valve intervention and those who did not.MethodsPersons aged ≥20 years were identified from the Quebec Integrated Chronic Disease Surveillance System using International Classification of Diseases and intervention codes in the hospital files.ResultsIn 2018, the crude prevalence and incidence of AS were 0.89% (99% CI 0.89 to 0.90) (n=59 025) and 1.39 per 1000 (1.35 to 1.43) (n=9105), respectively. Age-standardised prevalence and incidence of AS diagnosis increased between 2006 and 2018 from 0.67% (0.66 to 0.68) to 0.75% (0.74 to 0.76) and from 0.91 per 1000 (0.88 to 0.95) to 1.20 per 1000 (1.17 to 1.23), respectively. Among incident AS, the age-standardised percentage of valve interventions increased from 11.7% (10.9 to 12.6) to 14.5% (13.9 to 15.3). This increase was only observed in men. The 30-day mortality was stable among patients with incident AS treated conservatively, from 6.9% (6.5 to 7.4) to 7.3% (6.9 to 7.6), and decreased from 7.6% (6.1 to 9.3) to 3.8% (3.1 to 4.7) among operated patients with incident AS. This decrease was only observed in women. However, from 2010, the age-adjusted mortality among prevalent AS tended to be higher in women.ConclusionsIn the province of Quebec, age-standardised prevalence and incidence of AS diagnosis increased between 2006 and 2018. Among incident AS, there was an increase in valve intervention in men and a decrease in 30-day mortality in women who underwent valve intervention. Overall and age-standardised mortality remained higher in women.
Echo-guided left ventricular assist device speed optimisation for exercise maximisation
Authors: Stapor Maciej , Pilat Adam , Gackowski Andrzej , Misiuda Agnieszka , Gorkiewicz-Kot Izabela , Kaleta Michal , Kleczynski Pawel , Zmudka Krzysztof , Legutko Jacek , Kapelak Boguslaw , Wierzbicki Karol 
Published: March 2022

ObjectiveCurrent generation left ventricular assist devices (LVADs) operate with a fixed rotation speed and no automated speed adjustment function. This study evaluates the concept of physiological pump speed optimisation based on aortic valve opening (AVO) imaging during a cardiopulmonary exercise test (CPET).MethodsThis prospective crossover study (NCT05063006) enrolled patients with implanted third-generation LVADs with hydrodynamic bearing. After resting speed optimisation, patients were randomised to a fixed-modified speed or modified-fixed speed CPET sequence. Fixed speed CPET maintained baseline pump settings. During the modified speed CPET, the LVAD speed was continuously altered to preserve periodic AVO.ResultsWe included 22 patients, the mean age was 58.4±7 years, 4.5% were women and 54.5% had ischaemic cardiomyopathy. Exertional AVO assessment was feasible in all subjects. Maintaining periodic AVO allowed to safely raise the pump speed from 2900 (IQR 2640–3000) to 3440 revolutions per minute (RPM) (IQR 3100–3700; p<0.001). As a result, peak oxygen consumption increased from 11.1±2.4 to 12.8±2.8 mL/kg/min (p<0.001) and maximum workload from 1.1 (IQR 0.9–1.5) to 1.2 W/kg (IQR 0.9–1.7; p=0.028). The Borg scale exertion level decreased from 15.2±1.5 to 13.5±1.2 (p=0.005).ConclusionsTransthoracic AVO imaging is possible during CPETs in patients with LVAD. Dynamic echo-guided pump speed adjustment based on the AVO improves exercise tolerance and augments peak oxygen consumption and maximum workload.
Effect of a conditional cash transfer programme on infant up-to-date and timely vaccination
Authors: Souza Evelyn Lima de , Ferreira Vinicius Leati de Rossi , Waldman Eliseu Alves , Sato Ana Paula Sayuri 
Published: March 2022

BackgroundConditional cash transfer (CCT) programmes are one of the strategies to increase vaccination coverage among underprivileged families by conditioning cash transfer to the up-to-date immunisation of children. However, there are gaps in knowledge of its impact on vaccination at the recommended age (timely).MethodsWe performed two cross-sectional analyses of secondary data from a retrospective cohort, at the landmark ages of 12 and 24 months, to assess the effect of the Brazilian CCT on the up-to-date and timely vaccination in children born between 2014 and 2016 and resident in the city of Araraquara, São Paulo (Southeast Brazil). The Propensity Score Matching (PSM) was used to balance two pre-defined groups (beneficiaries and non-beneficiaries) according to the profile of socioeconomic and demographic characteristics.ResultsFrom a total of 7386 children within the cohort, 22.2% (1636) were from beneficiary families of the CCT. After the pairing by PSM, the final sample size included in the analyses was 1440 for each group. We found higher up-to-date vaccination coverage, at 12 (92.1%, 95% CI=90.6% to 93.5%) and 24 months (83.8%, 95% CI=81.8% to 85.7%), among the CCT beneficiaries compared with the non-beneficiaries (85.1%, 95% CI=83.2% to 86.9% at 12 months and 73.6%, 95% CI=71.2% to 75.8% at 24 months). The coverage of timely vaccination did not statistically differ between beneficiaries (41.5%, 95% CI=38.9% to 44.1% and 17.4%, 95% CI=15.4% to 19.4%) and non-beneficiaries (40.7%, 95% CI=38.1% to 43.3% and 17.1%, 95% CI=15.2% to 19.1%) at 12 and 24 months, respectively.ConclusionThe study highlights a positive effect of the CCT on vaccination coverage of the up-to-date infant vaccination schedule. However, there was no difference in timely vaccination.
Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer
Authors: Masuda Tsukasa , Tanaka Nobuyuki , Takamatsu Kimiharu , Hakozaki Kyohei , Takahashi Ryohei , Anno Tadatsugu , Kufukihara Ryohei , Shojo Kazunori , Mikami Shuji , Shinojima Toshiaki , Kakimi Kazuhiro , Tsunoda Tatsuhiko , Aimono Eriko , Nishihara Hiroshi , Mizuno Ryuichi , Oya Mototsugu 
Published: March 2022

BackgroundThe aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.MethodsWe performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.ResultsVarying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.ConclusionThe immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.
Harnessing radiotherapy-induced NK-cell activity by combining DNA damage–response inhibition and immune checkpoint blockade
Authors: Patin Emmanuel C , Dillon Magnus T , Nenclares Pablo , Grove Lorna , Soliman Heba , Leslie Isla , Northcote Davina , Bozhanova Galabina , Crespo-Rodriguez Eva , Baldock Holly , Whittock Harriet , Baker Gabriella , Kyula Joan , Guevara Jeane , Melcher Alan A , Harper James , Ghadially Hormas , Smith Simon , Pedersen Malin , McLaughlin Martin , Harrington Kevin J 
Published: March 2022

BackgroundDespite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.MethodsUsing the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.ResultsATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.ConclusionThis work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage–response inhibitors and immune checkpoint blockade.
Trajectories of mental health among UK university staff and postgraduate students during the pandemic
Authors: Carr Ewan , Oetzmann Carolin , Davis Katrina , Bergin-Cartwright Gabriella , Dorrington Sarah , Lavelle Grace , Leightley Daniel , Polling Catherine , Stevelink Sharon A M , Wickersham Alice , Vitiello Valentina , Razavi Reza , Hotopf Matthew 
Published: March 2022

ObjectivesThe COVID-19 pandemic has disrupted the social and working lives of many. Past studies have highlighted worsening mental health during the pandemic, but often rely on small samples or infrequent follow-up. This study draws on fortnightly assessments from a large occupational cohort to describe differing trajectories of mental health between April 2020 and April 2021 and individual characteristics associated with these trajectory types.MethodsKing’s College London Coronavirus Health and Experiences of Colleagues at King’s is an occupational cohort study at a large university in London, UK. Participants (n=2241) completed online questionnaires fortnightly between April 2020 and April 2021. Symptoms of anxiety and depression were assessed using Generalised Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9).ResultsOn average, participants reported low levels of anxiety and depression (GAD-7 and PHQ-9 scores of 0–9, consistent with ‘none’, ‘minimal’ or ‘mild’ symptoms) throughout the year, with symptoms highest in April 2020 and decreasing over the summer months when no lockdown measures were in place. However, we observed more severe and variable symptoms among subgroups of participants. Four trajectory types for anxiety and depression were identified: ‘persistent high severity’ (6%–7% of participants), ‘varying symptoms, opposing national cases’ (4%–8%), ‘varying symptoms, consistent with national cases’ (6%–11%) and ‘persistent low severity’ (74%–84%). Younger age, female gender, caring responsibilities and shielding were associated with higher severity trajectory types.ConclusionsThese data highlight differing individual responses to the pandemic and underscore the need to consider individual circumstances when assessing and treating mental health. Aggregate trends in anxiety and depression may hide greater variation and symptom severity among subgroups.
Evaluation of a health and social care programme to improve outcomes following critical illness: a multicentre study
Authors: Henderson Philip , Quasim Tara , Shaw Martin , MacTavish Pamela , Devine Helen , Daniel Malcolm , Nicolson Fiona , O’Brien Peter , Weir Ashley , Strachan Laura , Senior Lorraine , Lucie Phil , Bollan Lynn , Duffty Jane , Hogg Lucy , Ross Colette , Sim Malcolm , Sundaram Radha , Iwashyna Theodore J , McPeake Joanne 
Published: March 2022

RationaleAt present, clinicians aiming to support patients through the challenges after critical care have limited evidence to base interventions.ObjectivesEvaluate a multicentre integrated health and social care intervention for critical care survivors. A process evaluation assessed factors influencing the programme implementation.MethodsThis study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme. We compared patients who attended this programme with a usual care cohort from the same time period across nine hospital sites in Scotland. The primary outcome was health-related quality of life (HRQoL) measured via the EuroQol 5-dimension 5-level instrument, at 12 months post hospital discharge. Secondary outcome measures included self-efficacy, depression, anxiety and pain.Results137 patients who received the InS:PIRE intervention completed outcome measures at 12 months. In the usual care cohort, 115 patients completed the measures. The two cohorts had similar baseline demographics. After adjustment, there was a significant absolute increase in HRQoL in the intervention cohort in relation to the usual care cohort (0.12, 95% CI 0.04 to 0.20,p=0.01). Patients in the InS:PIRE cohort also reported self-efficacy scores that were 7.7% higher (2.32 points higher, 95% CI 0.32 to 4.31,p=0.02), fewer symptoms of depression (OR 0.38, 95% CI 0.19 to 0.76, p=0.01) and similar symptoms of anxiety (OR 0.58, 95% CI 0.30 to 1.13,p=0.11). There was no significant difference in overall pain experience. Key facilitators for implementation were: integration with inpatient care, organisational engagement, flexibility to service inclusion; key barriers were: funding, staff availability and venue availability.ConclusionsThis multicentre evaluation of a health and social care programme designed for survivors of critical illness appears to show benefit at 12 months following hospital discharge.
A Rectal CT Tumor Segmentation Method Based on Improved U-Net
Authors: Dong Haowei , Zhang Haifei , Wu Fang , Qiu Jianlin , Zhang Jian , Wang Haoyu 
Published: March 2022

Automatic and accurate segmentation of tumor area from rectal CT image plays an extremely key role in the treatment and diagnosis of rectal cancer. This paper proposes the MR-U-Net network model. The improvement is that a pair of encoder and decoder is added longitudinally to the U-shaped structure, which is the network structure of the fifth layer, and a residual module is added horizontally to the encoder and decoder of each layer. This model is used to conduct targeted research on the automatic segmentation method of rectal cancer. [H. Gao et al., Rectal tumor segmentation method based on U-Net improved model, J. Comput. Appl.40(8) (2020) 2392–2397] also improved U-Net and used the same dataset as this paper, but the Dice coefficient of all targets was only 83.15%, and the Dice coefficient of small targets was only 87.17%. This paper evaluates the improved MR-U-Net network model with the three indicators of precision, recall and Dice coefficient, and finds that in comparison to Ref. 4 the precision is 95.13%, 2.29% higher than the former work, recall is 94.28%, higher than the former work by 0.34%, Dice coefficient of all targets is 88.45%, increased by 5.3% compared with the former work, and the small targets Dice coefficient is increased by 1.28%, which is the best optimization state of this paper. Experiments show that for datasets with extremely skewed positive and negative samples, the MR-U-Net network structure after improving the hyperparameters in the optimizer can more accurately segment the rectal CT tumor lesion area.
Alternative ideas in cosmology
Authors: López-Corredoira Martín , Marmet Louis 
Published: March 2022

Some remarkable examples of alternative cosmological theories are reviewed here, ranging from a compilation of variations on the Standard Model through the more distant quasi-steady-state cosmology, plasma cosmology, or universe models as a hypersphere, to the most exotic cases including static models.The present-day Standard Model of cosmology, [Formula: see text]CDM, gives us a representation of a cosmos whose dynamics is dominated by gravity (Friedmann equations derived from general relativity) with a finite lifetime, large scale homogeneity, expansion and a hot initial state, together with other elements necessary to avoid certain inconsistencies with observations (inflation, nonbaryonic dark matter, dark energy, etc.). There are however some models with characteristics that are close to those of the Standard Model but differing in some minor aspects; we call these “variations on the Standard Model”. Many of these models are indeed investigated by some mainstream cosmologists: different considerations on CP violation, inflation, number of neutrino species, quark-hadron phase transition, baryonic or nonbaryonic dark-matter, dark energy, nucleosynthesis scenarios, large-scale structure formation scenarios; or major variations like a inhomogeneous universe, Cold Big Bang, varying physical constants or gravity law, zero-active mass (also called “[Formula: see text]”), Milne, and cyclical models.At the most extreme distance from the Standard Model, the static models, a noncosmological redshift includes “tired-light” hypotheses, which assume that the photon loses energy owing to an intrinsic property or an interaction with matter or light as it travels some distance, or other nonstandard ideas. Our impression is that none of the alternative models has acquired the same level of development as [Formula: see text]CDM in offering explanations of available cosmological observations. One should not, however, judge any theory in terms of the number of observations that it can successfully explain (ad hoc in many cases) given the much lower level of development of the alternative ones, but by the plausibility of its principles and its potential to fit data with future improvements of the theories. A pluralist approach to cosmology is a reasonable option when the preferred theory is still under discussion.
Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD–Driven AML
Authors: Pfeiffer Anamarija , Franciosa Giulia , Locard-Paulet Marie , Piga Ilaria , Reckzeh Kristian , Vemulapalli Vidyasiri , Blacklow Stephen C. , Theilgaard-Mönch Kim , Jensen Lars J. , Olsen Jesper V. 
Published: March 2022

Abstract

The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases. SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its autoinhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RAS/ERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD (internal tandem duplication)-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry–based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-cell acute lymphoblastic leukemia cell line and in the inv(16)/KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications.

Significance:
These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD–positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.
Phase II Study of Ramucirumab in Advanced Biliary Tract Cancer Previously Treated By Gemcitabine-Based Chemotherapy
Authors: Lee Sunyoung , Shroff Rachna T. , Makawita Shalini , Xiao Lianchun , Danner De Armas Anaemy , Bhosale Priya , Reddy Kavitha , Shalaby Ahmed , Raghav Kanwal , Pant Shubham , Wolff Robert A. , Javle Milind 
Published: March 2022

Abstract

Purpose:
VEGF receptor-2 (VEGFR-2)–mediated angiogenesis contributes to pathogenesis of biliary tract cancers (BTC). We investigated ramucirumab, a mAb targeting VEGFR-2 for treatment of advanced, chemorefractory BTC.

Patients and Methods:
This is a phase II, single-arm trial for advanced, unresectable, pre-treated patients with BTC with ECOG 0/1, adequate liver, renal, and marrow functions. Ramucirumab was administered at 8 mg/kg, 2 weekly with restaging performed 8 weekly. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Exploratory endpoints included correlation of tumor mutational status with PFS and OS.

Results:
61 patients were enrolled: the median age was 58.5 years; 59 with stage IV disease; 62%, intrahepatic cholangiocarcinoma; 22%, gallbladder cancer; and 16%, extrahepatic cholangiocarcinoma. All received prior chemotherapy: 52% had 1 prior, and rest ≥2 prior lines. Median treatment duration was 10.1 weeks (range, 2.1–86). Median PFS was 3.2 months [95% confidence interval (CI), 2.1–4.8]; median OS, 9.5 months (95% CI, 5.8–13.6). One (1.7%) patient achieved partial response; 26 (43.3%), stable disease; and 25 (41.7%), disease progression; DCR, 45%. Median 6-month PFS and OS rates were 32% (95% CI, 0.22–0.46) and 58% (95% CI, 0.47–0.72). The majority of toxicities were grade 1 or 2; grade 3 proteinuria (1, 2%), hypertension (13, 22%), and pulmonary embolism (1, 2%), and grade 4 gastrointestinal bleeding (1, 2%) occurred.

Conclusions:
Ramucirumab was well tolerated and resulted in PFS similar to that achieved with other chemotherapy regimens used historically for chemorefractory BTC.