bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the implementation of single points of access for unattached patients in primary care and their effects: a study protocol
Authors: Breton Mylaine , Lamoureux-Lamarche Catherine , Deslauriers Véronique , Laberge Maude , Arsenault Josée , Gaboury Isabelle , Beauséjour Marie , Pomey Marie-Pascale , Motulsky Aude , Talbot Annie , St-Yves Annie , Smithman Mélanie Ann , Deville-Stoetzel Nadia , Sauvé Carine , Abou Malham Sabina 
Published: March 2023

IntroductionAttachment to a primary care provider is an important component of primary care as it facilitates access. In Québec, Canada, attachment to a family physician is a concern. To address unattached patients’ barriers to accessing primary care, the Ministry of Health and Social Services mandated Québec’s 18 administrative regions to implement single points of access for unattached patients (Guichets d’accès première ligne(GAPs)) that aim to better orient patients towards the most appropriate services to meet their needs. The objectives of this study are to (1) analyse the implementation of GAPs, (2) measure the effects of GAPs on performance indicators and (3) assess unattached patients’ experiences of navigation, access and service utilisation.Methods and analysisA longitudinal mixed-methods case study design will be conducted. Objective 1. Implementation will be analysed through semistructured interviews with key stakeholders, observations of key meetings and document analysis. Objective 2. GAP effects on indicators will be measured using performance dashboards produced using clinical and administrative data. Objective 3. Unattached patients’ experiences will be assessed using a self-administered electronic questionnaire. Findings for each case will be interpreted and presented using a joint display, a visual tool for integrating qualitative and quantitative data. Intercase analyses will be conducted highlighting the similarities and differences across cases.Ethics and disseminationThis study is funded by the Canadian Institutes of Health Research (# 475314) and the Fonds de Soutien à l’innovation en santé et en services sociaux (# 5-2-01) and was approved by the CISSS de la Montérégie-Centre Ethics Committee (MP-04-2023-716).
Fidelity and tolerability of two high-intensity interval training protocols in patients with COPD: a randomised cross-over pilot study
Authors: Nymand Stine Buus , Hartmann Jacob , Rasmussen Iben Elmerdahl , Iepsen Ulrik Winning , Ried-Larsen Mathias , Christensen Regitse Højgaard , Berg Ronan Martin Griffin 
Published: March 2023

ObjectivesHigh-intensity interval training (HIIT) during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) may alleviate the symptom burden, but the fidelity and tolerability of HIIT using long or short intervals in patients with COPD are unknown.MethodsTwelve patients with moderate-to-severe COPD were included in a randomised cross-over pilot study. They completed two supervised HIIT protocols (4×4 and 10×1). To compare the two HIIT protocols, completed training amount, exercise intensity and perceived tolerability (assessed by a 10-point Likert scale) were integrated in a red–amber–green rating system. If a training session received a red ranking, it was considered unacceptable, if it received an amber ranking it was applicable with precautions, and if it received a green ranking it was considered feasible.ResultsAll patients completed the total training amount in both protocols. The 4×4 protocol resulted in three amber training sessions due to low perceived tolerability. The 10×1 protocol resulted in two red training sessions due to intensity reductions, and two amber training sessions because of low perceived tolerability. There was no statistical difference in perceived tolerability or time spent with an HR ≥85% of HRmax.ConclusionsHIIT using longer intervals (4×4) at a relatively lower intensity resulted in higher fidelity expressed by fewer adjustments to the protocol, whereas there was no difference between protocols in perceived tolerance. The 4×4 protocol seems to have a higher fidelity compared with the 10×1 protocol in patients with moderate-to-severe COPD.Trial registration numberNCT05273684.
Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression
Authors: Bruni Sofia , Mauro Florencia L , Proietti Cecilia J , Cordo-Russo Rosalia I , Rivas Martin A , Inurrigarro Gloria , Dupont Agustina , Rocha Dario , Fernández Elmer A , Deza Ernesto Gil , Lopez Della Vecchia Daniel , Barchuk Sabrina , Figurelli Silvina , Lasso David , Friedrich Adrián D , Santilli María C , Regge María V , Lebersztein Gabriel , Levit Claudio , Anfuso Fabiana , Castiglione Teresa , Elizalde Patricia V , Mercogliano Maria F , Schillaci Roxana 
Published: March 2023

BackgroundThe success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion.MethodsWe used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes.ResultsIn mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors.ConclusionsThese findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
Systemic inflammation shapes clinical outcomes in response to immune checkpoint blockade treatment: moving toward optimizing antitumor immunity
Authors: Zheng Ming 
Published: March 2023

BackgroundImmune checkpoint blockade (ICB) treatment may induce durable disease remission, but only in a minority of patients with cancer. One important question is how to identify patients who may benefit from ICB treatment. ICB treatment relies on unleashing patients’ pre-existing immune responses. Focusing on the key components of immune response, this study proposes the neutrophil-to-lymphocyte ratio (NLR) as a simplified indicator of patients’ immune status to predict ICB treatment outcomes.MethodsThis study analyzed a large pan-cancer cohort of 16 cancer types, including 1714 patients with cancer who received ICB treatment. Clinical outcomes in response to ICB treatment were measured by overall survival (OS), progression-free survival (PFS), objective response rate, and clinical benefit rate. The non-linear relationships of NLR with OS and PFS were investigated by a spline-based multivariate Cox regression model. A total of 1000 randomly resampled cohorts were bootstrapped to estimate the variability and reproducibility of NLR-related ICB responses.ResultsBy interrogating a clinically representative cohort, this study revealed a previously unreported finding that the pretreatment NLR levels were associated with ICB treatment outcomes in a U-shaped dose-dependent manner rather than a linear manner. An NLR range between 2.0 and 3.0 was remarkably associated with optimal ICB treatment outcomes, including increased patient survival, delayed disease progression, improved treatment response, and significant clinical benefit. Comparatively, either decreasing (< 2.0) or increasing (>3.0) NLR levels were indicators of worse ICB treatment outcomes. Furthermore, this study presents a comprehensive landscape of NLR-related ICB treatment outcomes across different patient populations defined by demographics, baseline characteristics, treatment, cancer-type-specific ICB responsiveness, and individual cancer type.ConclusionsThe NLR range from 2.0 to 3.0 might indicate an optimal balance between innate (neutrophils) and adaptive (lymphocytes) immune responses that potentiates antitumor immunity, which was observed in only 18.6% of patients. A majority of patients showed decreasing NLR (<2.00; 10.9% patients) or increasing NLR (>3.00; 70.5% patients), representing two distinct types of immune dysregulation associated with ICB resistance. This study translates routine blood tests into a precision medicine-based approach to immunotherapy, with important implications for clinicians in clinical decision-making as well as for regulatory agencies in drug approvals.
Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease
Authors: Leon Leticia , Madrid-Garcia Alfredo , Lopez-Viejo Patricia , González-Álvaro Isidoro , Novella-Navarro Marta , Freites Nuñez Dalifer , Rosales Zulema , Fernandez-Gutierrez Benjamin , Abasolo Lydia 
Published: March 2023

ObjectivesMost studies on difficult-to-treat rheumatoid arthritis (D2T RA) have focused on established RA. Here, we analyse whether disease activity in the early stages of RA could influence progression to a D2T RA under real-life conditions. Other clinical and treatment-related factors were also analysed.MethodsA longitudinal multicentre study of patients with RA was conducted from 2009 to 2018. Patients were followed up until January 2021. D2T RA was defined based on EULAR criteria (treatment failure, signs suggestive of currently active/progressive disease and management being perceived as problematic by the rheumatologist and/or patient). The main variable was disease activity in the early stages. The covariates were sociodemographic, clinical and treatment-related factors. We ran a multivariable logistic regression analysis to investigate risk factors associated with progression to D2T RA.ResultsThe study population comprised 631 patients and 35 (5.87%) developed D2T RA. At the time of diagnosis, the D2T RA group were younger, with a higher disability, 28-joint Disease Activity Score (DAS28) score, tender joint count and pain scores. In our final model, DAS28 was not statistically significantly associated with D2T RA. No differences were found between groups for therapy. Disability was independently associated with D2T RA (OR: 1.89; p=0.01).ConclusionsIn this cohort of patients newly diagnosed with RA, our results do not allow us to prove the influence of active disease according to DAS28. However, we did find that younger patients and those with elevated initial disability scores are more likely to develop D2T RA regardless of other factors.
Mg-doped LaAlO3 structure: a theoretical investigation of indirect to direct bandgap and brittle to ductile transition
Authors: Zahoor Aliza , Mahmood Tariq , Khan Muhammad Isa 
Published: March 2023

Integrating chemical dopants into a pure lattice has fueled a novel concept of tuning the physical and chemical properties of existing materials under and beyond ambient conditions. By using density functional theory (DFT) calculations, we report the structural, electronic, elastic, and optical properties of pure and Mg-doped LaAlO3 structure (La1- xMgxAlO3 and LaAl1- xMgxO3), respectively, with the doping concentrations of x = 0%, 20%, 40%, 60%, 80%, and 100%. Our results show that the doping of Mg along La sites introduce new band (s, p) in the valence bands that is moved towards the conduction bands with increase of doping ration (at x = 60% with a reduced bandgap of 0.04 eV), as well as indirect to direct bandgap transition along Al sites. The density of states shows that the valence band shifts towards the Fermi level by inducing a metallicity in La1-xMgxAlO3 format at 60% configuration. Elastically, LaAlO3 experiences brittle to ductile transition for both doping systems except LaAl1-xMgxO3 at 40% configuration. The higher ranges of optical peaks for both systems are identified for 0%‒40% ranges as compared to other configurations. Fortunately, this study reveals the tunability of LaAlO3 structure in structural, electronic, elastic, and optical aspects, and also extends the availability of this material for future optoelectronic and mechanical applications.
Thermal management of storage unit reporting unsteady physical behavior of NEPCM
Authors: Melaibari Ammar A. , Abu-Hamdeh Nidal H. , Daqrouq Khaled O. , Alkhateeb Abulhameed F. , Nusier Osama K. , Saad Hosam A. , Musa Awad 
Published: March 2023

Researchers always like to find way for improving the performance of system integrated with PCM. In this paper, the container was combined with fins and PCM was mixed with nanoparticles to obtain quicker discharging process. Two significant variables related to second technique are fraction of additives ([Formula: see text] and their shapes ([Formula: see text]. To involve these factors in equations, single phase formulation was applied. Low magnitude of velocity of liquid material in freezing leads to simplification of equations of this transient procedure. Galerkin method which was applied for this modeling has good accommodation with previous publication. As [Formula: see text] soars, the solidification time declines from 4802.97s to 4244.61s and 3738.37s when blade shape particles were applied. This means that adding additive can enhance the rate of process about 22.16%. Moreover, augmenting the shape factor to higher level causes time to drop about 5.7%.
ThermalProGAN: A sequence-based thermally stable protein generator trained using unpaired data
Authors: Huang Hui-Ling , Weng Chong-Heng , Nordling Torbjörn E. M. , Liou Yi-Fan 
Published: March 2023

Motivation: The synthesis of proteins with novel desired properties is challenging but sought after by the industry and academia. The dominating approach is based on trial-and-error inducing point mutations, assisted by structural information or predictive models built with paired data that are difficult to collect. This study proposes a sequence-based unpaired-sample of novel protein inventor (SUNI) to build ThermalProGAN for generating thermally stable proteins based on sequence information. Results: The ThermalProGAN can strongly mutate the input sequence with a median number of 32 residues. A known normal protein, 1RG0, was used to generate a thermally stable form by mutating 51 residues. After superimposing the two structures, high similarity is shown, indicating that the basic function would be conserved. Eighty four molecular dynamics simulation results of 1RG0 and the COVID-19 vaccine candidates with a total simulation time of 840[Formula: see text]ns indicate that the thermal stability increased. Conclusion: This proof of concept demonstrated that transfer of a desired protein property from one set of proteins is feasible. Availability and implementation: The source code of ThermalProGAN can be freely accessed at https://github.com/markliou/ThermalProGAN/ with an MIT license. The website is https://thermalprogan.markliou.tw:433 . Supplementary information: Supplementary data are available on Github.
Generalized black hole entropy in two dimensions
Authors: Nojiri Shin’ichi , Odintsov Sergei D. , Faraoni Valerio 
Published: March 2023

The Bekenstein–Hawking entropy of a black hole is proportional to its horizon area, hence in [Formula: see text] spacetime dimensions it is constant because the horizon degenerates into two points. This fact is consistent with Einstein’s gravity becoming topological in two dimensions. In [Formula: see text] gravity, which is non-trivial even in [Formula: see text], we find that the entropy is constant, as for Bekenstein–Hawking. As shown in Europhys. Lett. 139(6) (2022) 69001, arXiv: 2208.10146, two-dimensional [Formula: see text] gravity is equivalent to Jackiw–Teitelboim gravity, in turn, equivalent to the Sachdev–Ye–Kitaev model where the entropy becomes constant in the large [Formula: see text] limit. Several recently proposed entropies are functions of the Bekenstein–Hawking entropy and become constant in [Formula: see text], but in two-dimensional dilaton gravity entropies are not always constant. We study general dilaton gravity and obtain arbitrary static black hole solutions for which the non-constant entropies depend on the mass, horizon radius, or Hawking temperature, and constitute new proposals for a generalized entropy.
Effect of neural mobilisation in Bell’s palsy: A randomised controlled trial
Authors: Alharbi Raed , Kashoo Faizan Zaffar , Ahmed Mehrunnisha , Alqahtani Mazen , Aloyuni Saleh , Alzhrani Msaad , Alanazi Ahmad Dhahawi , Sidiq Mohammad , Alharbi Bander Hamud , Nambi Gopal 
Published: March 2023

Background: Neural mobilisation technique is effective in spinal nerve rehabilitation. However, no study has reported the effect of facial nerve mobilisation in acute Bell’s palsy.Objectives: The objective of our study was to evaluate the effect of facial neural mobilisation over conventional therapy in improving facial symmetry in patients with acute Bell’s palsy.Methods: A randomised controlled trial was conducted in the physical therapy department for 62 patients with acute Bell’s palsy. The intervention included 10 days of drug therapy including 3 weeks of conventional therapy to the experimental and the control group. However, the experimental group received additional nerve mobilisation technique aimed at mobilising the facial nerve at the origin of external auditory meatus. All participants were assessed at baseline and after three weeks using the Sunnybrook facial grading system (SBS) and Kinovea Movement Analysis Software (KMAS).Results: For primary outcome, analysis of covariance with baseline data as covariate showed a significant difference between groups for the post-test mean scores of SBS after 3 weeks (between-group difference, 9.2 [95% CI, 5.1–13.3], [Formula: see text]. Importantly, the effect size calculated by partial [Formula: see text] for neural mobilisation was 0.258 (small effect size). For secondary outcomes, independent sample t-test showed a significant difference between groups for the scores on KMAS after 3 weeks for zygomatic muscle (between-group difference, [Formula: see text] [95% CI, [Formula: see text] to [Formula: see text]], [Formula: see text]), frontalis muscle [Formula: see text] [95% CI, [Formula: see text] to [Formula: see text]], [Formula: see text], and orbicularis oris muscle [Formula: see text] [95% CI, [Formula: see text] to [Formula: see text]], [Formula: see text].Conclusion: Facial neural mobilisation is likely to be an effective adjunctive intervention in addition to conventional therapy in improving facial symmetry in acute Bell’s palsy.
Using Machine Learning to Understand Relocation Drivers of Urban Coastal Populations in Response to Flooding
Authors: Ramos-Valle Alexandra N. , Alland Joshua , Bukvic Anamaria 
Published: March 2023

Abstract
Many urban coastal communities are experiencing more profound flood impacts due to accelerated sea level rise that sometimes exceed their capacity to protect the built environment. In such cases, relocation may serve as a more effective hazard mitigation and adaptation strategy. However, it is unclear how urban residents living in flood-prone locations perceive the possibility of relocation and under what circumstances they would consider moving. Understanding the factors affecting an individual’s willingness to relocate because of coastal flooding is vital for developing accessible and equitable relocation policies. The main objective of this study is to identify the key considerations that would prompt urban coastal residents to consider permanent relocation because of coastal flooding. We leverage survey data collected from urban areas along the East Coast, assessing attitudes toward relocation, and design an artificial neural network (ANN) and a random forest (RF) model to find patterns in the survey data and indicate which considerations impact the decision to consider relocation. We trained the models to predict whether respondents would relocate because of socioeconomic factors, past exposure and experiences with flooding, and their flood-related concerns. Analyses performed on the models highlight the importance of flood-related concerns that accurately predict relocation behavior. Some common factors among the model analyses are concerns with increasing crime, the possibility of experiencing one more flood per year in the future, and more frequent business closures resulting from flooding.
Weakening of the Silk Road Pattern in August after the Mid-1990s
Authors: Wang Xi , Lu Riyu , Hong Xiaowei 
Published: March 2023

Abstract
This study identified that the Silk Road pattern (SRP), which is a teleconnection pattern along the Asian upper-tropospheric westerly jet, becomes significantly weakened in August after the mid-1990s. The SRP in August dominates the upper-tropospheric meridional wind variability over the Eurasian continent before the mid-1990s but does not afterward. Further results suggested that the summer North Atlantic Oscillation (SNAO) and the South Asian rainfall play a role in inducing this decadal weakening of SRP. Before the mid-1990s, the SNAO is stronger and its southern pole is located over northwestern Europe but is weakened and its southern pole shifts southwestward afterward, resulting in the decadal weakening of its contribution to the SRP. In addition, the relationship between the SRP and South Asian rainfall is substantially weakened after the mid-1990s, which also contributes to the weakening of SRP.
Processes of Colliding Cold Pools Derived from a 356-m-High Shenzhen Met-Tower during an Extremely Heavy Rainfall Event
Authors: Mai Chuying , Du Yu , Li Minghua 
Published: March 2023

Abstract
Convectively generated cold pools play a crucial role in the convection initiation and development, but observations of their vertical structure are insufficient. In this study, quantitative vertical evolutions of cold pools during a high-impact heavy rainfall event near the south coast of China were examined using observations from a 356-m-high Shenzhen Met-Tower, and their potential impacts on heavy rainfall were further discussed through high-resolution surface station network and radar observations. On 11 April 2019, heavy precipitation occurred near metropolitan Shenzhen, lasting for 50 min at its southern downtown and resulting in 11 deaths. During this event, a shallow cold pool was first observed by the tower and yielded a long-lasting cooling of 2.6 K. Approximately 1 h later, another deeper cold pool accompanied by a squall line was added from the west. This addition resulted in a more abrupt and intense surface temperature deficit (5.1 K) and stronger gusty winds (23 m s−1). When the two cold pools collided near Shenzhen, the low-level winds converged at their intersection, dynamically enhancing the heavy-rain-producing squall line. Moreover, the collision of the two cold pools reduced the temperature gradient at the northern edge of the merged cold pool, which could inhibit development of the squall line. The area south of the squall line became a relatively favorable environment for convection initiation, given the warm and moist oceanic environment. Consequently, the squall line turned northeast–southwest, forming a training line mode that was nearly parallel to the eastward movement. This training line mode prolonged the precipitation duration in the southern downtown area.