bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical stimulation to promote muscle and motor unit force and endurance after spinal cord injury
Authors: Gordon Tessa , Tyreman Neil 
Published: February 2023

AbstractFatigue is a common feature of paralysed skeletal muscle, hindering performance when subjected to functional electrical stimulation (ES) for movement. We asked whether (1) 20 Hz ES for 5% of each day (2.5 s on and 2.5 s off for 3 h) increases tibialis anterior and medial gastrocnemius muscle and motor unit (MU) endurance after paralysis by hemisection and deafferentation (HSDA), and (2) muscle length or loading affects their isometric contractile properties. The daily 5% ES increased muscle endurance, largely independent of muscle length or loading, but to a lesser extent than the daily 50% ES (2.5 s on and 2.5 s off for 24 h). The former was effective in counteracting the decline and slowing of muscle force promoted by the 50% ES. The altered muscle properties were confirmed at the MU level in final experiments once the properties had plateaued. Fast‐fatigable MUs were converted to fatigue‐intermediate and ‐resistant MUs that finally comprised ∼80% as compared to ∼10% of the total MU number in the daily 5% ES and the control normal groups, respectively. We conclude that the daily 5% ES regimen counteracts the fatigue of paralysed muscle without compromising contractile force, and thereby, is effective in conditioning muscle for effective movement.
imageKey points
We asked whether 20 Hz electrical stimulation (ES) for 5% of each day (2.5 s on and 2.5 s off for 3 h; 5% ES) preserves medial gastrocnemius and tibialis anterior muscle and MU isometric contractile forces and increases their endurance after paralysis.
Daily 5% ES promoted increased muscle endurance irrespective of the muscle length or loading but to a lesser extent than daily 50% ES (20 Hz ES 2.5 s on and 2.5 s off for 24 h).
5% ES was effective in counteracting decline and slowing of muscle force that resulted from 50% ES.
Motor units (MUs) were converted from fast fatigable to fatigue intermediate and resistant MUs, comprising ∼80% as compared to ∼10% in the control normal groups.
We conclude that the 5% ES regimen counteracts the fatigue of paralysed muscle without compromising contractile force, and thereby is effective in conditioning the muscle for effective movement.
Novel regenerative drug, SPG302 promotes functional recovery of diaphragm muscle activity after cervical spinal cord injury
Authors: Fogarty Matthew J. , Zhan Wen‐Zhi , Simmon Vincent F. , Vanderklish Peter W. , Sarraf Stella T. , Sieck Gary C. 
Published: February 2023

AbstractSpinal cord hemisection at C2 (C2SH), sparing the dorsal column is widely used to investigate the effects of reduced phrenic motor neuron (PhMN) activation on diaphragm muscle (DIAm) function, with reduced DIAm activity on the injured side during eupnoea. Following C2SH, recovery of DIAm EMG activity may occur spontaneously over subsequent days/weeks. Various strategies have been effective at improving the incidence and magnitude of DIAm recovery during eupnoea, but little is known about the effects of C2SH on transdiaphragmatic pressure (Pdi) during other ventilatory and non‐ventilatory behaviours. We employ SPG302, a novel type of pegylated benzothiazole derivative, to assess whether enhancing synaptogenesis (i.e., enhancing spared local connections) will improve the incidence and the magnitude of recovery of DIAm EMG activity and Pdi function 14 days post‐C2SH. In anaesthetised Sprague‐Dawley rats, DIAm EMG and Pdi were assessed during eupnoea, hypoxia/hypercapnia and airway occlusion prior to surgery (C2SH or sham), immediately post‐surgery and at 14 days post‐surgery. In C2SH rats, 14 days of DMSO (vehicle) or SPG302 treatments (i.p. injection) occurred. At the terminal experiment, maximum Pdi was evoked by bilateral phrenic nerve stimulation. We show that significant EMG and Pdi deficits are apparent in C2SH compared with sham rats immediately after surgery. In C2SH rats treated with SPG302, recovery of eupneic, hypoxia/hypercapnia and occlusion DIAm EMG was enhanced compared with vehicle rats after 14 days. Treatment with SPG302 also ameliorated Pdi deficits following C2SH. In summary, SPG302 is an exciting new therapy to explore for use in spinal cord injuries.
imageKey points
Despite advances in our understanding of the effects of cervical hemisection (C2SH) on diaphragm muscle (DIAm) EMG activity, very little is understood about the impact of C2SH on the gamut of ventilatory and non‐ventilatory transdiaphragmatic pressures (Pdi).
Recovery of DIAm activity following C2SH is improved using a variety of approaches, but very few pharmaceuticals have been shown to be effective. One way of improving DIAm recovery is to enhance the amount of latent local spared connections onto phrenic motor neurons. A novel pegylated benzothiazole derivative enhances synaptogenesis in a variety of neurodegenerative conditions.
Here, using a novel therapeutic SPG302, we show that 14 days of treatment with SPG302 ameliorated DIAm EMG and Pdi deficits compared with vehicle controls.
Our results show that SPG302 is a compound with very promising potential for use in improving functional outcomes post‐spinal cord injury.
Predicting Nonlinear Modal Properties by Measuring Free Vibration Responses
Authors: Huang Shih-Chun , Chen Hao-Wen , Tien Meng-Hsuan 
Published: February 2023

AbstractIdentifying dynamical system models from measurements is a central challenge in the structural dynamics community. Nonlinear system identification, in particular, is a big challenge as there are many possible combinations of model structures, which requires expert knowledge to construct an appropriate model. Furthermore, traditional nonlinear system identification methods require a steady excitation input that is not always available in many practical applications. Recently, a technique referred to as the sparse identification of nonlinear dynamics (SINDy) algorithm was developed to discover mathematical models of general nonlinear systems. The SINDy method finds a generalized linear state-space model for an autonomous nonlinear system by analyzing the collected response data. In this work, the SINDy method is adapted and combined with the shooting method and the numerical continuation technique to form a system identification framework that can predict the nonlinear modal properties of mechanical oscillators. The proposed framework predicts the nonlinear normal modes (NNMs) of these systems by processing the noised data of the systems' free vibration response. In addition, the NNMs and the internal resonance of nonlinear systems at a high energy level can be captured using the proposed framework by processing the response data at a lower energy level. The proposed method is numerically demonstrated on a 2-degree-of-freedom mechanical oscillator. Furthermore, the effects of the measurement error and the excitation condition on NNM prediction are investigated. The NNM prediction framework presented in this paper is fairly general and is applicable to a variety of nonlinear systems.
Compositions and ages of Early Cretaceous volcanic and plutonic rocks in central Tibet: Insights into the magmatic and uplift response to slab breakoff
Authors: Wu Hao , Liu Fei , Liu Xi-Jun , Wu Yan-Wang , Li Cai , Yang Rui 
Published: February 2023

AbstractWe present new zircon U-Pb ages and Hf isotope compositions as well as whole-rock major- and trace-element geochemical and Sr-Nd isotopic data for silicic plutonic and volcanic rocks from the Duolong area of central Tibet. Combined with existing data, our new data indicate that these plutonic and volcanic rocks were formed in two stages ca. 120 Ma and ca. 110 Ma, respectively, in a postcollisional extensional setting that was triggered by slab breakoff. The similar geochemical compositions of granitoids and rhyolites, combined with their close spatial and temporal relationships, suggest that they were both derived from juvenile crustal material within a single magmatic system. We propose that the two inferred crustal melting events in the Duolong area were caused by two episodes of deep mantle activity triggered by the transition of the plate subduction angle from steep to shallow in response to the ascent of buoyant continental lithosphere during slab breakoff. Furthermore, rapid surface uplift during the late Early Cretaceous caused by slab breakoff made an important contribution to the formation of the proto–Tibetan Plateau. This study provides new insights into postcollisional tectonomagmatism and plateau uplift in central Tibet triggered by slab breakoff. We propose more generally that tectonic uplift during postcollisional processes (i.e., slab breakoff and lithospheric delamination) is a major contributor to plateau uplift in collision zones.
Appendiceal adenocarcinoma is associated with better prognosis than cecal adenocarcinoma: a population-based comparative survival study
Authors: Chen George , Chen Kay , Sahyoun Laura , Zaman Saif , Protiva Petr 
Published: February 2023

ObjectiveAlthough appendiceal cancer remains a rare gastrointestinal malignancy compared with colorectal cancer, incidence rates of appendiceal cancer have increased in the last two decades. Appendiceal and cecal adenocarcinomas have distinct genomic profiles, but chemotherapy protocols for these malignancies are the same and survival outcomes between them have not been compared extensively. To this end, we conducted a comparative survival analysis of appendiceal and cecal adenocarcinomas.DesignUsing the Surveillance, Epidemiology and End Results (SEER) database, we identified individuals ≥30 years of age with appendiceal or cecal adenocarcinoma from 1975 to 2016. Demographic, clinical and county-level socioeconomic data were extracted using SEER*Stat software. Survival was compared by Mantel-Haenszel log-rank test, and survival curves were generated using the Kaplan-Meier method. Relative HRs for death in the 5-year period following diagnosis were calculated using multivariable Cox regression analysis, adjusted for all other covariates. The significance level was set at p<0.05 for two-tailed tests. Data were analysed using SAS V.9.4 and R software.ResultsWe identified 6491 patients with appendiceal adenocarcinoma and 99 387 patients with cecal adenocarcinoma. Multivariable Cox regression analysis demonstrated significantly higher cancer-specific and overall survival in appendiceal adenocarcinoma compared with cecal adenocarcinoma. Male sex, older age, earlier year of diagnosis, black race, single marital status, non-Hispanic ethnicity, and non-mucinous histology were associated with increased mortality rates. In addition, counties with lower percentage of individuals below the poverty line and higher colorectal cancer screening rates had better survival.ConclusionThis is the first study to show greater survival in appendiceal adenocarcinoma compared with cecal adenocarcinoma. We also highlighted novel associations of county-level socioeconomic factors with increased mortality in appendiceal adenocarcinoma. Future efforts to develop targeted molecular therapies and reduce socioeconomic barriers to diagnosis and treatment are warranted to improve survival.
Evaluating the implementation of community engagement guidelines (EVALUA GPS project): a study protocol
Authors: Cassetti Viola , López-Ruiz María Victoria , Domínguez Marta , Gallego-Royo Alba , García Ana María , Gea-Caballero Vicente , Nuñez Catalina , Paredes-Carbonell Joan Josep , Pérula-De Torres Luis Angel , Pola-Garcia Marina ,   EvaluAGPS Research Group, Benedé Azagra Carmen Belen 
Published: February 2023

IntroductionThe EVALUA GPS project aims to evaluate the impact of the implementation of the National Institute for Health Care and Excellence (NICE) guideline ‘Community engagement: improving health and well-being and reducing health inequalities’ adapted to the Spanish context.Methods and analysisPhase I: A tool will be designed to evaluate the impact of implementing the recommendations of the adapted NICE guideline. The tool will be developed through a review of the literature on implementation of public health guidelines between 2000 and 2021 and an expert’s panel consensus. Phase II: The developed tool will be implemented in 16 community-based programmes, acting as intervention sites, and 4 controls through a quasi-experimental pre–post study. Phase III: A final online web tool, based on all previously collected information, will be developed to support the implementation of the adapted NICE guidelines recommendations in other contexts and programmes.Data collection and analysisData will be collected through surveys and semistructured interviews. Quantitative and qualitative data will be analysed to identify implementation scenarios, changes in community engagement approaches, and barriers and facilitators to the implementation of the recommendations. All this information will be further synthesised to develop the online tool.Ethics and disseminationThe proposed research has been approved by the Clinical Research Ethics Committee of Aragon. Results will be presented at national and international conferences and published in peer-reviewed open access journals. The interactive online tool (phase III) will include examples of its application from the fieldwork.
Use of mental health services in the aftermath of COVID-19 waves: a retrospective study conducted in a French Psychiatric and Neurosciences University Hospital
Authors: Perozziello Anne , Sousa Daniel , Aubriot Béatrice , Dauriac-Le Masson Valérie 
Published: February 2023

ObjectiveThe COVID-19 pandemic and the restrictive measures taken to prevent its propagation had profound effects on mental health and well-being, especially in children and young adults (<25 years old). This study aimed to analyse the medium and long-term impact of the COVID-19 pandemic on the use of the mental health services, by age groups and gender.DesignWe conducted a retrospective study using the medical and administrative information system databases of patients, between 2019 and 2021.SettingThis study was conducted in the Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences.Outcome measuresWe reported three indicators: the number of new patients attending outpatient clinics, the number of emergency department (ED) visits and the number of hospital admissions.MethodsWe considered the weekly number of each indicator, by age groups and by gender. We also collected the reasons of ED visits and hospital admissions. The 2020 and 2021 data were compared with the same period in 2019. The evolution of the indicators over the 3 years was analysed with interrupted time-series analysis.ResultsAll three indicators showed a dramatic decrease during the first lockdown period (March 2020) especially for the youngest. In 2021, the activity resumed but without reaching its prepandemic level. Moreover, mental healthcare seeking was significantly lower since the beginning of the pandemic compared with the prepandemic period for all age groups, except for young women (<25 years old). Among them, there was a higher level of mental health services use in 2021, compared with 2019: +20% of new patients at the outpatient clinics, +39% of ED visits and+17% of hospital admissions.ConclusionsThe COVID-19 pandemic has had severe consequences on populations’ mental health, especially among young women, which seem to persist months after the end of restrictive measures.
Quantitative p53 immunostaining aids in the detection of prevalent dysplasia
Authors: Neyaz Azfar , Rickelt Steffen , Yilmaz Omer H , Parrack Paige H , Lu Chenyue , Yilmaz Osman , Wu Elizabeth Y , Choi Won-Tak , Gala Manish , Ting David T , Odze Robert D , Patil Deepa T , Deshpande Vikram 
Published: February 2023

AimsThe lack of accepted scoring criteria has precluded the use of p53 in routine practice. We evaluate the utility of automated quantitative p53 analysis in risk stratifying Barrett’s oesophagus (BE) patients using non-dysplastic BE (NDBE) biopsies in a multicentric cohort of BE progressor (P) and non-progressor (NP) patients.MethodsNDBE biopsies prior to the diagnosis of advanced neoplasia from 75 BE-P, and index and last surveillance biopsies from 148 BE-NP were stained for p53, and scored digitally as 1+, 2+ and 3+. A secondary cohort of 30 BE-P was evaluated.ResultsCompared with BE-NP, BE-P was predominantly men (p=0.001), ≥55 years of age (p=0.008), with longer BE segments (71% vs 33%; p<0.001). The mean number of 3+p53 positive cells and 3+ positive glands were significantly more in BE-P versus BE-NP NDBE biopsies (175 vs 9.7, p<0.001; 9.8 vs 0.1; p<0.001, respectively). At a cut-off of ≥10 p53 (3+) positive cells, the sensitivity and specificity of the assay to identify BE-P were 39% and 93%. On multivariate analysis, scoring p53 in NDBE biopsies, age, gender and length of BE were significantly associated with neoplastic progression. 54% of patients classified as prevalent dysplasia showed an abnormal p53 immunohistochemical stain. These findings were validated in the secondary cohort.ConclusionsAutomated p53 analysis in NDBE biopsies serves as a promising tool for assessing BE neoplastic progression and risk stratification. Our study highlights the practical applicability of p53 assay to routine surveillance practice and its ability to detect prevalent dysplasia.
ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer
Authors: Chen Huanhuan , Yang Keqing , Pang Lingxiao , Fei Jing , Zhu Yongliang , Zhou Jianwei 
Published: February 2023

BackgroundOvarian cancer is the deadliest type of malignant gynecological tumor. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are involved ovarian cancer and are closely related to adverse outcomes. However, the immunosuppressive mechanism of PMN-MDSCs remains elusive.MethodsThe types and numbers of ANKRD22-expressing cells were investigated by bioinformatics analysis and immunohistochemical staining.Ankrd22-/-C57BL/6 mice were constructed with CRISPR-Cas9 technology. Mouse PMN-MDSCs were obtained from bone marrow (BM)-derived CD11b+Ly6G+Ly6Clowcells sorted by fluorescence-activated cell sorting with treatment of GM-CSF and IL-6, and the immunosuppressive activity of PMN-MDSCs was evaluated by flow cytometry (FCM) and ELISA. The expression level of CCR2 and the exogenous glucose uptake capacity were determined by FCM. RT-qPCR was used to detectANKRD22expression in CD11b+HLA-DR-CD14-CD15+cells from human ovarian cancer tissues, and the correlations ofANKRD22expression with the clinical characteristics and prognosis of patients were evaluated by the χ2test.ResultsWe identified a novel protein involved in regulating the immunosuppressive ability of PMN-MDSCs, ANKRD22.Ankrd22expression was high in mouse CD11b+Ly6G+Ly6Clowcells and could be significantly downregulated after exposure to a simulated microenvironmental stimulus. Knockout ofAnkrd22increased the expression level of CCR2 of CD11b+Ly6G+Ly6Clowcells and the immunosuppressive activity of PMN-MDSCs. BM-derived CD11b+Ly6G+Ly6Clowcells ofAnkrd22-/-mice significantly promoted the proliferation of ovarian cancer cells in tumor xenograft mouse models. Mechanistically, RNA sequencing showed thatWdfy1expression was obviously increased inAnkrd22-knockout BM-derived CD11b+Ly6G+Ly6Clowcells and that ectopic expression ofWdfy1increased the levels ofArg1,Inos,IdoandPdl1inAnkrd22+/+PMN-MDSCs derived from BM-derived CD11b+Ly6G+Ly6Clowcells. Surprisingly, an ANKRD22-activating candidate small-molecule compound attenuated the immunosuppressive activity ofAnkrd22+/+PMN-MDSCs. Finally, we found that lowANKRD22levels in CD11b+HLA-DR-CD14-CD15+cells derived from primary ovarian tissues were associated with a more advanced International Federation of Gynecology and Obstetrics stage, a higher recurrence rate, and a higher neutrophil-to-lymphocyte ratio.ConclusionsThese results suggest that ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs.
Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models
Authors: Stirm Kristin , Leary Peter , Wüst Daria , Stark Dominique , Joller Nicole , Karakus Ufuk , Boyman Onur , Tzankov Alexandar , Müller Anne 
Published: February 2023

BackgroundRoughly half of all diffuse large B-cell lymphomas (DLBCLs) are infiltrated by large numbers of regulatory T-cells (Tregs). Although the presence of ‘effector’ Tregs in particular is associated with an inferior prognosis in patients on standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy, the role of this cell type during lymphoma initiation and progression is poorly understood.MethodsHere, we use tissue microarrays containing prospectively collected DLBCL patient specimens, as well as data from publicly available cohorts to explore the mutational landscape of Treg-infiltrated DLBCL. We further take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma.ResultsWe find that all genetic DLBCL subtypes, except for one characterized by co-occurringMYD88/CD79mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from naïve CD4+precursors on tumor contact. Treg ablation in Foxp3iDTRmice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4+T-cells, but not CD8+T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 activation to sustain durable responses.ConclusionThe combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies.