bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Characterization of the Highest Risk Adult Patients With Acute Myeloid Leukemia (AML) Through Multi-Omics Clustering
Authors: Nguyen Trinh , Pepper John W , Nguyen Cu , Fan Yu , Hu Ying , Chen Qingrong , Yan Chunhua , Meerzaman Daoud 
Published: October 2021

Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of cancers. While some patients respond well to chemotherapy, we describe here a subgroup with distinct molecular features that has very poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. Therefore, it is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics.Methods: We used a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup.Results: Multi-omics clustering analysis resulted in three primary clusters among 166 AML adult cancer cases in TCGA data. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to 2 years. The gene TP53 was mutated in most cases in this subgroup but not in all of them. The top six genes over-expressed in the HRMS subgroup included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-activated pathways related to immune function, cell proliferation, and DNA damage.Conclusion: A distinct subgroup of AML patients are not successfully treated with chemotherapy, and urgently need targeted therapeutics based on the molecular features of this subgroup. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several over-activated molecular pathways.
Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis
Authors: Green Samantha , Politis Marina , Rallis Kathrine S. , Saenz de Villaverde Cortabarria Alba , Efthymiou Athina , Mureanu Nicoleta , Dalrymple Kathryn V. , Scottà Cristiano , Lombardi Giovanna , Tribe Rachel M. , Nicolaides Kypros H. , Shangaris Panicos 
Published: October 2021

BackgroundSeveral studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes.ObjectiveThe aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB).MethodLiterature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed.ResultsFrom 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03–1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13–1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79–0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34–5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations.ConclusionLower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link.Systematic Review RegistrationPROSPERO, identifier CRD42020205469.
Anti-BCMA CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients With Extramedullary Disease: A Single Center Analysis of Two Clinical Trials
Authors: Que Yimei , Xu Menglei , Xu Yanjie , Almeida Varlene Daniela Fernandes , Zhu Li , Wang Zhiqiong , Wang Ying , Liu Xian , Jiang Lijun , Wang Di , Li Chunrui , Zhou Jianfeng 
Published: October 2021

BackgroundThe prognosis of relapsed/refractory multiple myeloma (RRMM) patients with the extramedullary disease was significantly poor. Extramedullary multiple myeloma (EMM) patients gained limited benefits from traditional drugs. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy seems to be a promising approach to treat RRMM patients. However, very few clinical studies are designed for EMM. Our study aimed to compare and assess the safety, efficacy, and pharmacokinetics of anti-BCMA CAR-T cell therapy in EMM and non-EMM.MethodsThe results from published anti-BCMA CAR-T clinical trials, in which raw data of EMM patients were available, were reviewed and summarized. Two trials conducted in our clinical centers were analyzed and presented with detailed data.ResultsAccording to published anti-BCMA CAR-T clinical trials, the ORR of EMM ranged from 57% to 100%, with the complete remission (CR) rate of 29% to 60%. Between February 22, 2017, and September 26, 2019, a total of 61 subjects (EMM 25; non-EMM 36) received anti-BCMA CAR-T cell infusion. The data-cutoff date was April 1, 2021. There were no statistical differences between EMM and non-EMM groups in adverse events (AEs), including cytokine release syndrome (CRS). The most common AEs of grade ≥ 3 in both groups were hematologic toxicities. There was no significant difference in the objective response rate (ORR) and ≥ complete remission (CR) rate between both groups. However, the ≥ CR rate of the EMM group was lower than the non-EMM group receiving the fully human anti-BCMA CAR-T cell therapy (p = 0.026). The median progression-free survival (PFS) for EMM and the non-EMM group was 121 days and 361 days, respectively (p = 0.001). The median overall survival (OS) for EMM and the non-EMM group was 248 days and 1024 days, respectively (p = 0.005). The Cmax and AUC0-28d for EMM group were lower than non-EMM group (Cmax, p = 0.016; AUC0-28d, p = 0.016). Extramedullary disease was an independent prognostic risk factor for PFS (hazard ratio, 2.576; 95% CI, 1.343 to 4.941; p = 0.004) and OS (hazard ratio, 2.312; 95% CI, 1.165 to 4.592; p = 0.017) in RRMM patients receiving anti-BCMA CAR-T cell therapy.ConclusionsBased on our results, EMM patients could benefit from the two anti-BCMA CAR products, although they had a shorter PFS and OS compared with non-EMM patients.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier ChiCTR-OPC-16009113 and ChiCTR1800018137.
Spatial Profiles of Intratumoral PD-1+ Helper T Cells Predict Prognosis in Head and Neck Squamous Cell Carcinoma
Authors: Yoshimura Kanako , Tsujikawa Takahiro , Mitsuda Junichi , Ogi Hiroshi , Saburi Sumiyo , Ohmura Gaku , Arai Akihito , Shibata Saya , Thibault Guillaume , Chang Young Hwan , Clayburgh Daniel R. , Yasukawa Satoru , Miyagawa-Hayashino Aya , Konishi Eiichi , Itoh Kyoko , Coussens Lisa M. , Hirano Shigeru 
Published: October 2021

BackgroundFunctional interactions between immune cells and neoplastic cells in the tumor immune microenvironment have been actively pursued for both biomarker discovery for patient stratification, as well as therapeutic anti-cancer targets to improve clinical outcomes. Although accumulating evidence indicates that intratumoral infiltration of immune cells has prognostic significance, limited information is available on the spatial infiltration patterns of immune cells within intratumoral regions. This study aimed to understand the intratumoral heterogeneity and spatial distribution of immune cell infiltrates associated with cell phenotypes and prognosis in head and neck squamous cell carcinoma (HNSCC).MethodsA total of 88 specimens of oropharyngeal squamous cell carcinoma, categorized into discovery (n = 38) and validation cohorts (n = 51), were analyzed for immune contexture by multiplexed immunohistochemistry (IHC) and image cytometry-based quantification. Tissue segmentation was performed according to a mathematical morphological approach using neoplastic cell IHC images to dissect intratumoral regions into tumor cell nests versus intratumoral stroma.ResultsTissue segmentation revealed heterogeneity in intratumoral T cells, varying from tumor cell nest-polarized to intratumoral stroma-polarized distributions. Leukocyte composition analysis revealed higher ratios of TH1/TH2 in tumor cell nests with higher percentages of helper T cells, B cells, and CD66b+granulocytes within intratumoral stroma. A discovery and validation approach revealed a high density of programmed death receptor-1 (PD-1)+helper T cells in tumor cell nests as a negative prognostic factor for short overall survival. CD163+tumor-associated macrophages (TAM) provided the strongest correlation with PD-1+helper T cells, and cases with a high density of PD-1+helper T cells and CD163+TAM had a significantly shorter overall survival than other cases.ConclusionThis study reveals the significance of analyzing intratumoral cell nests and reports that an immune microenvironment with a high density of PD-1+helper T cells in tumoral cell nests is a poor prognostic factor for HNSCC.
Implementation of the ABCDEF Bundle for Critically Ill ICU Patients During the COVID-19 Pandemic: A Multi-National 1-Day Point Prevalence Study
Authors: Liu Keibun , Nakamura Kensuke , Katsukawa Hajime , Nydahl Peter , Ely Eugene Wesley , Kudchadkar Sapna R. , Takahashi Kunihiko , Elhadi Muhammed , Gurjar Mohan , Leong Be Kim , Chung Chi Ryang , Balachandran Jayachandran , Inoue Shigeaki , Lefor Alan Kawarai , Nishida Osamu 
Published: October 2021

Background: Data regarding delivery of evidence-based care to critically ill patients in Intensive Care Units (ICU) during the COVID-19 pandemic is crucial but lacking. This study aimed to evaluate the implementation rate of the ABCDEF bundle, which is a collection of six evidence-based ICU care initiatives which are strongly recommended to be incorporated into clinical practice, and ICU diaries for patients with and without COVID-19 infections in ICUs, and to analyze the impact of COVID-19 on implementation of each element of the bundle and independent associated factors.Methods: A world-wide 1-day point prevalence study investigated the delivery of the ABCDEF bundle and ICU diary to patients without or with COVID-19 infections on 27 January 2021 via an online questionnaire. Multivariable logistic regression analysis with adjustment for patient demographics evaluated the impact of COVID-19 and identified factors in ICU administrative structures and policies independently associated with delivery.Results: From 54 countries and 135 ICUs, 1,229 patients were eligible, and 607 (49%) had COVID-19 infections. Implementation rates were: entire bundle (without COVID-19: 0% and with COVID-19: 1%), Element A (regular pain assessment: 64 and 55%), Element B (both spontaneous awakening and breathing trials: 17 and 10%), Element C (regular sedation assessment: 45 and 61%), Element D (regular delirium assessment: 39 and 35%), Element E (exercise: 22 and 25%), Element F (family engagement/empowerment: 16 and 30%), and ICU diary (17 and 21%). The presence of COVID-19 was not associated with failure to implement individual elements. Independently associated factors for each element in common between the two groups included presence of a specific written protocol, application of a target/goal, and tele-ICU management. A lower income status country and a 3:1 nurse-patient ratio were significantly associated with non-implementation of elements A, C, and D, while a lower income status country was also associated with implementation of element F.Conclusions: Regardless of COVID-19 infection status, implementation rates for the ABCDEF bundle, for each element individually and an ICU diary were extremely low for patients without and with COVID-19 infections during the pandemic. Strategies to facilitate implementation of and adherence to the complete ABCDEF bundle should be optimized and addressed based on unit-specific barriers and facilitators.
Muscle Selection and Dosing in a Phase 3, Pivotal Study of AbobotulinumtoxinA Injection in Upper Limb Muscles in Children With Cerebral Palsy
Authors: Oleszek Joyce , Tilton Ann , Carranza del Rio Jorge , Dursun Nigar , Bonikowski Marcin , Dabrowski Edward , Page Simon , Regnault Benjamin , Thompson Catherine , Delgado Mauricio R. 
Published: October 2021

Background: Guidelines recommend botulinum toxin-A in pediatric upper limb spasticity as part of routine practice. Appropriate dosing is a prerequisite for treatment success and it is important that injectors have an understanding on how to tailor dosing within a safe and effective range. We report upper limb dosing data from a phase 3 study of abobotulinumtoxinA injections in children with cerebral palsy.Methods: This was a double-blind, repeat-treatment study (NCT02106351). In Cycle 1, children were randomized to abobotulinumtoxinA at 2 U/kg control dose or clinically relevant 8 U/kg or 16 U/kg doses. Doses were divided between the primary target muscle group (PTMG, wrist or elbow flexors) and additional muscles tailored to clinical presentation. During Cycles 2–4, children received doses of 8 U/kg or 16 U/kg and investigators could change the PTMG and other muscles to be injected. Injection of muscles in the other upper limb and lower limbs was also permitted in cycles 2–4, with the total body dose not to exceed 30 U/kg or 1,000 U (whichever was lower) in the case of upper and lower limb treatment.Results: 212 children were randomized, of which 210 received ≥1 abobotulinumtoxinA injection. Per protocol, the elbow and wrist flexors were the most commonly injected upper limb muscles. Across all 4 cycles, the brachialis was injected in 89.5% of children (dose range 0.8–6 U/kg), the brachioradialis in 83.8% (0.4–3 U/kg), the flexor carpi ulnaris in 82.4% (0.5–3 U/kg) and the flexor carpi radialis in 79.5% (0.5–4 U/kg). Other frequently injected upper limb muscles were the pronator teres(70.0%, 0.3–3 U/kg). adductor pollicis (54.3%, 0.3-1 U/kg), pronator quadratus (44.8%, 0.1–2 U/kg), flexor digitorum superficialis (39.0%, 0.5-4 U/kg), flexor digitorum profundus (28.6%, 0.5–2 U), flexor pollicis brevis/opponens pollicis (27.6%, 0.3-1 U/kg) and biceps (27.1%, 0.5–6 U/kg). AbobotulinumtoxinA was well-tolerated at these doses; muscular weakness was reported in 4.3% of children in the 8 U/kg group and 5.7% in the 16 U/kg group.Conclusions: These data provide information on the pattern of injected muscles and dose ranges used in this study, which were well-tolerated. Per protocol, most children received injections into the elbow and wrist flexors. However, there was a wide variety of other upper limb muscles injected as physicians tailored injection patterns to clinical need.
Immediate Effect of Dry Needling at Myofascial Trigger Point on Hand Spasticity in Chronic Post-stroke Patients: A Multicenter Randomized Controlled Trial
Authors: Zhang Zengqiao , Wang Wu , Song Yongjia , Zhai Tianjun , Zhu Yan , Jiang Liming , Li Qunfeng , Jin Lei , Li Kunpeng , Feng Wei 
Published: October 2021

Background: Hand spasticity after stroke influences the rehabilitation of hand function. Immediate and effective relief of spasticity potentially creates conditions for later rehabilitation training, which has far-reaching significance in the smooth transition of patients to the recovery period.Objective: To evaluate the immediate effect of dry needling (DN) at myofascial trigger point on hand spasticity in stroke patients.Methods: This was a prospective, evaluator blind, multicenter, randomized controlled study. A total of 210 participants were randomly divided into DN group (DN, N = 70), sham dry needling group (SDN, N = 70), and control group (N = 70). Participants in the DN group were treated with DN at myofascial trigger point five times (30 min each time) every week for 4 weeks. Subjects in the SDN group were manipulated the same way as in the DN group, except that the acupuncture site was located in the area adjacent to the myofascial trigger point, which constituted a SDN. Routine rehabilitation treatment was performed for participants in the two groups and in the control group. The primary evaluation index was the immediate effect of hand spasticity relief. Secondary evaluation indicators included the cumulative effect of hand spasticity relief from baseline to week 4, and the changes in flexion angles of the wrist, thumb, and fingers 2–5 in the rest position before, immediately after, and 4 weeks after intervention.Results: The immediate effective rate of spasticity relief (thumb, fingers 2–5, and wrist) of patients with different degrees of spasticity in the DN group was higher than that in the control and SDN groups (thumb, χ2 = 55.833, P &lt; 0.001; fingers 2–5, χ2 = 68.096, P &lt; 0.001; wrist, χ2 = 49.180, P &lt; 0.001) (P &lt; 0.05). The effective rate of spasticity relief from baseline to 4 weeks in the DN group exceeded that in the control group and SDN groups (thumb, χ2 = 8.806, P = 0.012; fingers 2–5, χ2 = 8.087, P = 0.018; and wrist, χ2 = 8.653, P = 0.013) (P &lt; 0.05). No difference in immediate and cumulative effect was found between the control group and SDN group. The change of joints flexion angles in resting position before and after each treatment in the DN group was higher than that in the control and SDN groups (P &lt; 0.05), but it was not significantly different between the control group and SDN group. At 4 weeks, although the change in the DN group was higher than that in the control group and SDN group, this difference was not statistically significant (P &gt; 0.05).Conclusion: Dry needling can relieve varying degrees of hand spasticity instantly in post-stroke.Trial Registration:www.chictr.org.cn, ChiCTR1900022379.
Treatment Outcome and Risk Factors of Adult Newly Diagnosed Epilepsy: A Prospective Hospital-Based Study in Northeast China
Authors: Li Nan , Li Jing , Chen Yanyan , Chu Chaojia , Lin Weihong 
Published: October 2021

Objective: The study was conducted to summarize the treatment outcomes of newly diagnosed epilepsy (NDE) and analyse the risk factors for refractory epilepsy (RE) in Northeast China.Methods: A total of 466 adult patients with NDE were consecutively enrolled in this programme. Clinical data were collected at baseline and each follow-up. Several scales concerning recognition and mood were also completed at the first visit.Results: Seizure-free status was achieved by 52% (n = 244) of the patients; however, 15% (n = 68) manifested RE. A total of 286 (61%) patients continued with the first ASM as monotherapy, among which 186 (40%) patients became seizure-free. Fifteen (22%) patients with RE became seizure-free following ASM adjustment and 34 patients (14%) had breakthrough seizures after being classified as seizure-free. One patient developed RE after attaining seizure-free status. Breakthrough seizures during the first expected interictal interval [Odds ratio (OR) = 5.81, 95% CI: 2.70–12.50], high seizure frequency at baseline (OR = 1.24, 95% CI: 1.04–1.49), younger age of onset (OR = 1.42, 95% CI: 1.12–1.79), and male sex (OR = 2.64, 95% CI: 1.26–5.53) were risk factors for RE.Significance: Treatment outcomes of the majority of NDE cases are good. New risk factors could help physicians more promptly and accurately identify patients who are likely to develop RE. Seizure-free state is not long enough to commence the withdrawal of ASMs. RE is not permanent and seizure-free may be achieved subsequently by appropriate drug adjustment.
Resting-State Functional Magnetic Resonance Imaging Networks as a Quantitative Metric for Impact of Neurosurgical Interventions
Authors: Yang Peter H. , Hacker Carl D. , Patel Bhuvic , Daniel Andy G. S. , Leuthardt Eric C. 
Published: October 2021

Objective: Resting-state functional MRI (rs-fMRI) has been used to evaluate brain network connectivity as a result of intracranial surgery but has not been used to compare different neurosurgical procedures. Laser interstitial thermal therapy (LITT) is an alternative to conventional craniotomy for the treatment of brain lesions such as tumors and epileptogenic foci. While LITT is thought of as minimally invasive, its effect on the functional organization of the brain is still under active investigation and its impact on network changes compared to conventional craniotomy has not yet been explored. We describe a novel computational method for quantifying and comparing the impact of two neurosurgical procedures on brain functional connectivity.Methods: We used a previously described seed-based correlation analysis to generate resting-state network (RSN) correlation matrices, and compared changes in correlation patterns within and across RSNs between LITT and conventional craniotomy for treatment of 24 patients with singular intracranial tumors at our institution between 2014 and 2017. Specifically, we analyzed the differences in patient-specific changes in the within-hemisphere correlation patterns of the contralesional hemisphere.Results: In a post-operative follow-up period up to 2 years within-hemisphere connectivity of the contralesional hemisphere after surgery was more highly correlated to the pre-operative state in LITT patients when compared to craniotomy patients (P = 0.0287). Moreover, 4 out of 11 individual RSNs demonstrated significantly higher degrees of correlation between pre-operative and post-operative network connectivity in patients who underwent LITT (all P &lt; 0.05).Conclusion: Rs-fMRI may be used as a quantitative metric to determine the impact of different neurosurgical procedures on brain functional connectivity. Global and individual network connectivity in the contralesional hemisphere may be more highly preserved after LITT when compared to craniotomy for the treatment of brain tumors.