bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer
Authors: Yap Timothy A. , Vieito Maria , Baldini Capucine , Sepúlveda-Sánchez Juan Manuel , Kondo Shunsuke , Simonelli Matteo , Cosman Rasha , van der Westhuizen Andre , Atkinson Victoria , Carpentier Antoine F. , Löhr Mario , Redman Rebecca , Mason Warren , Cervantes Andres , Le Rhun Emilie , Ochsenreither Sebastian , Warren Louise , Zhao Yumin , Callies Sophie , Estrem Shawn T. , Man Michael , Gandhi Leena , Avsar Emin , Melisi Davide 
Published: September 2021

Abstract

Purpose:
A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.

Patients and Methods:
This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation).

Results:
Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel.

Conclusions:
LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.
Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer–Associated Fibroblasts
Authors: Helms Erin J. , Berry Mark W. , Chaw R. Crystal , DuFort Christopher C. , Sun Duanchen , Onate M. Kathrina , Oon Chet , Bhattacharyya Sohinee , Sanford-Crane Hannah , Horton Wesley , Finan Jennifer M. , Sattler Ariana , Makar Rosemary , Dawson David W. , Xia Zheng , Hingorani Sunil R. , Sherman Mara H. 
Published: September 2021

AbstractCancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin.Significance:By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs.See related commentary by Cukierman, p. 296.This article is highlighted in the In This Issue feature, p. 275
Small NGOs and Agenda-Setting in Global Conservation Governance: The Case of Pangolin Conservation
Authors: Shibaike Takumi 
Published: September 2021

Abstract
The study of global environmental governance suggests that agenda-setting power is concentrated in a handful of high-profile, leading nongovernmental organizations (NGOs). The recent rise of interest in pangolin conservation constitutes a deviant case in this theoretical tradition. In order to explain the puzzle, I introduce a new theory of small NGO influence and illustrate the mechanisms through the case study of pangolin conservation. Based on in-depth interviews with conservation NGOs, I show how small NGOs raised the salience of pangolin trafficking in global conservation governance by appealing to the shared values of the people who are highly interested in conservation. Moreover, the targeting of traditional Chinese medicine as the driver of pangolin extinction, while unintentionally, helped raise the salience of pangolin trafficking by leveraging the rise of anti-Chinese sentiment in the Global North. Finally, small NGOs were able to use their expertise to guide leading NGOs and state officials in rule-making processes. The findings offer a corrective to the hierarchical view of civil society, calling for more careful evaluations of small NGOs in global conservation governance.
Autologous Adipose Tissue Injection of Vocal Cords in Presbyphonia
Authors: González‐Herranz Ramón , Navarro‐Mediano Andrés , Hernández‐García Estefanía , Plaza Guillermo 
Published: September 2021

ObjectiveThis series evaluates the long‐term results of autologous adipose injection (AAI) in patients older than 65 years with presbyphonia.Study DesignRetrospective cohort study.SettingAcademic secondary medical center.MethodsThis was a retrospective study with a minimum follow‐up of 12 months. All patients underwent AAI for atrophy of both vocal folds due to presbyphonia. We measured subjective parameters as Voice Handicap Index–10 (VHI‐10) or GRBAS scale (grade, roughness, breathiness, asthenia, strain) and objective measures such as maximum phonation time (MPT) or square pixel closure defect. We reviewed the medical records of patients undergoing AAI during the 2011‐2018 period. An analysis of the demographic variables of the group was performed, as well as the values of VHI‐10, GRBAS, and MPT, and the minimum closure defect measured in square pixels and the number of closed frames in the glottal cycle before and after the intervention.ResultsAt 12 months, 17 of 18 patients reported subjective and VHI‐10 improvement. The mean preoperative VHI‐10 (26.7) was significantly higher than the postoperative value (14.4), and the GRBAS scale had a preoperative mean of 8.7 and a postoperative mean of 4.3, both with statistical significance. MPT increased from 7.7 to 12.4 seconds (P <. 0001). The minimum closure defect measurements obtained in square pixels changed from 305 to 124, achieving complete closure in 3 patients. The closed phase of the glottal cycle change from 14.3% to 38.2% after the AAI.ConclusionsAAI improves long‐term vocal fold closure, demonstrating utility in patients with presbyphonia.
Managing post-stroke fatigue: A qualitative study to explore multifaceted clinical perspectives
Authors: Drummond Avril , Nouri Fiona , Ablewhite Joanne , Condon Laura , das Nair Roshan , Jones Amanda , Jones Fiona , Sprigg Nikola , Thomas Shirley 
Published: September 2021

Introduction Post-stroke fatigue (PSF) is common and debilitating. However, while its effective management is a priority for clinicians and stroke survivors, there remains little evidence to provide guidance or underpin practice. Our aim, therefore, was to gain insights into the experiences of clinicians who routinely manage patients with fatigue. Method Qualitative interview study. The target was to recruit a purposeful sample of approximately 20 participants with expertise in managing PSF and fatigue arising from other conditions. Maximum variation sampling was used to ensure a balance of participants across different settings. Data were analysed using a framework approach, iteratively developed and refined by including emergent themes. Results We recruited 20 participants: nine occupational therapists (OTs), five physiotherapists, three nurses and three psychologists, which included three ‘fatigue experts’ from Europe and Australia. Analysis generated core themes around management and strategies used; these were similar regardless of professional background, clinical or geographical setting or condition treated. OTs felt a particular responsibility for fatigue management, although multidisciplinary teamwork was stressed by all. Conclusion There are clear similarities in clinicians’ experiences of managing PSF and fatigue across different conditions and also across professional groups. Clinicians rely predominantly on their own clinical knowledge for guidance.
A comparative study of intralesional bleomycin versus cryotherapy in the treatment of condyloma accuminata
Authors: Shahidi-Dadras Mohammad , Gholizadeh Nasim , Dadkhahfar Sahar , Gheisari Mehdi , Heydarifakher Parsa , Moslemi Haghighi Shima , Mozafari Nikoo 
Published: September 2021

Bleomycin is an antineoplastic agent, which is used off label for various dermatologic conditions. There are numerous reports on the use of intralesional bleomycin (ILB) for the treatment of common warts. However, reports on the efficacy of bleomycin in the treatment of anogenital warts (AGWs) are still limited. The aim is to compare the efficacy/tolerability and recurrence rates of AGW treatment with ILB versus cryotherapy. In this prospective study, 50 patients with AGWs were assigned either to receive triple freeze–thaw cycle of cryotherapy or to receive 1.5 mg/mL ILB for a maximum of four sessions with 3-week intervals. Clinical efficacy was determined by the percentage of the patients with complete clearance. The patients with complete clearance were visited by passing 3 months from the last treatment session to evaluate any recurrence. Of 44 patients completing the study, 16 of 21 (76.19%) patients in the ILB group and 15 of 23 (65.22%) patients in the cryotherapy group showed complete resolution ( p value = .425). Moreover, recurrence occurred after 3 months in 18.75% and 46.66% of the ILB and the cryotherapy groups’ patients, respectively ( p value = .096). The most common local adverse events in both treatment groups were pain, dyspigmentation, and ulceration/erosion, while the delayed ulceration and secondary infection were only observed in the bleomycin group. Intralesional bleomycin is as effective as cryotherapy in the treatment of AGWs, but it is more invasive and associated with post-treatment pain, the delayed ulceration, and cutaneous infection. Intralesional bleomycin is not accompanied with the major risk of necrosis or fibrosis, so the use of ILB in the anogenital area is likely to be safe. This clinical trial was registered in Iranian Registry of Clinical Trials site with code: IRCT20190519043631N1.
Transition outcomes for young people discharged from adolescent medium secure services in England: A qualitative study exploring adolescents’ and carers’ experiences
Authors: Livanou Maria I , Bull Marcus , Lane Rebecca , D’Souza Sophie , El Asam Aiman , Singh Swaran P 
Published: September 2021

Background Young people in secure services present with multiple vulnerabilities; therefore, transition periods are especially challenging for this group. In this study, we followed up young people discharged from adolescent medium secure services to adult and community settings with the aim to explore transition experiences and outcomes. Methods Participants were recruited from 15 child and adult mental health services in England. We conducted qualitative semi-structured interviews with 13 young people, aged 18–19 years, moving from adolescent medium secure units 2–6 months post-transition, and five carers 1–3 months pre-transition. Thematic analysis was performed to identify predetermined or data-driven themes elicited from face-to-face interviews. Results The findings indicated poor transition outcomes for young people with the most severe mental health symptoms and those who committed serious offences. Three overarching themes were identified: (1) unsettling environmental factors within adult services; (2) experiences of transition management and preparation and (3) parental experiences of transition process and engagement with adult services. Conclusion The findings of this study indicate that young people and carers value ongoing involvement in the transition process by well-informed parallel care. They also highlight the need for a national integrative care model that diverges from the traditional ‘one-size-fits-all’ approach.
A Prediction Model for Primary Anterior Cruciate Ligament Injury Using Artificial Intelligence
Authors: Tamimi Iskandar , Ballesteros Joaquin , Lara Almudena Perez , Tat Jimmy , Alaqueel Motaz , Schupbach Justin , Marwan Yousef , Urdiales Cristina , Gomez-de-Gabriel Jesus Manuel , Burman Mark , Martineau Paul Andre 
Published: September 2021

Background: Supervised machine learning models in artificial intelligence (AI) have been increasingly used to predict different types of events. However, their use in orthopaedic surgery has been limited. Hypothesis: It was hypothesized that supervised learning techniques could be used to build a mathematical model to predict primary anterior cruciate ligament (ACL) injuries using a set of morphological features of the knee. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Included were 50 adults who had undergone primary ACL reconstruction between 2008 and 2015. All patients were between 18 and 40 years of age at the time of surgery. Patients with a previous ACL injury, multiligament knee injury, previous ACL reconstruction, history of ACL revision surgery, complete meniscectomy, infection, missing data, and associated fracture were excluded. We also identified 50 sex-matched controls who had not sustained an ACL injury. For all participants, we used the preoperative magnetic resonance images to measure the anteroposterior lengths of the medial and lateral tibial plateaus as well as the lateral and medial bone slope (LBS and MBS), lateral and medial meniscal height (LMH and MMH), and lateral and medial meniscal slope (LMS and MMS). The AI predictor was created using Matlab R2019b. A Gaussian naïve Bayes model was selected to create the predictor. Results: Patients in the ACL injury group had a significantly increased posterior LBS (7.0° ± 4.7° vs 3.9° ± 5.4°; P = .008) and LMS (–1.7° ± 4.8° vs –4.0° ± 4.2°; P = .002) and a lower MMH (5.5 ± 0.1 vs 6.1 ± 0.1 mm; P = .006) and LMH (6.9 ± 0.1 vs 7.6 ± 0.1 mm; P = .001). The AI model selected LBS and MBS as the best possible predictive combination, achieving 70% validation accuracy and 92% testing accuracy. Conclusion: A prediction model for primary ACL injury, created using machine learning techniques, achieved a >90% testing accuracy. Compared with patients who did not sustain an ACL injury, patients with torn ACLs had an increased posterior LBS and LMS and a lower MMH and LMH.
Sickle cell disease promotes sex-dependent pathological bone loss through enhanced cathepsin proteolytic activity in mice
Authors: Selma Jada , Song Hannah , Rivera Christian , Douglas Simone , Akella Abhiramgopal , Bollavaram Keval , Thompson Nishone , Platt Manu O. , Botchwey Edward A. 
Published: September 2021

Abstract
Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis, osteopenia, and other bone-related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD). Previous SBD models have failed to distinguish the age- and sex-specific characteristics of bone morphometry. In this study, we use the Townes mouse model of SCD to assess the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by using high-resolution quantitative micro–computed tomography and the three-dimensional reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. SCD female mice in particular are prone to trabecular bone loss, whereas cortical bone degradation occurs in both sexes. We also describe the impact of genetic knockdown of cathepsin K– and E-64–mediated cathepsin inhibition on SBD.
Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies
Authors: Davids Matthew S. , O’Connor Owen A. , Jurczak Wojciech , Samaniego Felipe , Fenske Timothy S. , Zinzani Pier Luigi , Patel Manish R. , Ghosh Nilanjan , Cheson Bruce D. , Derenzini Enrico , Brander Danielle M. , Reeves James A. , Knopińska-Posłuszny Wanda , Allan John N. , Phillips Tycel , Caimi Paolo F. , Lech-Maranda Ewa , Burke John M. , Agajanian Richy , Pettengell Ruth , Leslie Lori A. , Cheah Chan Y. , Fonseca Gustavo , Essell James , Chavez Julio C. , Pagel John M. , Sharman Jeff P. , Hsu Yanzhi , Miskin Hari P. , Sportelli Peter , Weiss Michael S. , Flinn Ian W. 
Published: September 2021

Abstract
Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.
The prevalence and profile of autism in individuals born preterm: a systematic review and meta-analysis
Authors: Laverty Catherine , Surtees Andrew , O’Sullivan Rory , Sutherland Daniel , Jones Christopher , Richards Caroline 
Published: September 2021

Abstract
Introduction
Preterm birth (<37 weeks) adversely affects development in behavioural, cognitive and mental health domains. Heightened rates of autism are identified in preterm populations, indicating that prematurity may confer an increased likelihood of adverse neurodevelopmental outcomes. The present meta-analysis aims to synthesise existing literature and calculate pooled prevalence estimates for rates of autism characteristics in preterm populations.

Methods
Search terms were generated from inspection of relevant high-impact papers and a recent meta-analysis. Five databases were searched from database creation until December 2020 with PRISMA guidelines followed throughout.

Results
10,900 papers were retrieved, with 52 papers included in the final analyses, further classified by assessment method (screening tools N=30, diagnostic assessment N=29). Pooled prevalence estimates for autism in preterm samples was 20% when using screening tools and 6% when using diagnostic assessments. The odds of an autism diagnosis were 3.3 times higher in individuals born preterm than in the general population.

Conclusions
The pooled prevalence estimate of autism characteristics in individuals born preterm is considerably higher than in the general population. Findings highlight the clinical need to provide further monitoring and support for individuals born preterm.