bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers
Authors: Rotow Julia , Patel Jyoti D. , Hanley Matthew P. , Yu Helena , Awad Mark , Goldman Jonathan W. , Nechushtan Hovav , Scheffler Matthias , Kuo Chih-Hsi S. , Rajappa Senthil , Harada Guilherme , Clifford Sarah , Santucci Alison , Silva Laura , Tupper Rebecca , Oxnard Geoffrey R. , Kherani Jennifer , Drilon Alexander 
Published: March 2023

Abstract

Purpose:
Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non–small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion–mediated osimertinib resistance has not previously been published.

Patients and Methods:
Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected.

Results:
Fourteen patients with EGFR-mutant and RET fusion–positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%–75%, n = 12], 83% (95% CI, 55%–95%), and 7.9 months (range, 0.8–25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4–ALK/STRN–ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms.

Conclusions:
For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination.
See related commentary by Krebs and Popat, p. 2951
Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan 
Published: March 2023

Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of Delta-24-RGDOX. We found TAA-targeting T cells injected into one subcutaneous tumor showed tumor tropism. Delta-24-RGDOX sustained the systemic tumor regression mediated by the T cells, leading to improved survival rate. Further analysis revealed that, in mice with disseminated B16-OVA tumors, Delta-24-RGDOX increased CD8+ leukocyte density within treated and untreated tumors. Importantly, Delta-24-RGDOX significantly reduced the immunosuppression of endogenous OVA-specific CTLs while increasing that of CD8+ leukocytes and, to a lesser extent, adoptive pmel-1 T cells. Consequently, Delta-24-RGDOX drastically increased the density of the OVA-specific CTLs in both tumors, and the combination synergistically enhanced the effect. Consistently, the splenocytes from the combination group showed a significantly stronger response against other TAAs (OVA and TRP2) than gp100, resulted in higher activity against tumor cells. Therefore, our data demonstrate that, as an adjuvant therapy followed TAA-targeting T cells in localized treatment, Delta-24-RGDOX activates TME and promotes antigen spread, leading to efficacious systemic antitumor immunity to overcome tumor relapse.

Significance:
Adjuvant therapy with oncolytic viruses promotes antigen spread to potentiate localized intratumoral adoptive T-cell therapy with limited TAA targets, leading to sustainable systemic antitumor immunity to overcome tumor relapse.
Avaliação funcional do doente com dor crônica
Authors: Yeng Lin Tchia , Teixeira Manoel Jacobsen , Romano Miriam A. , Greve Maria Julia D’Andrea , Kaziyama Helena H. S. 
Published: March 2023

A avaliação de doentes com dor é necessária para estimar a magnitude e a natureza das variadas facetas da dor e de suas repercussões presentes, quantificar os resultados dos tratamentos e suas complicações, comparar resultados observados em momentos diferentes no mesmo doente ou em doentes diferentes, na mesma instituição ou outras instituições. Uma anamnese detalhada da dor e um exame físico global (neurológico e músculo-esquelético) são importantes na formulação das hipóteses diagnósticas e auxiliam na projeção de prognósticos a reduzir as complicações e possibilitam a seleção de esquemas terapêuticos mais racionais. Os métodos de avaliação devem ser consistentes, sensíveis, específicos e mensurar a dimensão avaliativa, sensitiva e afetiva, suas implicações nas atividades de vida diária e prática, suas repercussões psicossociais, os fatores que modificam a dor, atitudes frentea ela, crenças, determinar as doenças causais concorrentes ou conseqüentes, os antecedentes individuais e familiares, hábitos, dados do exame físico, déficits e incapacidades que possam fornecer subsídios para o diagnóstico das condições clínicas e das conseqüências da dor. Vários procedimentos de avaliação da dor e de funcionalidade foram desenvolvidos, alguns já validados e outros em vias de validação em nosso meio.
Características clínicas e morbidade de recém nascidos filhos de mães adolescentes em hospital universitário.
Authors: Fiorelli Lilian Renata , Krebs Vera Lúcia Jornada 
Published: March 2023

Objetivo: Descrever as características clínicas e a morbidade entre os recém nascidosde mães adolescentes em hospital universitário. Métodos: Estudo observacional de 220 recém-nascidos de mães com idade < 19 anos, no período de abril a setembro de 2003, cujos dados foram obtidos por análise de prontuários. Para comparar as características neonatais de acordo com a idade materna utilizou-se o teste exato de Fisher. Resultados:Houve 1552 partos, sendo 220 (14,2%) mães adolescentes; 50% foram partos normais, 28,6% fórcipe e 21,4% cesárea. A idade materna variou entre 14,2 e 18,9 anos (média = 17,3),havendo 33 (15%) menores de 16 anos; 49,6% não fizeram pré-natal ou compareceram em até 5 consultas. O uso de drogas, ocorreu em 18,6% das mães. O peso de nascimento variou de 430g a 4335g (3006 ± 587 g); houve 12,3% pré-termos, 12,7% recém-nascidos de baixo peso e 12 (5,4%) pequenos para idade gestacional. A asfixia perinatal ocorreu em 2,2% dos casos e 4,1% apresentaram malformações congênitas (malformações múltiplas, cardiopatia,displasia congênita do quadril, papiloma pré-auricular, hemangioma gigante). Em 49,5% dos casos ocorreram patologias, principalmente trauma obstétrico, desconforto respiratório, eicterícia com mortalidade de 1,8%. Conclusões: O pré-natal foi ausente ou incompleto em 49% das mães, sendo freqüente o uso de drogas durante a gestação. A freqüência de malformações foi semelhante à da população geral. A prematuridade, o peso de nascimento< 1500 g, a asfixia perinatal e a mortalidade foram significativamente maiores entre os recém nascidos de mães com idade < 16 anos.
Activin Receptor-Like Kinase 3 Directly Couples Gαq (Guanine Nucleotide-Binding Protein Subunit αq)/ Gαq (Guanine Nucleotide-Binding Protein Subunit α11) to Regulate Vascular Contractility
Authors: Cai Zeyu , Xie Nan , Gong Ze , Yang Zhao , Lin Feng , Li Zhiqing , Dai Rongbo , Chen Yufei , Zhang Siting , Zhu Shirong , Zhou Shuhua , Lin Jingyu , Yu Fang , Liu Limei , Sun Jinpeng , Zhou Jing , Li Wei , Xiong Chunyang , Fu Yi , Cong Xin , Kong Wei 
Published: March 2023

Background:
Vascular smooth muscle cell (VSMC) contractility is critical for blood pressure regulation and vascular homeostasis. Identifying the key molecule that maintains VSMC contractility may provide a novel therapeutic target for vascular remodeling. ALK3 (activin receptor-like kinase 3) is a serine/threonine kinase receptor, and deletion of ALK3 causes embryonic lethality. However, little is known about the role of ALK3 in postnatal arterial function and homeostasis.

Methods:
We conducted in vivo studies in a tamoxifen-induced postnatal VSMC-specific ALK3 deletion mice suitable for analysis of blood pressure and vascular contractility. Additionally, the role of ALK3 on VSMC was determined using Western blot, collagen-based contraction assay and traction force microscopy. Furthermore, interactome analysis were performed to identify the ALK3-associated proteins and bioluminescence resonance energy transfer assay was used to characterize Gαq activation.

Results:
ALK3 deficiency in VSMC led to spontaneous hypotension and impaired response to angiotensin II in mice. In vivo and in vitro data revealed that ALK3 deficiency impaired contraction force generation by VSMCs, repressed the expression of contractile proteins, and inhibited the phosphorylation of myosin light chain. Mechanistically, Smad1/5/8 signaling mediated the ALK3-modulated contractile protein expressions but not myosin light chain phosphorylation. Furthermore, interactome analysis revealed that ALK3 directly interacted with and activated Gαq (guanine nucleotide-binding protein subunit αq)/Gα11 (guanine nucleotide-binding protein subunit α11), thereby stimulating myosin light chain phosphorylation and VSMC contraction.

Conclusions:
Our study revealed that in addition to canonical Smad1/5/8 signaling, ALK3 modulates VSMC contractility through direct interaction with Gαq/Gα11, and therefore, might serve as a potential target for modulating aortic wall homeostasis.
Hobbes Among the Savages: Politics, War, and Enmity in the So-called State of Nature
Authors: Hillani Allan M. 
Published: March 2023

Abstract
In this article I argue that Thomas Hobbes’s theory of the “state of nature” should be understood as describing a thoroughly political situation. Hobbes’s exemplification of the state of nature by resorting to the “savages” of America should be taken in its ultimately paradoxical character, one that puts in question the stark opposition between a prepolitical natural state and the properly political state resulting from the “social contract.” Through the lenses of ethnographic studies and anthropological theory, I propose a reinterpretation of Hobbes’s characterization of the state of nature as a state of war. In the first section, I present my interpretation of Hobbes’s understanding of war, arguing that war is characterized not by actual battle but by the uncertainty of conflict, already entailing a social dimension to it. In the second section, I engage with Pierre Clastres’s theory of the society against the State to discuss how, for Amerindian peoples, war not only has a social character but is itself the basis of sociality. In the last section, I discuss Eduardo Viveiros de Castro’s theory of potential affinity to propose that Hobbes’s state of nature is also a form of schematization of alterity as enmity. I conclude by showing how this provides an understanding of peace as a precarious situation, one that is the outcome of ethical practices ultimately independent from the State.
Hate Speech and Atrocity Prevention in Asia: Patterns, Trends and Strategies
Authors: Jacob Cecilia , Morada Noel M. 
Published: March 2023

Abstract
This article introduces the conceptual and analytical framework for this special issue on hate speech and atrocity prevention in Asia. It defines hate speech and incitement, and explains the process and context through which hate speech and incitement operates as a risk factor for atrocities. It also provides an explanation of the international legal framework regulating hate speech and incitement that informs the approach of the articles in this issue.
Large Fraction of Winter Precipitation Variability in Two Major Himalayan Basins Explained by Atmospheric Rivers
Authors: Lyngwa Rosa Vellosa , Hassan Waqar Ul , Nayak Munir Ahmad , Azam Mohd. Farooq 
Published: March 2023

Abstract
Atmospheric rivers (ARs) have the potential to generate large-impact hydrometeorological events over mountainous topography. In this study, we investigate ARs’ impacts on the hydrology of Indus basin (IB) and Ganga basin (GB), two highly populated basins of the Himalayas. We used the recently developed 37-yr-long ERA5-based AR database over the Himalayas to explore the influence of ARs on total and extreme precipitation, snowfall, and floods over these basins. We find that ARs contribute ∼25% to the annual rainfall in the IB and ∼15% in the GB. Over the mountainous regions, ARs contribute more than 50% to winter precipitation in Karakoram (KA), Hindu–Kush (HK), central (CH), and western Himalayas (WH), and respectively explain over 75%, 57%, 42%, and 30% of their interannual variability. The seasonal rainfall extremes over the mountain foothills are most often (50%–100%) associated with ARs in winter and spring, whereas the summer and autumn extremes over the plains and mountains foothills appear moderately associated with ARs (10%–40%). The two most catastrophic flood events (2014 Kashmir flood and 2013 Uttarakhand flood) in these basins are found to be linked with category 5 ARs. Upon further examination of floods over a long period, we noted that 56% and 73% of the floods in IB and GB, respectively, are related to ARs. Thus, our results establish that the variance of ARs is a major source of hydroclimate variability in the two Himalayan basins.
Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism
Authors: Park Haesuk , Jones Bobby L. , Huang Pei-Lin , Kang Hye-Rim , Dietrich Eric A. , DeRemer Christina E. , Lo-Ciganic Wei-Hsuan 
Published: March 2023

Background: Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. Objective: We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. Methods: Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. Results: Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. Conclusion and relevance: This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.
Fetal Supraventricular Tachycardia: Histologic Evidence of Accessory Pathways Due to Incomplete Annulus Fibrosus Formation
Authors: Fritsch Michael K. , Gotteiner Nina , Rehman Jamaal A. , Price Erica , Ernst Linda M. 
Published: March 2023

Background: Atrioventricular (AV) reentrant tachycardia is a common type of supraventricular tachycardia (SVT) that occurs in the fetus and neonate. Although many tachycardias resolve within several weeks of birth or respond to medical management, disruptions in the cardiac annulus fibrosus and development of additional accessory pathways may lead to refractory dysrhythmia resulting in fetal hydrops and ultimately, fetal death. Objectives: While accessory pathways have been well documented anatomically in adult and childhood tachyarrhythmias, there are no reports of the histology of these pathways in human fetuses with SVT. Research Design, Subjects, Measures: This is a small case series of 2 fetuses with a history of SVT that resulted in fetal hydrops. Results: In both cases, examination of the cardiac conduction system was unremarkable and examination of the atrioventricular junction revealed a focally thinned and/or discontinuous annulus fibrosus with documented direct continuity between the atrial and ventricular myocardium in 1 case. Conclusions: This case series demonstrates that thinning or absence of the annulus fibrosus is a feature seen in fetal SVT, and the development of subsequent aberrant AV connections due to defective formation of the annulus fibrosus suggests a possible cause for these arrhythmias.
Doxycycline sclerotherapy in patients with periorbital lymphatic malformation: A case series and literature review
Authors: Lai Kenneth K.H. , Kwok Yuen Ting , Lam Stacey C. , Lam Matthew C.W. , Yuen Hunter K.L. 
Published: March 2023

Purpose To describe and report the outcomes of doxycycline sclerotherapy in patients with periorbital lymphatic malformations(LMs). Basic procedures A retrospective review of consecutive patients diagnosed with periorbital LMs and who received doxycycline sclerotherapy at Hong Kong Eye Hospital and Queen Elizabeth Hospital, Hong Kong between January 2016 and June 2022. Doxycycline was prepared with a concentration of 100 mg diluted in 10 mL water for injection. A 23-gauge needle aiming at the center of the macrocyst was used to aspirate fluid from the lesion; this was then followed by an intralesional injection of 0.5 to 2 ml of doxycycline depending on the size of the cavity. Main findings A total of eight patients(six females) were included in this study. All of them received doxycycline sclerotherapy for periorbital LMs(five extraconal, three intraconal). The median age for receiving sclerotherapy was 29 years old. Seven patients had macrocystic LMs, and one had mixed macro- and microcystic LM. Two of the LMs had venous components radiologically. The average number of sclerotherapy treatment in one patient was 1.4 ± 0.7times. Seven of the eight patients had excellent response radiologically or clinically. One patient showed a satisfactory response after three cycles of sclerotherapy. No recurrence was experienced at median follow-up of 14 months. None of the patients experienced visual threatening or systemic complication. Principle conclusions Our preliminary experience with doxycycline sclerotherapy has shown encouraging results for the treatment of macrocystic or mixed-type periorbital LMs, with a favourable safety profile. Further clinical trials with longer follow-ups are warranted on this topic.
An Occupation-Based Lifestyle Lecture Intervention as Part of Inpatient Addiction Recovery Treatment: Exploring Occupational Performance, Balance and Personal Recovery
Authors: Ryan Deirdre , Naughton Marie , de Faoite Meabh , Dowd Tara , Morrissey Ann-Marie 
Published: March 2023

Introduction: Substance use disorders (SUDs) and addictive behaviours are growing problems which negatively impact health and wellbeing. Occupational therapy can support recovery by facilitating engagement in everyday activities that promote health. To date, the inclusion of occupational therapy in addiction recovery is limited and the evidence base for occupation-focused interventions is lacking. This study explores the impact of an occupational therapy-led intervention on self-reported occupational performance and occupational balance issues for people living with SUDs within an inpatient addiction service. Methodology: A quantitative pre and post-test study was implemented. The Canadian Personal Recovery Outcome Measure (C-PROM) was the sole outcome measure. The C-PROM is a self-report measure which aims to measure personal views of recovery based on rating activity engagement. The cohort of participants were recruited from referrals into 2 inpatient addiction recovery treatment programmes using purposive sampling. Descriptive statistics were run, and a Wilcoxon Signed Rank Test was used to analyse pre and post-test scoring. Results: Sixteen participants (9 male and 7 female) completed the intervention and outcome measure. The majority of participants (31.3%, n = 5) were between 45 and 54 years old. 25% of the sample (n = 4) were in the 35 to 44 age bracket while 18.8% (n = 3) were aged 55 to 64. The majority of participants (68.8%, n = 11) reported substance misuse as their main healthcare concern. The mean score on the C-PROM was significantly higher after participants received the intervention when compared with baseline scoring. Conclusion: Following engagement with an occupational therapist-led intervention participants reported increased engagement in activities and occupational performance. Participants also reported improved occupational balance and increased awareness of personal recovery needs. Further research is required to explore the effectiveness of this intervention in larger samples and to explore the transferability and sustainability of skills post discharge.