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The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization’s new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022–2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a ‘neurological revolution’ across four key pillars — surveillance, prevention, acute care and rehabilitation — termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Given the limited right to assembly in China, a mass feminist movement that confronts the Communist Party is unlikely to materialize, argues historian Maura Elizabeth Cunningham. But fragmented and incremental pushes for women's rights will continue for years to come, and they will be no less revolutionary for being quiet.

Is China bent on world domination? Although Americans perceived the Soviet Union as posing the greatest Cold War-era military challenge, they also periodically feared a “China threat” during those decades. Since the days of Mao, the PRC’s penchant for staging parades showing off its...

What were the main early dynasties? A standard way to break up Chinese history is to start with 221 b.c.e., the year that Qin Shi Huang transformed various small states into something big enough to qualify as an empire. There were earlier...

Who was Sun Yat-sen? Sun Yat-sen has been hailed as the founding father of the ROC and likened to George Washington in more than a few Chinese textbooks. Sun has the rare distinction of having been treated as a hero on both sides of...

What is the most common thing Americans get wrong about China? The preceding chapters have drawn attention to some important sources of US misunderstanding of Chinese realities. Discussion of the One-Child Policy, for example, noted a tendency for Americans to treat unintended side-effects of...

Who was Deng Xiaoping? Deng’s first revolutionary experiences were as a student in France in the 1920s, when he developed a lasting friendship with a fellow radical youth named Zhou Enlai (throughout much of the Mao era, the second-most-important person in China) and became...

Summary This letter addresses the controversial issue of the use of oral corticosteroids during wheezing exacerbations in preschool-aged children by demonstrating findings of a prematurely terminated multi-center clinical trial, discussing lessons learned, and suggesting future directions.

Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived from pediatric solid tumors against a collection of ∼3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors.

Evidence indicates that nurses inconsistently engage in evidence-based practice (EBP). This cross-sectional study of 402 nurses at a medical-surgical hospital identifies strategies for augmenting EBP. Nurses' EBP beliefs scores were higher than their EBP implementation scores. Those with baccalaureate/postgraduate degrees had higher EBP beliefs and implementation scores than those with associate degrees or diplomas. Bedside or direct care nurses were less likely to have baccalaureate/higher degrees and had lower EBP beliefs and implementation scores than did those nurses not serving in direct care roles.

Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

Purpose To report the overall survival (OS) and clinical characteristics of BRAF inhibitor–naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation–positive metastatic melanoma. Methods BRAF inhibitor–naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non–randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. Results For BRAF inhibitor–naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. Conclusion Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor–naive patients with BRAF V600 mutation–positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

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Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft–bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

TPS1114 Background: Advanced or metastatic ER+BC (estrogen receptor positive breast cancer) is an incurable illness that will prove fatal for most afflicted women. Current standards of care include endocrine, targeted, and chemotherapy. Preclinical data suggest that reducing expression of the estrogen receptor (ER) as well as other ER-responsive genes may provide therapeutic benefit for women for whom endocrine therapy alone has proven inadequate. The bromodomain (BRD) and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) bind to acetyl-histone residues and epigenetically control transcription of genes driving cell survival and proliferation. In preclinical models, BET proteins reduce ER expression and down regulate ER-dependent gene expression and may be a novel therapeutic target in multiple tumors e.g. ER+BC. GSK525762 is a pan-BET inhibitor showing strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. The combination of BET agents with endocrine therapy may provide therapeutic benefit and restore sensitivity to ER targeting agents like fulvestrant. Methods: The study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control (Phase II) study with oral administration of GSK525762 in combination with fulvestrant in advanced or metastatic ER+BC subjects, whose disease has progressed on prior treatment with ≥ 1 line of endocrine therapy. Phase I of the study is designed as parallel single arms to determine the recommended Phase 2 dose based on safety, tolerability, PK, and efficacy profiles in two distinct populations of ER+ BC: 1. Subjects with disease that progressed on anti-estrogen and/or ≥ 1 AIs, OR. 2. Subjects with disease that progressed on CDK4/6 inhibitor plus letrozole. Phase I will employ a Bayesian predictive adaptive design. Phase II of the study is a randomized, double-blind, placebo-controlled study, the composition of which will be selected at the end of Phase I. Patients must have received < 3 lines of anti-cancer therapy (≤1 line of chemo), measurable disease, and PS 0-1. Funding: GSK. Clinical trial information: NCT02964507.

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [¹⁴C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.

This chapter begins with a brief history of athletics in late Imperial and early-Republican China. It offers a close reading of issues of Liangyou from the magazine's launch in 1926 through 1932 to examine how the depiction of sportswomen in this publication changed over time. One of Liangyou 's trademark features is that almost every issue of the magazine featured a cover photograph of a "beautiful girl" from Shanghai. While the beautiful girls of the magazine's covers and the debutantes of its society pages pose for the camera, the women who appear in Liangyou sports features are truly modern girls in motion. Early Chinese reformers might have hoped that participation in athletics would serve to emancipate women, but Tiyu huanghou and Liangyou both offer examples of how women's sports could be used to satisfy the male gaze and present a model of femininity for female viewers to reproduce. Keywords: early Chinese reformers; early-Republican China; femininity; Liangyou ; Shanghai; sportswomen; Tiyu huanghou

9010^ Background: D, a selective BRAF inhibitor, and T, a reversible, highly selective allosteric inhibitor of MEK1/2, are approved monotherapies, and an FDA approved combination therapy for BRAFV6...

3517 Background: BRAF V600 mutations occur in 5-15% of metastatic CRC and predict poor prognosis. Although highly effective in BRAF mutant melanoma, BRAF inhibitor monotherapy has shown poor effica...

This study has examined the effect of an alpha-1 adrenergic agonist (phenylephrine HCl, 2.5%) and a non-selective alpha antagonist (thymoxamine HCl, 0.5%) on tonic accommodation (TA). TA was measured at 1 min intervals throughout a 45 min period using an objective infra-red optometer (Canon Autoref R-1). Additionally pupil diameter and the near-point of accommodation (NPA) were monitored in order to assess the efficacy of the instilled drug. A double-blind protocol was adopted between thymoxamine, phenylephrine and a saline control for 7 emmetropic subjects. There was no significant difference between the values of TA obtained under the three pharmacological conditions. However, both adrenergic agents induced changes in pupil diameter and NPA. Furthermore in all conditions TA increased by approximately 0.25D while the subject sat passively in darkness. The data indicates that alpha-adrenergic innervation alters the closed-loop accommodative response independently of TA.

Data dictionaries (DD) hold information about data held by an organization. The most important features of DDs to an auditor are security and reporting. DDs can be difficult to compare as there is no agreed standard for their design. One company had problems in finding a suitable DD and implementing it.