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This paper investigates the sluicing-like constructions (SLCs) in Isbukun Bunun, a language which always places its wh-words at the left-peripheral position, and it is argued that genuine sluicing is not available in this language. The evidence in favor of the pseudo-sluicing analysis draws on the behavior of how-phrases, the failure of implicit discourse anaphoric arguments and the absence of sloppy identity reading in Isbukun SLCs. These properties are otherwise hard to accommodate in a movement and deletion approach but rather follow from the view that SLCs in Isbukun Bunun are derived from independent syntactic operations including pro-drop.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease. Mutations in desmosome gene Plakophilin-2 (PKP2) account for 45% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. We demonstrated that a single-dose cardiac AAV9:PKP2 gene delivery effectively prevented disease development before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. These results indicate that cardiac AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Pheochromocytomas are rare neuroendocrine tumors that may secrete catecholamines, resulting in a wide array of clinical symptoms. While patients classically present with hypertension, headache, diaphoresis, and flushing, these symptoms are present in only 40% of cases. Here, we describe a 70-year-old woman whose predominant symptom was unexplained severe weight loss over a 12-month period associated with fatigue, anxiety, and palpitations at her endocrinologist and geriatrician visits. Diagnostic imaging was performed to assess for malignancy and demonstrated a 2.0 cm × 2.0 cm left adrenal mass. The diagnosis of pheochromocytoma was confirmed by elevated plasma normetanephrine levels. After a 2-week alpha blockade with doxazosin, the patient underwent robotic left adrenalectomy. Following surgery, the patient regained weight, and her hypertension also improved significantly. We hope this uncommon clinical presentation in an older adult characterized by weight loss and frailty will increase the awareness of atypical pheochromocytoma symptomatology, particularly in older individuals.

In DESTINY-Breast01 (NCT03248492) and DESTINY-Breast03 (NCT03529110), trastuzumab deruxtecan (T-DXd) demonstrated unprecedented activity in patients (pts) with HER2+ (immunohistochemistry 3+; immunohistochemistry 2+/in situ hybridization+) advanced metastatic breast cancer (mBC), leading to regulatory approvals in several countries for HER2+ unresectable/mBC after a prior anti–HER2-based regimen. DESTINY-Breast02 (NCT03523585) is a phase 3 trial of T-DXd vs treatment of physician’s choice (TPC) in patients with centrally confirmed HER2+ mBC previously treated with trastuzumab emtansine (T-DM1). It acts as a confirmatory study for the pivotal phase 2 DESTINY-Breast01 trial. Here we report the primary results of DESTINY-Breast02. Methods: Pts with HER2+ mBC were randomized 2:1 to receive T-DXd or TPC (trastuzumab + capecitabine or lapatinib + capecitabine) and stratified by hormone receptor (HR) status (HR+/HR-), prior pertuzumab treatment, and history of visceral disease. The primary endpoint of this time-driven primary analysis was progression-free survival (PFS) as determined by blinded independent central review (BICR). The powered secondary endpoint was overall survival (OS). Other secondary endpoints included confirmed objective response rate (ORR) by BICR, duration of response (DoR) by BICR, PFS by investigator assessment, safety, and others. Results: 608 pts were randomized to receive T-DXd (n = 406) or TPC (n = 202). Pts receiving T-DXd and TPC had a median age of 54.2 years (range, 22.4-88.5 years) and 54.7 years (range, 24.7-86.5 years), respectively, with a median of 2 (range, 0-10 and range,1-8) prior lines of systemic therapy (excluding hormone therapy) in the metastatic setting. Median treatment duration was 11.3 mo in the T-DXd arm and ~4.5 mo in the TPC arm. Efficacy and safety results are shown in the table below. T-DXd significantly improved PFS (HR, 0.36; 95% CI, 0.28-0.45; P Conclusions: Results from DESTINY-Breast02 confirmed the clinical benefit and superiority of T-DXd over conventional chemotherapy-based regimens in pts with HER2+ mBC previously treated with T-DM1, as evidenced by significant and clinically meaningful improvements in PFS and OS. These data, together with earlier reported results from the DESTINY-Breast03 study of T-DXd vs T-DM1 solidify T-DXd as an optimal treatment option in pts with progressive HER2+ mBC across broad settings. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Caylin Bosch, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy and Safety Results for T-DXd and TPC in Patients With HER2+ mBC Previously Treated With T-DM1 Citation Format: Ian Krop, Yeon H. Park, Sung-Bae Kim, Giuliano Borges, Sercan Aksoy, Joaquin Gavila Gregori, Rebecca Roylance, Elgene Lim, Rinat Yerushalmi, Flora Zagouri, Francois P. Duhoux, Tanja Fehm, Toshimi Takano, Anton Egorov, Iris Wu, Jillian Cathcart, Changan Chu, Fabrice Andre. GS2-01 Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-01.

A basket trial investigates the effects of one drug on multiple tumor indications. To discontinue potentially inactive indications early, an interim futility analysis is usually conducted for each indication individually once it reaches the pre-specified sample size. As enrollment rates vary among indications, the futility decisions for slow-enrolling indications could be made much later than other fast-enrolling indications, which could delay the overall decision for the trial significantly. To accelerate the futility decision in early-stage exploratory basket trials and potentially reallocate resources to other compounds earlier while still controlling the global type-I and type-II errors, we propose an optimal two-stage basket trial design with one aggregated futility analysis by aggregating (e.g., pooling) all indications together. The total sample size across all indications is pre-specified for the futility analysis, while the sample size per indication can be adapted to the enrollment rate. The final analysis is performed using the pruning and pooling approach (Chen et al. 2016). The design parameters are optimized by minimizing the expected total sample size under the null hypothesis, while explicitly controlling the global type-I and the type-II error rates. Simulation studies demonstrate that the proposed design has better operating characteristics than the designs with individual futility analysis (Zhou et al. 2019; Wu et al. 2021), while allowing for earlier futility decision.

By drawing on new verbal reduplication data of tentative constructions in Mandarin Chinese, this paper provides an interesting argument for the conception of phases and its corollary, Phase Impenetrability Condition (Chomsky 2001, 2004, 2008). In particular, it is observed that common lexical verbs are compatible with two templatic reduplication patterns whereas an independent light verb is only allowed to occur in one reduplicative form. We demonstrate that the noted discrepancies can receive a proper characterization by admitting the special status of spelled‐out light verb v and the phase it introduces in a phase‐based model of syntax‐morphology interface computation, where it is hypothesized that derivations must proceed cyclically and locally.

This paper examines the morpho-syntactic properties of elements that realize adverbial meanings in Isbukun Bunun and investigates how its adverbs are syntactically represented. I show that most adverbial meanings are realized as verbs in this language, with only a few adverbial expressions realized as adverbs in the traditional sense. Specifically, the adverbial verbs, just like typical verbs, have to occur sentence-initially, take inflectional morphology and attract cliticization, whereas the genuine adverbs are invariable in form and exhibit relatively free distribution. The paper also presents evidence which bears on the debate concerning the syntax of adverbials and shows that a hybrid treatment is needed in which phrasal adverbs are adjoined to clauses while adverbial verbs are located in strictly-ordered functional projections in the backbone of the clause.

This paper develops the empirical and theoretical basis for the necessity in admitting the operation of verb-stranding ellipsis (VVPE) in Chinese. I present new arguments showing that, though two analytic possibilities — null argument analysis and VVPE analysis — are in principle available in the grammar of Chinese, they can be differentiated in specific syntactic environments. In particular, I show that the existing null argument approaches would have difficulty in accounting for the following facts: disjunction of multi-constituent elements under negation, the difference of island effects in the presence of a linguistic antecedent, the verb identity requirement and the possibility of having part of the idiomatic expression as the missing gap. Therefore, it is argued that VVPE must remain a viable syntactic operation in Chinese when a null object analysis is unavailable.

This paper investigates the correlative construction in Isbukun Bunun, an Austronesian language spoken in Taiwan. I show that in this language the correlative clause and its associated anaphoric element do not form a constituent at any point in the derivation. Drawing on evidence from island-insensitivity, the absence of Condition C effects and non-constituency facts, I propose that the syntactic relation between the correlative clause and the nominal correlate is derived by a base-generated adjunction structure. Moreover, I argue that the correlative clause, which behaves as a generalized quantifier, binds the nominal correlate phrase in the matrix clause, which is construed as a bound variable. The proposed quantificational binding view is further shown to capture the types of correlate phrases allowed in Isbukun Bunun correlatives. Resume: Cet article etudie la construction correlative de l’Isbukun Bunun, une langue austronesienne parlee a Taiwan. Je demontre que la proposition correlative et l’element anaphorique avec lequel elle est associee ne forment pas un constituant dans cette langue. En raison de l’absence de la sensibilite aux ilots, de l’absence des effets de la Condition C et de l’absence de la constitution syntaxique, je propose que la relation entre la correlative et le correlat nominal est derivee par l’adjonction dans une position de base. En outre, je propose que la correlative, dont le comportement est similaire a celui d’un quantificateur generalise, lie le correlat nominal dans la proposition principale lequel est interprete comme une variable liee. Cette analyse explique les types de correlats qui sont autorises dans la langue.

The primary goal of an exploratory oncology clinical trial is to identify an effective drug for further development. To account for tumor indication selection error, multiple tumor indications are often selected for simultaneous testing in a basket trial. In this article, we propose optimal and minimax two-stage basket trial designs for exploratory clinical trials. Inactive tumor indications are pruned in stage 1 and the active tumor indications are pooled at end of stage 2 to assess overall effectiveness of the test drug. The proposed designs explicitly control the type I and type II error rates with closed-form sample size formula. They can be viewed as a natural extension of Simon's optimal and minimax two-stage designs for single arm trials to multi-arm basket trials. A simulation study shows that the proposed design method has desirable operating characteristics as compared to other commonly used design methods for exploratory basket trials.

This paper investigates the syntactic status of nominal modifiers in Isbukun Bunun, an Austronesian language spoken in Taiwan. In Isbukun Bunun, nominal modifiers such as possessors, adjectives, demonstratives, and relative clauses precede the head noun they modify, and they may or must be linked to the head noun by an associative marker tu. Based on the observed NP-ellipsis facts and the formal licensing condition, I argue that the associative marker tu is a complementizer, and the structure it introduces should be accommodated under the adjunction analysis, whereas various existing alternative complementation approaches that view tu as a head selecting the modified phrase as its complement fail to capture the noted properties regarding ellipsis. 1. INTRODUCTION. (1) In many languages, complex noun phrases contain an apparently meaningless, and sometimes optional, element whose function is to provide a link between modifiers and modifiees. The existence of such a linking element or associative marker is attested in several Formosan Austronesian languages (He et al. 1986; Huang 1997,2000; Chang 2000; Wu 2000; Zeitoun 2000; Tang 2007), and in a considerable number of other languages (cf den Dikken and Singhapreecha 2004), as exemplified in (1): (1) a. PAIWAN va'uan a kun new A skirt 'a new skirt' b. AMIS ma-su'su'-ay a tamdaw AV-fat-FAC A person 'a fat person' c. THAI khon thii ken person THII smart 'a smart person' d. MANDARIN CHINESE huangse de chenshan yellow DE shirt 'a yellow shirt' In the principles-and-parameters framework, grammatical constructions arise from the universal principles that work in tandem with parameters with values set for particular languages; therefore, it is very often shown that some intuitively equivalent constructions in two languages involve very different syntactic representations, since there are no a priori universal rules specific to a given construction. This paper examines complex noun phrases in Isbukun Bunun (often referred to as just Isbukun in this paper), and explores the nature of the associative element tu as well as the modification structure in this language. I will examine the existing approaches to such linking elements and investigate whether phrases like (2) should be analyzed as a relative construction or a pure complex nominal construction--or even some other construction. In particular, a careful examination of Isbukun nominal structure shows that Kayne's (1994) antisymmetry theory, which hypothesizes that phrase structure is universally head-initial, does not account for the syntactic patterns of complex noun phrases in Isbukun. (2) ISBUKUN BUNUN madiav *(tu) ulus AV.yellow TU clothes 'yellow clothes' This paper is structured as follows. Section 2 first provides some basics of the morphosyntax of Isbukun, and subsequently introduces the Isbukun tu-construction that is the focus of this study. Section 3 discusses possible accounts for the associative marker as pointed out in the literature, and further argues that tu is a complementizer that introduces an adjoined pure sentential modifier phrase to the modifiee, mainly based on the evidence from ellipsis. Section 4 concludes the paper. 2. THE EMPIRICAL BASE. Bunun is a Formosan Austronesian language spoken in Taiwan. The current study is based on the Isbukun dialect spoken in Taitung County. (2) Isbukun Bunun is a predicate-initial, or more specifically VSO, language (He et al. 1986; Li 1997; Huang 1997; Jeng 1999; Zeitoun 2000; Wu 2013). Just like many other Formosan and Western Austronesian languages, Isbukun Bunun permits a range of arguments to serve as the syntactically most prominent NP of the clause, marked by the a nominative case marker. Such an a-marked phrase has been known by a number of names in the Austronesian literature, including "subject," "topic," and "pivot"; here 1 will refer to it as the subject for ease of presentation, though this term should be regarded with caution. …

This paper presents a self-paced reading experiment comparing the processing of subject-extracted relative clauses (SRCs) and object-extracted relative clauses (ORCs) in supportive contexts in Chinese. It is argued that lack of a consistent pattern in the literature for the comparison between Chinese SRCs and ORCs is due to potential temporary ambiguity in these constructions in null contexts. By placing the materials in contexts biased towards a relative clause (RC) interpretation, we limit the effects of temporary ambiguity. The results of the experiment demonstrate that SRCs are read more slowly than ORCs in supportive contexts. These results provide evidence for working memory-based sentence processing theories whereby processing difficulty increases for connecting sentence elements that are further apart. Some convergent evidence that strengthens these conclusions comes from recent research on aphasic populations where a dissociation between English and Chinese RC processing has been revealed: whereas English aphasic patients have more difficulty with ORCs and Chinese aphasic patients have more difficulty with SRCs (Su, Lee, & Chung, 2007). Taken together, these results support the idea that sentence processing is constrained by working memory limitations., National Science Foundation (U.S.) (Grant No. 0844472)

This paper studies the restructuring phenomenon in Isbukun Bunun, which exhibits special morphology and syntax that distinguish it from sentences containing common infinitives. I demonstrate that a subclass of predicates should be analyzed as restructuring predicates in Isbukun Bunun, since they apparently create transparent domains for syntactic operations such as passivization and clitic placement. I argue that the lack of clause-boundedness effects in restructuring follows trivially from the functionally impoverished structure of the restructuring infinitives, so that this construction lacks clausal properties throughout the derivation.

This paper has two main goals. First, I demonstrate how the peculiar morphosyntactic properties of the theme NPs in Isbukun Bunun existential sentences can be derived under an expletive account. The properties under investigation include structural Case marking, the emergence of definiteness restrictions, and the resistance of theme NPs to A-extraction. Second, I argue for a small clause analysis of existential sentences in Isbukun Bunun. In particular, based on word orders, island effects, the comparison with possessive constructions, and the coordination facts, I argue that the existential predicate in Isbukun Bunun selects a small clause as its sole internal argument. I also discuss how the proposal developed for Isbukun Bunun might generalize to, and shed light on, the impersonal constructions in natural languages.

Cardiac resynchronization therapy, which involves the placement of a pacing lead in the right atrium and in each ventricle, is effective in treating heart failure that is caused by left bundle branch block and cardiomyopathy. The left ventricular lead is usually placed into a lateral branch of the coronary sinus via the subclavian route. When the subclavian route is unavailable, insertion of a standard, passive-fixation coronary sinus lead via the femoral approach is feasible; however, the likelihood of subsequent dislodgment is high. Herein, we describe the placement of a novel, self-retaining, active-fixation coronary sinus lead--the Attain StarFix Model 4195 OTW Lead--in an elderly heart-failure patient, via the femoral approach. We believe that this is the 1st report of this procedure.