A Fallacy of Division: The Failure of Market Concentration as a Measure of Competition in U.S. Banking

Empirical literature and related legal practice using concentration as a proxy for competition measurement are prone to a fallacy of division, as concentration measures are appropriate for perfect competition and perfect collusion but not intermediate levels of competition. Extending the classic Cournot-type competition model of Cowling and Waterson (1976) and Cowling (1976) used to derive the Hirschman-Herfindahl Index (HHI) of market concentration, we propose an adaptation of this model that allows collusive rents for all, none, or some of the firms in a market. Application of our model to data for U.S. commercial banks in the period 1984-2004 confirms that concentration measures are unreliable competition metrics. While collusion is prevalent in the banking industry at the state level, the critical market shares at which market power is achieved, rents earned from collusion, and collusive concentration levels vary widely across states. These and other results lead us to conclude that a fallacy of division exists in concentration-based competition tests.SCP hypothesis, competition, Cournot, conjectural variation, efficiency hypothesis

CRISPR-Cas9 mediated cell line engineering of apoptosis pathways increases antibody expression with site-specific modifications for antibody drug conjugation

New generation of antibody drug conjugates (ADCs) have expanded the repertoire of antibody drugs in the clinic and the market for cancer and inflammation indications by using highly stable linkers to attach potent small-molecule drug to various targeting antibodies. The drug and site of drug linkage to the antibody can have profound impact on the physiochemical properties and pharmacological profile of the ADC. Ambrx has developed a technology, Eukaryotic Chemical Orthogonal Directed Engineering (EuCODE), which allows non-natural amino acids with diverse physicochemical and biological properties to be genetically encoded and site-specifically incorporated into proteins/antibodies in mammalian cells. The non-natural amino acid provides a handle for the attachment of a small-molecule drug to generate homogenous ADC with a defined Drug-to-Antibody Ratio (DAR). To establish a CHO expression system for high production of monoclonal antibodies (mAbs) containing non-natural amino acids, we successfully generated a EuCODE platform cell line stably expressing engineered amber suppressor tRNA and its cognate tRNA synthetase specific for non-natural amino acid para-acetyl phenylalanine (pAF). When transfected with antibody of interest engineered with amber nonsense codon (TAG) at selected sites suitable for drug conjugation, this EuCODE platform cell line generates stable cell lines producing pAF containing mAbs for site-specifically conjugated ADC. In order to improve production titers of pAF containing antibody and achieve a robust platform, the platform cell line and stable cell lines were further evolved using CRISPR/Cas9 genome editing technology to sequentially knock out selected genes in glutamine synthesis and apoptosis pathways to improve selection efficiency and prevent loss of viable cell mass in production cultures, respectively. Inhibition of apoptosis pathway leads to dramatic increase in viable cell mass and results in extended production time and increased productivity. Phenotypic and genetic properties of these CRISPR engineered cell lines and product quality of the antibody will be discussed in the context of using the platform to develop a commercial manufacturing cell line

Sir2-Independent Life Span Extension by Calorie Restriction in Yeast

Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes

Confucian Principles: A Study of Chinese Americans’ Interpersonal Relationships in Selected Children’s Picturebooks

[[abstract]]There has not been enough critical analysis of children’s literature by and about Chinese Americans, especially when compared to other minority groups in the United States. In particular, Chinese American historical books lack extensive analysis. It is important to reflect cultural accuracy in literature and to help children develop clear concepts of self and others by providing precise cultural and physical characteristics of people. While cultural authenticity allows children the opportunity to see a reflection of real experiences within a book instead of seeing stereotypes or misrepresentations, obtaining correct information about a certain time period can help children to see images of immigration accurately represented in literature. Using the Confucian delineation of interpersonal relationships as the major criterion of cultural authenticity, this article examines three currently available children’s picturebooks set in the historical period between 1848 and 1885. In addition to exploring how Chinese Americans’ interpersonal relationships are portrayed in these children’s historical books, this article argues for more proactive inclusion of the diversity in selection of picturebooks.[[notice]]補正完

The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.Peer reviewe

Patients' attitudes and experiences of transition from paediatric to adult healthcare in rheumatology: a qualitative systematic review

Objectives. We aimed to describe patients' attitudes and experiences of transition from paediatric to adult healthcare in rheumatology to inform patient-centred transitional care programmes. Methods. We searched MEDLINE, EMBASE, PsycINFO and CINAHL to August 2019 and used thematic synthesis to analyse the findings. Results. From 26 studies involving 451 people with juvenile-onset rheumatic conditions we identified six themes: a sense of belonging (comfort in familiarity, connectedness in shared experiences, reassurance in being with others of a similar age, desire for normality and acceptance); preparedness for sudden changes (confidence through guided introductions to the adult environment, rapport from continuity of care, security in a reliable point of contact, minimizing lifestyle disruptions); abandonment and fear of the unknown (abrupt and forced independence, ill-equipped to hand over medical information, shocked by meeting adults with visible damage and disability, vulnerability in the loss of privacy); anonymous and dismissed in adult care (deprived of human focus, sterile and uninviting environment, disregard of debilitating pain and fatigue); quest for autonomy (controlled and patronized in the paediatric environment, liberated from the authority of others, freedom to communicate openly); and tensions in parental involvement (overshadowed by parental presence, guilt of excluding parents, reluctant withdrawal of parental support). Conclusion. Young people feel dismissed, abandoned, ill-prepared and out of control during transition. However, successful transition can be supported by preparing for changes, creating a sense of belonging and negotiating parental involvement and autonomy. Incorporating patient-identified priorities into transitional services may improve satisfaction and outcomes in young people with juvenile-onset rheumatic conditions.A.T. is supported by a National Health and Medical Research Council Fellowship (ID 1106716)

Patient and parent perspectives on transition from paediatric to adult healthcare in rheumatic diseases: an interview study.

OBJECTIVES: To describe the experiences, priorities, and needs of patients with rheumatic disease and their parents during transition from paediatric to adult healthcare. SETTING: Face-to-face and telephone semistructured interviews were conducted from December 2018 to September 2019 recruited from five hospital centres in Australia. PARTICIPANTS: Fourteen young people and 16 parents were interviewed. Young people were included if they were English speaking, aged 14-25 years, diagnosed with an inflammatory rheumatic disease (eg, juvenile idiopathic arthritis, juvenile dermatomyositis, systemic lupus erythematosus, panniculitis, familial Mediterranean fever) before 18 years of age. Young people were not included if they were diagnosed in the adult setting. RESULTS: We identified four themes with respective subthemes: avoid repeat of past disruption (maintain disease stability, preserve adjusted personal goals, protect social inclusion); encounter a daunting adult environment (serious and sombre mood, discredited and isolated identity, fear of a rigid system); establish therapeutic alliances with adult rheumatology providers (relinquish a trusting relationship, seek person-focused care, redefine personal-professional boundaries, reassurance of alternative medical supports, transferred trust to adult doctor) and negotiate patient autonomy (confidence in formerly gained independence, alleviate burden on patients, mediate parental anxiety). CONCLUSIONS: During transition, patients want to maintain disease stability, develop a relationship with their adult provider centralised on personal goals and access support networks. Strategies to comprehensively communicate information between providers, support self-management, and negotiate individualised goals for independence during transition planning may improve satisfaction, and health and treatment outcomes

Co-creation using crowdsourcing to promote PrEP adherence in China: study protocol for a stepped-wedge randomized controlled trial.

BACKGROUND: Adherent pre-exposure prophylaxis (PrEP) uptake can prevent HIV infections. Despite the high HIV incidence, Chinese key populations have low PrEP uptake and adherence. New interventions are needed to increase PrEP adherence among key populations in China. Co-creation methods are helpful to solicit ideas from the community to solve public health problems. The study protocol aims to describe the design of a stepped-wedge trial and to evaluate the efficacy of co-created interventions to facilitate PrEP adherence among key populations in China. METHODS: The study will develop intervention packages to facilitate PrEP adherence among Chinese key populations using co-creation methods. The study will then evaluate the efficacy of the co-created intervention packages using a stepped-wedge randomized controlled trial. This four-phased closed cohort stepped-wedge design will have four clusters. Each cluster will start intervention at three-month intervals. Seven hundred participants who initiated PrEP will be recruited. Participants will be randomized to the clusters using block randomization. The intervention condition includes receiving co-created interventions in addition to standard of care. The control condition is the standard of care that includes routine clinical assessment every 3 months. All participants will also receive an online follow-up survey every 3 months to record medication adherence and will be encouraged to use a WeChat mini-app for sexual and mental health education throughout the study. The primary outcomes are PrEP adherence and retention in PrEP care throughout the study period. We will examine a hypothesis that a co-created intervention can facilitate PrEP adherence. Generalized linear mixed models will be used for the primary outcome analysis. DISCUSSION: Developing PrEP adherence interventions in China faces barriers including suboptimal PrEP uptake among key populations, the lack of effective PrEP service delivery models, and insufficient community engagement in PrEP initiatives. Our study design addresses these obstacles by using co-creation to generate social media-based intervention materials and embedding the study design in the local healthcare system. The study outcomes may have implications for policy and intervention practices among CBOs and the medical system to facilitate PrEP adherence among key populations. TRIAL REGISTRATION: The study is registered in Clinical Trial databases in China (ChiCTR2100048981, July 19, 2021) and the US (NCT04754139, February 11, 2021)

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified

Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel

10.1371/journal.pone.0093409PLoS ONE94-POLN