Broad Selection Research Articles

The association between drugs and vaccines commonly prescribed to older people and bullous pemphigoid: a case-control study.

Bullous pemphigoid (BP) is an autoimmune skin disease that affects mainly older people. Numerous drugs have been previously associated with BP based on case series and small hospital-based studies. More reliable and precise estimates of associations between a broad selection of drugs/vaccines and BP will enable greater awareness of potential increased risk of BP following certain medicines and help identify clinical, histological and genomic characteristics of drug-induced BP for different types of culprit drugs. Greater awareness could lead to earlier recognition or suspicion of BP and referral to a dermatologist for diagnosis. Earlier diagnosis may lead to less aggressive treatment and improved well-being. To determine the association between drugs/vaccines commonly prescribed to older people and BP risk. We conducted a population-based nested case-control study between 1998-2021 using electronic primary care records from the Clinical Practice Research Datalink. We matched BP cases with up to 5 controls. Exposures were drugs/vaccines commonly prescribed to older people. We used multivariable conditional logistic regression adjusting for multiple drug use. For antibiotics, we considered prescriptions may be prescribed for undiagnosed symptoms of BP which resemble skin infection (protopathic bias) in a sensitivity analysis. Antibiotics were the therapeutic group associated with the highest risk of BP (OR: 4.60; 95%CI 4.40-4.80). However, after adjusting for protopathic bias, the OR reduced to 2.08 (95%CI 1.99-2.17). After adjusting for protopathic bias, of all antibiotic classes and subclasses, penicillins and penicillinase-resistant penicillins had the strongest associations with BP risk (OR: 3.44; 95%CI 3.29-3.60; sensitivity analysis OR; 1.74; 1.66-1.84 and OR: 7.56; 95%CI 7.15-8.00; sensitivity analysis OR: 2.64; 95%CI 2.45-2.85, respectively). Other drugs strongly associated with increased risk were gliptins (OR: 2.77; 95% CI 2.37-3.23), and second-generation antipsychotics (OR: 2.58; 95%CI 2.20-3.03). Healthcare professionals need to be aware of BP risk in older people particularly when prescribing penicillinase-resistant penicillins, gliptins, and second-generation antipsychotic drugs to recognise and manage BP early. Due to the low prevalence of disease, we do not suggest avoidance of drugs/vaccines to prevent BP. Further research should consider recency, dosage, and duration of antibiotic treatments.

Is Click Fading the Brick Experience of Buyers During Festivities?

This study explores the impact of technology and e-commerce on the festive shopping experience of Indian consumers. It highlights the shift from traditional in-store shopping to digital interactions and analyzes how brands enhance physical store experiences to increase foot traffic during the festive season. Findings suggest that while online shopping offers unparalleled convenience and a broad product selection, retailers must innovate and adapt to retain the charm and emotional connection associated with in-store shopping. This research aims to provide insights for both retailers and consumers regarding the evolving shopping landscape.

PPh3-catalyzed chemoselective reduction of aldehydes to alcohols

Reduction of aldehydes to alcohols is a fundamental organic transformation, typically achieved through metal-catalyzed reductions or by the use of hydride-based reagents. However, these conventional methods often go through harsh conditions with expensive catalysts and additional reductants, limiting their broader applications. In this study, for the first time we introduce an efficient, metal-free reduction strategy using triphenylphosphine (PPh3) and KOtBu in MeOH. This method exhibits broad functional group tolerance, mild environment and selectivity in reducing aldehydes even in the presence of other reactive functionalities (NO2, CN, ketone, etc.). Key features highlight this novel approach with practicality, scalability to gram scales and excellent yields for the reduction of varied aldehydes to alcohols (30 examples; 65–95 % Yields).

Porous Copolymers of 3-(Trimethoxysilyl)propyl Methacrylate with Trimethylpropane Trimethacrylate Preparation: Structural Characterization and Thermal Degradation

Porous polymeric microspheres are among the most effective adsorbents. They can be synthesized from numerous monomers using different kinds of polymerization techniques with a broad selection of synthesis factors. The main goal of this study was to prepare copolymeric microspheres and establish the relationship between copolymerization parameters and the porosity and thermal stability of the newly synthesized materials. Porous microspheres were obtained via heterogenous radical copolymerization using 3-(trimethoxysilyl)propyl methacrylate (TMPSM) as functional monomers and trimethylolpropane trimethacrylate (TRIM) as the crosslinker. In the course of the copolymerization, toluene or chlorobenzene was used as the pore-forming diluent. Consequently, highly porous microspheres were produced. Their specific surface area was established by a nitrogen adsorption/desorption method and it was in the range of 382 m2/g to 457 m2/g for toluene and 357–500 m2/g in the case of chlorobenzene. The thermal degradation process was monitored by thermogravimetry and differential scanning calorimetry methods in inert and oxidative conditions. The copolymers were stable up to 269–283 °C in a helium atmosphere, whereas in synthetic air the range was 266–298 °C, as determined by the temperature of 5% mass loss. Thermal stability of the investigated copolymers increased along with an increasing TMPSM amount in the copolymerization mixture. In addition, the poly(TMSPM-co-TRIM) copolymers were effectively used as the stationary phase in GC analyses.

Structural basis for sequence context-independent single-stranded DNA cytosine deamination by the bacterial toxin SsdA.

DNA deaminase toxins are involved in interbacterial antagonism and the generation of genetic diversity in surviving bacterial populations. These enzymes have also been adopted as genome engineering tools. The single-stranded (ss)DNA deaminase SsdA represents the bacterial deaminase toxin family-2 (BaDTF2) and it deaminates ssDNA cytosines with little sequence context dependence, which contrasts with the AID/APOBEC family of sequence-selective ssDNA cytosine deaminases. Here we report the crystal structure of SsdA in complex with a ssDNA substrate. The structure reveals a unique mode of substrate binding, in which a cluster of aromatic residues of SsdA engages ssDNA in a V-shaped conformation sharply bent across the target cytosine. The bases 5' or 3' to the target cytosine are stacked linearly and make few sequence-specific protein contacts, thus explaining the broad substrate selectivity of SsdA. Unexpectedly, SsdA contains a β-amino acid isoaspartate, which is important for enzymatic activity and may contribute to the stability of SsdA as a toxin. Structure- function studies helped to design SsdA mutants active in human cells, which could lead to future applications in genome engineering.

Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

Using Digital Game Wordwall in Supporting English Vocabulary Mastery

English, a global language, weaves through education, business, relationships, technology, and science. Mastering vocabulary is pivotal for English proficiency. Utilizing media for vocabulary learning engages and challenges students, rendering the process more enjoyable and effective. This study looks into the effectiveness of using the digital game Wordwall to assist English Vocabulary Mastery at SMP Negeri 8 Samarinda. This study is being undertaken with the eighth graders of SMP Negeri 8 Samarinda. In this study, the researcher uses a mixed method with quasi-experimental design to compare two classes. The focus of this research is eighth grade, namely VIII C and VIII D. VIII D is the experimental class with 21 students and VIII C is the control class with 27 students. The quantitative data is acquired using multiple choice and fill-in-the-blank tests. Qualitative data is gathered through interviews. The results suggest that Wordwall media is effective in improving the vocabulary. Furthermore, Wordwall is a game/application that adds excitement, enthusiasm, and enjoyment to the learning environment. Wordwall entices students to use the application because to its appealing interface, simple gameplay, and broad selection of games.

Chromatographic evaluation and application of nitrogenous heterocyclic ring-bonded stationary phase in hydrophilic interaction liquid chromatography

Hydrophilic interaction liquid chromatography (HILIC) based on polar stationary phases has vital research significance in the separation of polar compounds. Numerous HILIC stationary phases with different structures have been developed, which do not have universal properties and broad selectivity, making it a challenge to select the suitable column based on the properties of the samples. Consequently, it is particularly important to develop a bonded phase capable of separating a wide variety of samples, while having enhanced retention, improved selectivity, symmetric peak shape and good stability. Herein, a novel nitrogen-containing heterocyclic bonded phase with multiple functionalities, such as thioether, amino and hydroxyl groups (named AMTA) was employed as HILIC stationary phase. Detailed chromatographic evaluations were carried out, and the results showed that it was superior to other hydrophilic chromatographic columns in terms of selectivity, peak shapes and practical sample separation. Lastly, it has been verified that AMTA exhibited high orthogonality with the XBridge C18 column of reversed-phase liquid chromatography (RPLC) mode. In summary, we anticipate our assay to be instructive to other researchers in developing the HILIC stationary phase.

Visible Light‐Induced Cyanomethyl Radical Triggered Cascade Cyclization of Phenyl‐Linked 1,6‐Enynes with a‐Halogenated Acetonitriles

Photo‐promoted cyanomethyl radical procedures for the preparation of 2,3‐dihydro‐1H‐indenes and 2,8‐dihydrocyclopenta[a]indenes from phenyl‐linked 1,6‐enynes with α‐halogenated acetonitriles are reported. The iodocyanomethylation/cyclization is performed via an atom‐transfer radical addition (ATRA) strategy under photocatalyst‐ and oxidant‐free conditions. In particular, the photoinduced cyanomethylative cascade bicyclization is carried out under the fac‐Ir(ppy)3/Na2CO3 catalystic symtem and visible light irradiation. These methods offer a one‐step and atom‐economical access to diverse cyano‐group containing five‐membered rings with broad substrate scope and high selectivity. A plausible reaction mechanism is also proposed.

Accelerated differentiation of neo-W nuclear-encoded mitochondrial genes between two climate-associated bird lineages signals potential co-evolution with mitogenomes.

There is considerable evidence for mitochondrial-nuclear co-adaptation as a key evolutionary driver. Hypotheses regarding the roles of sex-linkage have emphasized Z-linked nuclear genes with mitochondrial function (N-mt genes), whereas it remains contentious whether the perfect co-inheritance of W genes with mitogenomes could hinder or facilitate co-adaptation. Young (neo-) sex chromosomes that possess relatively many N-mt genes compared to older chromosomes provide unprecedented hypothesis-testing opportunities. Eastern Yellow Robin (EYR) lineages in coastal and inland habitats with different climates are diverged in mitogenomes, and in a ~ 15.4 Mb nuclear region enriched with N-mt genes, in contrast with otherwise-similar nuclear genomes. This nuclear region maps to passerine chromosome 1A, previously found to be neo-sex in the inland EYR genome. To compare sex-linked Chr1A-derived genes between lineages, we assembled and annotated the coastal EYR genome. We found that: (i) the coastal lineage shares a similar neo-sex system with the inland lineage, (ii) neo-W and neo-Z N-mt genes are not more diverged between lineages than are comparable non-N-mt genes, and showed little evidence for broad positive selection, (iii) however, W-linked N-mt genes are more diverged between lineages than are their Z-linked gametologs. The latter effect was ~7 times stronger for N-mt than non-N-mt genes, suggesting that W-linked N-mt genes might have diverged between lineages under environmental selection through co-evolution with mitogenomes. Finally, we identify a candidate gene driver for divergent selection, NDUFA12. Our data represent a rare example suggesting a possible role for W-associated mitochondrial-nuclear interactions in climate-associated adaptation and lineage differentiation.

Discovery of the 1-naphthylamine biodegradation pathway reveals a broad-substrate-spectrum enzyme catalyzing 1-naphthylamine glutamylation.

1-Naphthylamine (1NA), which is harmful to human and aquatic animals, has been used widely in the manufacturing of dyes, pesticides, and rubber antioxidants. Nevertheless, little is known about its environmental behavior and no bacteria have been reported to use it as the growth substrate. Herein, we describe a pathway for 1NA degradation in the isolate Pseudomonas sp. strain JS3066, determine the structure and mechanism of the enzyme NpaA1 that catalyzes the initial reaction, and reveal how the pathway evolved. From genetic and enzymatic analysis, a five gene-cluster encoding a dioxygenase system was determined to be responsible for the initial steps in 1NA degradation through glutamylation of 1NA. The γ-glutamylated 1NA was subsequently oxidized to 1,2-dihydroxynaphthalene which was further degraded by the well-established pathway of naphthalene degradation via catechol. A glutamine synthetase-like (GS-like) enzyme (NpaA1) initiates 1NA glutamylation, and this enzyme exhibits a broad substrate selectivity toward a variety of anilines and naphthylamine derivatives. Structural analysis revealed that the aromatic residues in the 1NA entry tunnel and the V201 site in the large substrate-binding pocket significantly influence NpaA1's substrate preferences. The findings enhance understanding of degrading polycyclic aromatic amines, and will also enable the application of bioremediation at naphthylamine contaminated sites.

Hydride Shuttle Catalysis: From Conventional to Inverse Mode.

Hydride shuttle catalysis has emerged as a powerful synthetic platform, enabling the selective formation of C-C bonds to yield sp3-rich structures. By virtue of the compelling reactivity of sterically encumbered Lewis acids from the frustrated Lewis pair regime, hydride shuttle catalysis enables the regioselective functionalization of alkyl amines at either the α- or β-position. In contrast to classical Lewis acid reactivity, the increased steric hindrance prevents interaction with the Lewis basic amine itself, instead leading to reversible abstraction of a hydride from the amine α-carbon. The created positive charge facilitates the occurrence of transformations before hydride rebound or a similar capture event happen. In this Perspective, we outline a broad selection of transformations featuring hydride shuttle catalysis, as well as the recently developed approach of inverse hydride shuttle catalysis. Both strategies give rise to a wide array of functionalized amines and offer elegant approaches to otherwise elusive bond formations.

Anatomical conservatism in the wood and bark of the species-rich Byrsonimoid clade (Malpighiaceae)

Abstract The byrsonimoids include approximately 152 species of trees and shrubs native to the Neotropical region. The clade is monophyletic and consists of three genera: Byrsonima, Blepharandra, and Diacidia. Byrsonima woods are among the most well-known within the Malpighiaceae due to their economic importance. Nonetheless, here for the first time we explore the interspecific stem anatomical diversity of Byrsonima, its similarities and differences to Blepharandra and Diacidia, and how the previously proposed taxonomic circumscriptions for the genus Byrsonima are reflected or not in their wood and bark anatomy. Using a newly reconstructed phylogeny for the Malpighiaceae focusing on the clade Byrsonimoid and a broad selection of species, we conducted phylogenetic comparative analyses to determine how wood and bark traits have evolved across evolutionary time. Our results indicate stem anatomical homogeneity within the clade, particularly in wood traits. On one hand, the presence of septate fibres and prismatic crystals in the rays distinguishes Byrsonima from other members of the clade, but on the other hand, wood and bark traits do not support the classical infrageneric classifications for the genus. The bark in byrsonimoids displays the entire range of variation known for sclerenchyma in this tissue, from cells that can be considered true fibres to fibre-sclereids and typical true sclereids. Ancestral character state reconstructions revealed that radial arrangement, septate fibres, thin heterocellular rays, marginal parenchyma, and prismatic crystals are ancestral traits within the clade, with homoplasy common within the group. These observations demonstrate anatomical conservatism within the Byrsonimoid clade, which might be either related to their proposed recent diversification or a highly effective set of positively selected features.

Tolerance of Young Blackberries to a Selection of Preemergence Herbicides and Rates

Limited preemergence herbicides are registered for new blackberry (Rubus subgenus Rubus) plantings. This greenhouse experiment was designed to investigate the effects of a broad selection of preemergence herbicides at multiple rates on blackberry transplants. Screening was initiated Aug 2021 and repeated Mar 2022 in Fayetteville, AR, USA, in a greenhouse at the Milo J. Shult Agricultural Research and Extension Center. ‘Ouachita’ blackberry plugs were transplanted into utility pots that contained field soil and growth media treated with preemergence herbicides. After transplanting, plant height was measured from the substrate to the highest apical meristem of 25 representative plants. Initial blackberry plant heights were 13.5 and 9.2 cm in 2021 and 2022, respectively. Twenty-five treatments were evaluated, consisting of 12 preemergence herbicides at 1× and 2× field rates, and one untreated control. Herbicide treatments included diuron, flumioxazin, halosulfuron, indaziflam, mesotrione, napropamide, oryzalin, pendimethalin, rimsulfuron, S-metolachlor, simazine, and sulfentrazone applied to substrate in containers at their respective 1× or 2× field rates. Data were collected on plant height, blackberry injury ratings, internode length, leaf chlorophyll content, and destructive harvest, including leaf count, leaf dry biomass, and aboveground dry biomass. Specific leaf areas and leaf area-to-dry matter ratios were calculated. When observed, plant injury tended to increase from 7 days after treatment (DAT) until 42 DAT. Greater injury levels were observed in response to treatment with mesotrione at the 1× (78%) and 2× rates (90%), halosulfuron at the 1× rate (58%), halosulfuron at the 2× rate (68%), and diuron at the 2× rate (73%). Injury from diuron was rate dependent, with the 1× rate causing relatively low injury (19%). At both the 1× and 2× rates, flumioxazin, indaziflam, napropamide, S-metolachlor, and pendimethalin treatments exhibited similar responses to the untreated control.

CRISPR Tools for Engineering Prokaryotic Systems: Recent Advances and New Applications.

In the past decades, the broad selection of CRISPR-Cas systems has revolutionized biotechnology by enabling multimodal genetic manipulation in diverse organisms. Rooted in a molecular engineering perspective, we recapitulate the different CRISPR components and how they can be designed for specific genetic engineering applications. We first introduce the repertoire of Cas proteins and tethered effectors used to program new biological functions through gene editing and gene regulation. We review current guide RNA (gRNA) design strategies and computational tools and how CRISPR-based genetic circuits can be constructed through regulated gRNA expression. Then, we present recent advances in CRISPR-based biosensing, bioproduction, and biotherapeutics across in vitro and in vivo prokaryotic systems. Finally, we discuss forthcoming applications in prokaryotic CRISPR technology that will transform synthetic biology principles in the near future.

Precision Mars Entry Navigation with Atmospheric Density Adaptation via Neural Networks

Spacecraft entering Mars require precise navigation algorithms capable of accurately estimating the vehicle’s position and velocity in dynamic and uncertain atmospheric environments. Discrepancies between the true Martian atmospheric density and the onboard density model can significantly impair the navigation performance. This work introduces a new approach to online filtering for Martian entry using a neural network to estimate atmospheric density and employing a “consider” analysis to account for the uncertainty in the estimate. The network is trained on an exponential atmospheric density model, and its parameters are dynamically adapted in real time to account for any mismatch between the true and estimated densities. The adaptation of the network is formulated as a maximum likelihood problem by leveraging the measurement innovations of the filter to identify optimal network parameters. Within the context of the maximum likelihood approach, incorporating a neural network enables the use of stochastic optimizers known for their efficiency in the machine learning domain. Performance comparisons are conducted against two online adaptive approaches, covariance matching and state augmentation and correction, in various realistic Martian entry navigation scenarios. The results show superior estimation accuracy compared to other approaches and precise alignment of the estimated density with a broad selection of realistic Martian atmospheres sampled from perturbed Mars Global Reference Atmospheric Model data.

Validation of quantitative magnetic resonance imaging techniques in head and neck healthy structures involved in the salivary and swallowing function: Accuracy and repeatability

Background and PurposeRadiation-induced damage to the organs at risk (OARs) in head-and-neck cancer (HNC) patient can result in long-term complications. Quantitative magnetic resonance imaging (qMRI) techniques such as diffusion-weighted imaging (DWI), DIXON for fat fraction (FF) estimation and T2 mapping could potentially provide a spatial assessment of such damage. The goal of this study is to validate these qMRI techniques in terms of accuracy in phantoms and repeatability in-vivo across a broad selection of healthy OARs in the HN region. Materials and MethodsScanning was performed at a 3 T diagnostic MRI scanner, including the calculation of apparent diffusion coefficient (ADC) from DWI, FF and T2 maps. Phantoms were scanned to estimate the qMRI techniques bias using Bland-Altman statistics. Twenty-six healthy subjects were scanned twice in a test–retest study to determine repeatability. Repeatability coefficients (RC) were calculated for the parotid, submandibular, sublingual and tubarial salivary glands, oral cavity, pharyngeal constrictor muscle and brainstem. Additionally, a linear mixed-effect model analysis was used to evaluate the effect of subject-specific characteristics on the qMRI values. ResultsBias was 0.009x10-3 mm2/s for ADC, -0.7 % for FF and -7.9 ms for T2. RCs ranged 0.11–0.25x10-3 mm2/s for ADC, 1.2–6.3 % for FF and 2.5–6.3 ms for T2. A significant positive linear relationship between age and the FF and T2 for some of the OARs was found. ConclusionThese qMRI techniques are feasible, accurate and repeatable, which is promising for treatment response monitoring and/or differentiating between healthy and unhealthy tissues due to radiation-induced damage in HNC patients.

Morphology and systematics of a new fossil snake from the early Rupelian (Oligocene) White River Formation, Wyoming

Abstract Extinct snake taxa are recognized primarily from isolated vertebrae. A new specimen from the early Oligocene of Wyoming provides a rare opportunity to examine four nearly complete and articulated fossil snakes. Informally assigned previously to the ‘erycine’ vertebral form taxa Ogmophis and Calamagras, a detailed comparison reveals that this fossil snake exhibits vertebral differences from both taxa and is, furthermore, a new taxon, Hibernophis breithaupti gen. et sp. nov., based on a combination of apomorphies such as absence of basal tubera, low subrectangular prootic, low parasphenoid wings obscuring the anterior opening of the Vidian canal, and foramen for the mandibular branch of the trigeminal nerve posteriorly displaced inside the adductor fossa of the compound. Parsimony and Bayesian phylogenetic analysis of combined morphological and molecular data from a broad selection of snakes places Hibernophis breithaupti as sister taxon to all other booids, distant from both Old and New World ‘erycines’. However, an alternative position close to New World ‘erycines’ and ungaliophiines cannot be rejected.

FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .

Brain, behavior, cognition, and physical health in first-onset adolescent anorexia nervosa: The BRAVE Study design and cohort profile

Background Anorexia nervosa is a severe psychiatric disorder with a heterogeneous course with one of the highest rates of morbidity and mortality of all psychiatric disorders. Little is known about factors that predict both course and treatment outcomes of this disorder. The BRAVE Study is a longitudinal first-onset anorexia nervosa cohort study focusing on four topics of interest in girls only: (1) behavior, (2) neurobiology, (3) cognitive functions, and (4) physical health. Objective The goal of this paper is to introduce the BRAVE Study. The primary aim of the BRAVE Study is to identify predictors of treatment response in a large sample of 12-to-22-year-old females with first-onset typical or atypical anorexia nervosa. The second aim is to longitudinally investigate the association between clinically significant changes in eating disorder symptoms with the underlying behavioral, neurobiological, cognitive and physical health changes. The results of this study will allow us to develop more precise treatment strategies in order to provide more optimal treatment. Methods and analysis The BRAVE Study implements a longitudinal case-control design. Study recruitment was designed within a collaborative network of 16 Dutch mental health organizations, each with expertise in the diagnosis and treatment of patients with anorexia nervosa. After obtaining informed consent, assessments were performed at baseline and one-year follow-up. Patients with anorexia nervosa received treatment as usual. The primary outcome measures at one year are restoration of weight and a reduction of eating disorder symptomatology. Predictive measures include neurobiological, cognitive, behavioral and physical health measures. Sample description In the BRAVE Study 79 girls with anorexia nervosa and 75 typically developing girls were included between May 2017 and October 2021. This period of time partially overlapped with the COVID-19 pandemic. 72% of the girls with anorexia nervosa and 88% of the typically developing girls also completed measurements at follow-up. The mean time between data collections points was 13 months. The groups were comparable in education level of their mothers, neurodevelopmental disorders, and ethnical background. The girls with anorexia nervosa were slightly younger than the typically developing girls. Conclusion The BRAVE Study aligns with one of the most important study priorities in the field of anorexia nervosa by examining (i) predictors of treatment response and (ii) investigating how symptoms with eating disorder symptoms track with changes in neurobiological, cognitive, behavorial and physical health functioning. Moreover, the study is innovative by its longitunal case control design, relatively large study sample and broad selection of measures.