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Background: Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell–mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. Methods: DREAMM‐4 (NCT03848845) was an open‐label, single‐arm, phase 1/2 study divided into dose‐escalation (part 1) and dose‐expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Results: Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti–B‐cell maturation antigen therapy achieved partial response or better, including two who had B‐cell maturation antigen–refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf‐related ocular events, quality‐of‐life measures remained stable over time. No new safety signals were observed. Conclusions: The results of DREAMM‐4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www.ClinicalTrials.gov as NCT03848845. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid‐β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy. [ABSTRACT FROM AUTHOR]

Objectives: Cervical chordoma is a rare, low‐grade primary bone tumor occurring in the axial skeleton. Due to challenges in surgical exposure caused by anatomic location, patients may experience dysfunction in speech and swallowing. The objective of this study was to characterize speech and swallowing outcomes for patients undergoing surgical resection of cervical chordoma. Moreover, we detail in‐depth two cases with similar initial presentations to compare prognostic factors and management strategies. Methods: Eleven patients with histologically confirmed cervical chordoma treated between 1993 and 2020 were included in this retrospective case series. Outcomes measured included overall survival, disease‐free survival, need for enteral feeds, as well as results of modified barium swallow study (MBSS) and fiberoptic laryngoscopy. Results: The mean age at diagnosis was 55.9 years. The patient population was 81.8% male. Mean survival after diagnosis was 96 months. Four (36.4%) patients required post‐operative MBSS and demonstrated aspiration. All four of these patients presented with tumors in the superior cervical spine and received surgeries utilizing anterior approaches. Of the four, 2 required enteral feeds long‐term. Four (36.4%) patients endorsed dysphonia. One patient developed post‐operative right vocal fold paresis. The remaining three patients experienced stable dysphonia pre‐ and post‐operatively. Additionally, three (27%) patients required tracheostomy placement, two of which remained in place long‐term. Conclusions: Dysphagia is a common side effect of cervical chordoma resection. It is associated with the use of an anterior approach during resection and with tumors located in the superior cervical spine. Patients with postoperative dysphagia should receive early multidisciplinary swallow rehabilitation. Level of Evidence: 4 Laryngoscope, 134:3706–3712, 2024 [ABSTRACT FROM AUTHOR]

We investigated how apparent threat of an ambiguous stimuli modulates infants' looking to interaction partners of varying familiarity (mother, familiar experimenter, unfamiliar experimenter). We hypothesized a preference for familiar informants under higher apparent threat, but a preference for unfamiliar informants under lower apparent threat. The informant encouraged infants (N = 104, 8–13 months) to cross a visual cliff in one of two apparent threat conditions (lower vs. higher drop‐off). Under lower threat, infants looked equally long to all informants, but switched gazes more often between their mother and the cliff. Infants explored the cliff more and crossed more often in the mother condition compared to the other two conditions. They also expressed less negative affect in the presence of the mother compared to the unfamiliar experimenter, but not compared to the familiar experimenter. Under high threat, a similar pattern emerged, except that looking duration to the unfamiliar informant was shorter compared to the low threat condition. Heart rate acceleration appeared when infants were placed on the cliff compared to a baseline phase. Higher levels of negative affectivity (but not higher arousal) were observed under higher compared to lower threat. Overall, we found little evidence of the influence of threat within the visual cliff task. We argue that infants may have perceived the cliff as quite challenging even in the lower threat condition and call for more research on the situational embeddedness of early social learning processes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Myzus persicae, a serious sap‐sucking pest of a large variety of host plants in agriculture, is traditionally controlled using chemical insecticides but there is interest in using biopesticides as restrictions are increasingly placed on the use of broad‐spectrum pesticides. RESULTS: Here, we show that in Petri dish experiments, high concentrations of the fungal entomopathogen Beauveria bassiana led to rapid mortality of M. persicae, although at a low concentration (1 × 104 conidia mL−1) there is a hormetic effect in which survival and fecundity are enhanced. Hormetic effects persisted across a generation with reduced development time and increased fecundity in the offspring of M. persicae exposed to B. bassiana. The whole‐plant experiment points to a hormetic effect being detected in two out of three tested lines. The impact of these effects might also depend on whether M. persicae was transinfected with the endosymbiont Rickettsiella viridis, which decreases fecundity and survival compared with aphids lacking this endosymbiont. This fecundity cost was ameliorated in the generation following exposure to the entomopathogen. CONCLUSION: Although B. bassiana is effective in controlling M. persicae especially at higher spore concentrations, utilization of this entomopathogen requires careful consideration of hormetic effects at lower spore concentrations, and further research to optimize its application for sustainable agriculture is recommended. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The present paper reports a remote carbon‐to‐carbon boryl migration via an intramolecular 1,4‐B/Cu shift, which establishes an in situ stereospecific electrophilic trap on the alkene moiety. The synthetic application is developed to prepare functionalized cyclopentenes by means of a palladium‐catalyzed regioselective intramolecular coupling that completes a strategic cyclopropanation and generates valuable structural bicyclic systems. The mechanism is characterized by DFT (density functional theory) calculations which showed that the 1,4‐migration proceeds through an intramolecular, nucleophilic attack of the copper‐alkyl moiety on the boron atom bonded to the C(sp2), leading to a 5‐membered boracycle structure. The computation of the 1,3‐ and 1,4‐B/Cu shifts is also compared as is the impact of the endo‐ or exocyclic alkene on the reaction kinetics. [ABSTRACT FROM AUTHOR]

We executed this study to determine if chemerin‐like receptor 1 (CMKLR1), a Gi/o protein‐coupled receptor expressed by leukocytes and non‐leukocytes, contributes to the development of phenotypic features of non‐atopic asthma, including airway hyperresponsiveness (AHR) to acetyl‐β‐methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non‐atopic asthma in wild‐type mice and mice incapable of expressing CMKLR1 (CMKLR1‐deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non‐atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi‐functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1‐deficient as compared to wild‐type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype‐related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype‐related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3. [ABSTRACT FROM AUTHOR]

Neocortex expansion during evolution is linked to higher numbers of neurons, which are thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells during development. Here, we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla cerebral organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of basal progenitor cells, whereas EREG ablation in human cortical organoids reduces proliferation in the subventricular zone. Treatment of cortical organoids with EPIREGULIN promotes a further increase in proliferation of gorilla but not of human basal progenitor cells. EPIREGULIN competes with the epidermal growth factor (EGF) to promote proliferation, and inhibition of the EGF receptor abrogates the EPIREGULIN-mediated increase in basal progenitor cells. Finally, we identify putative cis-regulatory elements that may contribute to the observed inter-species differences in EREG expression. Our findings suggest that species-specific regulation of EPIREGULIN expression may contribute to the increased neocortex size of primates by providing a tunable pro-proliferative signal to basal progenitor cells in the subventricular zone. Synopsis: Growth factors have been hypothesized to regulate the proliferative capacity of basal progenitor cells during neocortex development. This study reveals that expression of the growth factor EPIREGULIN, encoded by EREG, supports proliferation of basal progenitor cells in the developing neocortex of primates. EREG is expressed in the developing neocortex of primates but not of mice. Addition of EPIREGULIN to the developing mouse neocortex promotes basal progenitor proliferation. EREG ablation in human cortical organoids reduces basal progenitor proliferation. EPIREGULIN signals via the EGF receptor and competes with EGF to promote proliferation. Several putative cis-regulatory elements may contribute to the inter-species differences in EREG expression. EPIREGULIN competes with EGF to promote proliferation of basal progenitor cells in primates, which may contribute to their neocortex expansion. [ABSTRACT FROM AUTHOR]

Summary: Background: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. Aims: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) – considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris‐II criteria as a surrogate for successful aetiological treatment. Methods: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. Results: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9–69.2] years; 88.1% female; MELD‐Na: 13.5 [IQR: 11.0–15.0]) were included and followed for 41.9 (IQR: 11.0–70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD‐Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris‐II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant‐free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver‐related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. Conclusions: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver‐related complications still occur after recompensation, patients should remain under close follow‐up. [ABSTRACT FROM AUTHOR]

Lung cancer screening involves the use of thoracic CT for both detection and measurements of suspicious lung nodules to guide the screening management. Since lung cancer screening eligibility typically requires age over 50 years along with >20 pack‐year tobacco exposure, thoracic CT scans also frequently reveal evidence for pulmonary emphysema as well as coronary artery calcification. These three thoracic diseases are collectively three of the leading causes of premature death across the world. Screening for the major thoracic diseases in this heavily tobacco‐exposed cohort is broadening the focus of lung cancer screening to a more comprehensive health evaluation including discussing the relevance of screen‐detected findings of the heart and lung parenchyma. The status and implications of these emerging issues were reviewed in a multidisciplinary workshop focused on the process of quantitative imaging in the lung cancer screening setting to guide the evolution of this important new area of public health. [ABSTRACT FROM AUTHOR]

Bi‐allelic variants in VWA1, encoding Von Willebrand Factor A domain containing 1 protein localized to the extracellular matrix (ECM), were linked to a neuromuscular disorder with manifestation in child‐ or adulthood. Clinical findings indicate a neuromyopathy presenting with muscle weakness. Given that pathophysiological processes are still incompletely understood, and biomarkers are still missing, we aimed to identify blood biomarkers of pathophysiological relevance: white blood cells (WBC) and plasma derived from six VWA1‐patients were investigated by proteomics. Four proteins, BET1, HNRNPDL, NEFM and PHGDH, known to be involved in neurological diseases and dysregulated in WBC were further validated by muscle‐immunostainings unravelling HNRNPDL as a protein showing differences between VWA1‐patients, healthy controls and patients suffering from neurogenic muscular atrophy and BICD2‐related neuromyopathy. Immunostaining studies of PHGDH indicate its involvement in apoptotic processes via co‐localisation with caspase‐3. NEFM showed an increase in cells within the ECM in biopsies of all patients studied. Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular disorders before. CRP elevated in plasma also showed an increase in the extracellular space of VWA1‐mutant muscle. Results of our combined studies for the first time describe pathophysiologically relevant biomarkers for VWA1‐related neuromyopathy and suggest that VWA1‐patient derived blood might hold the potential to study disease processes of clinical relevance, an important aspect for further preclinical studies. [ABSTRACT FROM AUTHOR]

A visible‐light‐induced iron‐catalyzed α‐alkylation of ketones with allylic and propargylic alcohols as pro‐electrophiles is reported. The diaminocyclopentadienone iron tricarbonyl complex plays a dual role by harvesting light and facilitating dehydrogenation and reduction steps without the help of any exogenous photosensitizer. γ,δ‐Unsaturated ketones can now be accessed through this borrowing hydrogen methodology at room temperature. Mechanistic investigations revealed that the steric hindrance on the δ‐position of either the dienone or ene‐ynone intermediate is the key feature to prevent or decrease the competitive 1,6‐reduction (and consequently the formation of the saturated ketone) and to favor the synthesis of a set of non‐conjugated enones and ynones. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma (CAP) is a source of cell‐damaging oxidant molecules that may be used as low‐cost cancer treatment with minimal side effects. Liquids treated with cold plasma and enriched with oxidants are a modality for non‐invasive treatment of internal tumors with cold plasma via injection. However, liquids are easily diluted with body fluids which impedes high and localized delivery of oxidants to the target. As an alternative, plasma‐treated hydrogels (PTH) emerge as vehicles for the precise delivery of oxidants. This study reports an optimal protocol for the preparation of injectable alginate PTH that ensures the preservation of plasma‐generated oxidants. The generation, storage, and release of oxidants from the PTH are assessed. The efficacy of the alginate PTH in cancer treatment is demonstrated in the context of cancer cell cytotoxicity and immunogenicity–release of danger signals and phagocytosis by immature dendritic cells, up to now unexplored for PTH. These are shown in osteosarcoma, a hard‐to‐treat cancer. The study aims to consolidate PTH as a novel cold plasma treatment modality for non‐invasive or postoperative tumor treatment. The results offer a rationale for further exploration of alginate‐based PTHs as a versatile platform in biomedical engineering. [ABSTRACT FROM AUTHOR]

Cholesteric liquid crystal oligomers are an interesting class of temperature responsive structurally colored materials. However, the role of endcap molecules in these oligomers is rather unexplored. In this work, we demonstrate the role of endcap molecules on structural color stability and hypsochromic shift in temperature‐responsive cholesteric liquid crystal oligomers. First, new liquid crystal monoacrylate endcap molecules are synthesized, which are then used to synthesize various cholesteric liquid crystal oligomers. In addition, cholesteric oligomers using commercial monoacrylate endcap molecules are also prepared. It is found that the molecular weight and the polydispersity of the oligomers can be tuned by the endcapping molecules. The oligomers are used to produce reflective, structurally colored coatings. It was found that the coatings using the commercial monoacrylate lose their color and crystallize over time, most likely due to the presence of crystalline dimers. The coatings containing the newly synthesized monoacrylate endcap molecules did not exhibit this crystallization, resulting in structurally colored coatings that remained stable over time. These latter coatings possessed temperature responsive hypochromic behavior, which makes them interesting for advanced optical applications. [ABSTRACT FROM AUTHOR]

Introduction: Liver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low‐ and middle‐income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV. Methods: We conducted a cross‐sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA‐Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration‐controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula. Results: Overall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45−56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1−8.4) and 28.4% (95% CI 26.5−30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10−2.40), overweight/obesity (OR = 2.50, 95% CI 1.69−3.75), T2DM (OR 2.26, 95% CI 1.46−3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46−6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti‐HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29−5.51), T2DM (OR 2.06, 95% CI 1.47−2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27−2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31−2.16). Conclusions: Metabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings. [ABSTRACT FROM AUTHOR]

A systematic procedure is introduced for modeling charge‐neutral non‐polar surfaces of ionic minerals containing polyatomic anions. By integrating distance‐ and charge‐based clustering to identify chemical species within the mineral bulk, our pipeline, PolyCleaver, renders a variety of theoretically viable surface terminations. As a demonstrative example, this approach was applied to forsterite (Mg2SiO4), unveiling a rich interface landscape based on interactions with formaldehyde, a relevant multifaceted molecule, and more particularly in prebiotic chemistry. This high‐throughput method, going beyond techniques traditionally applied in the modeling of minerals, offers new insights into the potential catalytic properties of diverse surfaces, enabling a broader exploration of synthetic pathways in complex mineral systems. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study aimed to assess whether social relationships in mid‐life reduce the risk of dementia related to amyloid burden. METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990–1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012–2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid‐life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS: Among 310 participants without dementia, strong mid‐life social relationships were associated independently with lower dementia risk. Elevated late‐life brain amyloid was associated with greater dementia risk. DISCUSSION: Although mid‐life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia. [ABSTRACT FROM AUTHOR]

Purpose: Systematic repurposing of approved medicines for another indication may accelerate drug development in oncology. We present a strategy combining biomarker testing with drug repurposing to identify new treatments for patients with advanced cancer. Methods: Tumours were sequenced with the Illumina TruSight Oncology 500 (TSO‐500) platform or the FoundationOne CDx panel. Mutations were screened by two medical oncologists and pathogenic mutations were categorised referencing literature. Variants of unknown significance were classified as potentially pathogenic using plausible mechanisms and computational prediction of pathogenicity. Gain of function (GOF) mutations were evaluated through repurposing databases Probe Miner (PM), Broad Institute Drug Repurposing Hub (Broad Institute DRH) and TOPOGRAPH. GOF mutations were repurposing events if identified in PM, not indexed in TOPOGRAPH and excluding mutations with a known Food and Drug Administration (FDA)‐approved biomarker. The computational repurposing approach was validated by evaluating its ability to identify FDA‐approved biomarkers. The total repurposable genome was identified by evaluating all possible gene‐FDA drug‐approved combinations in the PM dataset. Results: The computational repurposing approach was accurate at identifying FDA therapies with known biomarkers (94%). Using next‐generation sequencing molecular reports (n = 94), a meaningful percentage of patients (14%) could have an off‐label therapeutic identified. The frequency of theoretical drug repurposing events in The Cancer Genome Atlas pan‐cancer dataset was 73% of the samples in the cohort. Conclusion: A computational drug repurposing approach may assist in identifying novel repurposing events in cancer patients with no access to standard therapies. Further validation is needed to confirm a precision oncology approach using drug repurposing. [ABSTRACT FROM AUTHOR]

To improve spatiotemporal data collection and inform future spurdog Squalus acanthias stock assessment, a new dedicated longline survey was initiated in 2021 in coastal waters of southern Norway. The survey comprised a mixture of randomly predefined stations to facilitate unbiased abundance estimates and supplementary stations including informant putative hotspots. During 25 survey days in autumn 2021, 287 stations were sampled, of which 280 were categorized as "satisfactory" in terms of gear quality deployment. Spurdog catches (n = 954) were more abundant in southeast coastal shallower waters (19–150 m). No length, sex, or maturity stratified schooling behavior was found with increasing catches. Females were more abundant and larger than males, but males were older. Growth and reproduction parameters were within ranges reported for the stock. Our results provide valuable input for spurdog survey designs with regards to optimizing boat time, location of stations, and biological sampling protocols. The survey provides important data for monitoring the spurdog stock and other data‐limited species, especially considering the newly re‐opened spurdog fishery but also to study possible future effects of climatic changes on spurdog distribution. [ABSTRACT FROM AUTHOR]

During geomagnetic storms relativistic outer radiation belt electron flux exhibits large variations on rapid time scales of minutes to days. Many competing acceleration and loss processes contribute to the dynamic variability of the radiation belts; however, distinguishing the relative contribution of each mechanism remains a major challenge as they often occur simultaneously and over a wide range of spatiotemporal scales. In this study, we develop a new comprehensive model for storm-time radiation belt dynamics by incorporating electron wave-particle interactions with parallel propagating whistler mode waves into our global test-particle model of the outer belt. Electron trajectories are evolved through the electromagnetic fields generated from the Multiscale Atmosphere-Geospace Environment (MAGE) global geospace model. Pitch angle scattering and energization of the test particles are derived from analytical expressions for quasi-linear diffusion coefficients that depend directly on the magnetic field and density from the magnetosphere simulation. Using a study of the 17 March 2013 geomagnetic storm, we demonstrate that resonance with lower band chorus waves can produce rapid relativistic flux enhancements during the main phase of the storm. While electron loss from the outer radiation belt is dominated by loss through the magnetopause, wave-particle interactions drive significant atmospheric precipitation. We also show that the storm-time magnetic field and cold plasma density evolution produces strong, local variations of the magnitude and energy of the wave-particle interactions and is critical to fully capturing the dynamic variability of the radiation belts caused by wave-particle interactions. [ABSTRACT FROM AUTHOR]

The standard treatment in glioblastoma includes maximal safe resection followed by concomitant radiotherapy plus chemotherapy and adjuvant temozolomide. The first follow‐up study to evaluate treatment response is performed 1 month after concomitant treatment, when contrast‐enhancing regions may appear that can correspond to true progression or pseudoprogression. We retrospectively evaluated 31 consecutive patients at the first follow‐up after concomitant treatment to check whether the metabolic pattern assessed with multivoxel MRS was predictive of treatment response 2 months later. We extracted the underlying metabolic patterns of the contrast‐enhancing regions with a blind‐source separation method and mapped them over the reference images. Pattern heterogeneity was calculated using entropy, and association between patterns and outcomes was measured with Cramér's V. We identified three distinct metabolic patterns—proliferative, necrotic, and responsive, which were associated with status 2 months later. Individually, 70% of the patients showed metabolically heterogeneous patterns in the contrast‐enhancing regions. Metabolic heterogeneity was not related to the regions' size and only stable patients were less heterogeneous than the rest. Contrast‐enhancing regions are also metabolically heterogeneous 1 month after concomitant treatment. This could explain the reported difficulty in finding robust pseudoprogression biomarkers. [ABSTRACT FROM AUTHOR]

This study demonstrates the feasibility and performance of the point‐resolved spectroscopy (PRESS)‐based, single‐shot diffusion trace‐weighted sequence in quantifying the trace apparent diffusion coefficient (ADC) in phantom and in vivo using a 3‐T MRI/MRS scanner. The single‐shot diffusion trace‐weighted PRESS sequence was implemented and compared with conventional diffusion‐weighted (DW)‐PRESS variants using bipolar and unipolar diffusion‐sensitizing gradients. Nine phantom datasets were acquired using each sequence, and seven volunteers were scanned in three different brain regions to determine the range and variability of trace ADC values, and to allow a comparison of trace ADCs among the sequences. This sequence results in a comparatively stable range of trace ADC values that are statistically significantly higher than those produced from unipolar and bipolar DW‐PRESS sequences. Only total n‐acetylaspartate, total creatine, and total choline were reliably estimated in all sequences with Cramér–Rao lower bounds of, at most, 20%. The larger trace ADCs from the single‐shot sequences are probably attributable to the shorter diffusion time relative to the other sequences. Overall, this study presents the first demonstration of the single‐shot diffusion trace‐weighted sequence in a clinical scanner at 3 T. The results show excellent agreement of phantom trace ADCs computed with all sequences, and in vivo ADCs agree well with the expected differences between gray and white matter. The diffusion trace‐weighted sequence could provide an estimate of the trace ADC in a shorter scan time (by nearly a factor of 3) compared with conventional DW‐PRESS approaches that require three separate orthogonal directions. [ABSTRACT FROM AUTHOR]

Objective: Monosynaptically cortically innervated α‐motoneurons are early and strongly involved in amyotrophic lateral sclerosis (ALS). Consequently, the muscles that receive the strongest direct corticomotoneuronal input are the clinically most affected. To objectify this concept in vivo through morphological image correlates, whole‐body magnetic resonance imaging (MRI) with muscle signal analysis was performed in patients with ALS compared to healthy controls. Methods: Modified Dixon‐based whole‐body MRI was acquired in patients with ALS (n = 33) and matched healthy controls (n = 30). Manual labeling of limb muscle MRI was performed, and a specific subset of nine muscles, selected as pairs of muscle groups with different corticomotoneuronal input, was analyzed per subject based on their volume, fat fraction, and functional remaining muscle area (fRMA). Results: Statistical analysis of 978 muscles in total revealed significantly decreased volumes, decreased fRMA, and increased fat fraction in the muscles of patients with ALS compared to controls. The clinical degree of pareses of directly innervated muscles was significantly worse than that of less directly innervated muscles in each comparison. The muscles receiving stronger direct corticomotoneuronal input showed more pronounced morphological involvement compared to those with less monosynaptic corticomotoneuronal input (fRMA, significant in three pairwise comparisons). Interpretation: In conclusion, whole‐body MRI‐based muscle analysis provided additional evidence for a characteristic pattern of pareses in ALS. This technical approach (parameterization and quantification of muscle alterations from MRI) to patients with ALS could pave the way for the future establishment of a diagnostic algorithm of muscle MRI for ALS and may serve as a biomarker. [ABSTRACT FROM AUTHOR]

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen‐related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric‐specific factors may need to be considered. [ABSTRACT FROM AUTHOR]

The deciduous tree‐herbivorous caterpillar‐insectivorous bird food chain is a well‐studied system for investigating the impacts of climate change across trophic levels. To date, across Europe, most attention has focused on the impacts of increasing spring temperature on changes to phenology in Oak‐dominated (Quercus spp.) woodlands. Paridae species and Pied Flycatcher Ficedula hypoleuca are the most studied secondary consumers, all of which demonstrate an advancement in reproductive phenology with increases in spring temperature. Shifts in climate and phenology may also impact on reproductive investment in clutch size, and the effects of climate on phenology and clutch size may vary depending on woodland composition. To date, the effects of among‐habitat variation in phenology and reproductive investment have received little attention. Insectivorous birds inhabiting woodlands that differ in tree composition may differ in the timing of breeding, due to local tree leafing phenology acting as a cue for egg‐laying date and/or clutch size. Moreover, for most insectivorous birds, woodland composition within a territory is likely to be the main determinant of food availability for both adults and chicks. Consequently, if warming springs affect the temporal patterns of food availability differently across different woodland compositions, this may affect the optimal average local phenology for nesting birds. Here, using data from 34 long‐term (mean 15 years) nest monitoring sites across the UK, we investigate the effect of woodland tree composition and temperature on Blue Tit Cyanistes caeruleus first egg date (FED) and clutch size. We supplemented the nest monitoring data by quantifying woodland composition, at a site level, through modified point counts. We predict that birds breeding in woodlands with greater proportions of late‐leafing species, such as Oak and Ash Fraxinus excelsior, will breed later than those breeding in woodlands with greater proportions of early‐leafing species, such as Birch Betula spp. and Beech Fagus sylvatica. We found no evidence for differences in Blue Tit FED or clutch size in relation to the proportion of any of the tree species investigated, after controlling for temperature and latitude (FED: −3.4 and 2.2, clutch size: −0.4 and − 0.2 eggs for one‐unit increase in temperature and latitude, respectively). In recent decades and across all sites, clutch size has decreased as spring temperatures have increased, a strategy which could allow birds flexibly to adjust their breeding phenology such that nestling demand coincides with peak food availability. The lack of an effect of woodland composition on Blue Tit phenology suggests Blue Tits do not fine‐tune their reproductive phenology to the local tree composition. Whether this lack of evidence for phenological divergence is due to an absence of divergent selection on breeding phenology and clutch size or to gene flow is not clear. [ABSTRACT FROM AUTHOR]

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation. [ABSTRACT FROM AUTHOR]

Hybrid breeding of wheat (Triticum aestivum L.) is limited by its self‐pollinating nature. Past cross‐pollination improvements mostly focused on optimizing male traits. We tested the hybrid seed yield of 100 diverse elite lines treated with a chemical hybridization agent (CHA) and pollinated by non‐sterilized male plants in multi‐environmental field trials. Plant height and phenological traits of female plants were also assessed. In parallel, control experiments without CHA sterilization were conducted to measure per se yield of the tested material. Hybrid seed yield variation is of quantitative genetic nature, and, despite the large environmental influence, this trait has a strong genotypic component and is highly heritable (h2 =.77). The lack of correlation between hybrid seed yield and per se yield suggests a non‐shared genetic control. Phenological traits and their interactions are important factors explaining together ~1/3 of hybrid seed yield variation. In contrast to plant height and flowering traits, which are influenced by major genetic factors, no significant marker–trait associations were found for the hybrid seed yield, thus suggesting a highly polygenic genetic architecture and the need of larger populations to investigate female hybrid seed yield. [ABSTRACT FROM AUTHOR]

De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction‐based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand‐coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction‐based de novo design to the design of synthetically accessible and biologically active compounds as proof‐of‐concept of our reaction vector‐based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible. [ABSTRACT FROM AUTHOR]

Addressing flow disruptions (FDs) in neurosurgery requires a multifaceted approach. Strategies like improved communication protocols, minimizing interruptions, improving coordination among team, optimizing operating room layout, and promoting user‐centered design can help mitigate the challenges and enhance the overall flow and safety of neurosurgical procedures. Thirty neurosurgery cases were observed at two tertiary care facilities. The data collected were from wheels into the operating room to wheels out from the operating room. Data points were categorized using a human factors taxonomy known as RIPCHORD‐TWA (Realizing Improved Patient Care Through Human‐Centered Operating Room Design for Threat Window Analysis). Of the 541 total disruptions observed, coordination issues were the most prevalent (26.25%), followed by layout issues (26.06%), issues related to interruption (22.55%), communication (22.37%), equipment issues (2.40%) and usability issues (0.37%) comprised the remainder of the observations. This translated into one disruption every 2.7 min. Instead of focusing exclusively on errors and adverse events, we propose conceptualizing the accumulation of disruptions as "threat windows" to analyze potential threats to the integrity of the care system. This perspective allows for the improved identification of system weaknesses or threats, affording us the ability to address these inefficiencies and intervene before errors and adverse events may occur. [ABSTRACT FROM AUTHOR]

Steel fiber‐reinforced concrete (SFRC) has proven to be a suitable structural material for constructing elevated flat slabs, and several existing office and residential buildings, in which SFRC was used for these components, highlighted the positive outcomes from both technical and sustainability perspectives. However, research on the influence of fiber orientation on the flexural performance of SFRC slabs is relatively scarce despite the fact that a number of studies revealed that the use of constitutive models derived from three‐point bending tests on notched beams leads to overestimations of the bearing capacity of statically indeterminate slabs. In this context, this study aims at presenting an extensive experimental program that consisted of testing three SFRC slabs (3.0 × 3.0 × 0.1 m3) subjected to point load under a statically indeterminate test configuration. The testing procedure was followed by the extraction of 88 cores in order to analyze both fiber distribution and orientation by means of a non‐destructive inductive method. The results indicate that lower orientation numbers were observed in cylinders drilled from the slabs in comparison with those observed in the 150 × 150 × 600 mm3 notched reference beams tested to characterize the pre‐ and post‐cracking flexural performance of the SFRC produced. Based on these results, a straightforward design‐oriented approach to compute an orientation factor was proposed and considered to develop the constitutive law used to simulate the structural response of SFRC slabs by means of nonlinear finite element model. The numerical simulation results showed a good agreement with the experimental response, this evidencing that the orientation factor may permit to account for the differences caused by geometric and statistical scale‐induced factors between both the beams used for the SFRC flexural properties characterization and slabs produced with the same SFRC. [ABSTRACT FROM AUTHOR]

Conventional reinforced concrete for building partition walls has proven numerous advantages (in terms for instance of acoustic performance and robustness) with respect to other existing alternatives. However, its use leads to high material consumption and environmental footprint together with time‐consuming processes for placing steel reinforcement. To reduce time‐consuming processes and carbon footprint, the replacement of ordinary steel reinforcement by structural macrofibers is envisioned as a suitable solution due to: (1) the acceptance of fiber reinforced concrete (FRC) for structural applications in various guidelines (as Annex L of FprEN 1992‐1‐1:2023, draft for future Eurocode 2) and (2) the fact that the amounts of fibers necessary to reach the required mechanical performance of the FRC for crack control are expected to be economically competitive. Additionally, within the spectra of types of macrofibers capable of efficiently reinforce concrete, macrosynthetic fibers (MSFs) were considered in this research due to their benefits in terms of durability performance and reduced environmental impact (potential to use cements with lower clinker content and reduced thickness of elements). Aiming at confirming both the constructability, casting procedure and structural performance of macrosynthetic fiber reinforced concrete (MSFRC) partition walls, these walls were constructed in a real building in Switzerland. In this article, the design process is presented as well as the associated MSFRC material and structural experimental programmes, conducted both in laboratory and on‐site. In addition, several FEM‐modeling considerations as well as quality control and construction aspects observed during the implementation process are raised. Finally, for reference purposes, a first approach to the economic and environmental impact (CO2eq‐based) of such MSFRC walls is presented. [ABSTRACT FROM AUTHOR]

Kelp forests are among the most valuable ecosystems on Earth, but they are increasingly being degraded and lost due to a range of human‐related stressors, leading to recent calls for their improved management and conservation. One of the primary tools to conserve marine species and biodiversity is the establishment of marine protected areas (MPAs). International commitments to protect 30% of the world's ecosystems are gaining momentum, offering a promising avenue to secure kelp forests into the Anthropocene. However, a clear understanding of the efficacy of MPAs for conserving kelp forests in a changing ocean is lacking. In this perspective, we question whether strengthened global protection will create meaningful conservation outcomes for kelp forests. We explore the benefits of MPAs for kelp conservation under a suite of different stressors, focusing on empirical evidence from protected kelp forests. We show that MPAs can be effective against some drivers of kelp loss (e.g., overgrazing, kelp harvesting), particularly when they are maintained in the long‐term and enforced as no‐take areas. There is also some evidence that MPAs can reduce impacts of climate change through building resilience in multi‐stressor situations. However, MPAs also often fail to provide protection against ocean warming, marine heatwaves, coastal darkening, and pollution, which have emerged as dominant drivers of kelp forest loss globally. Although well‐enforced MPAs should remain an important tool to protect kelp forests, successful kelp conservation will require implementing an additional suite of management solutions that target these accelerating threats. [ABSTRACT FROM AUTHOR]

In this study, we examine whether investments in fixed (identifiable) intangible assets and tangible assets are sensitive to cash flow and the extent to which this sensitivity differs for firms with different levels of financial constraints. Using both UK private and public firms' data, our overall analysis shows strong positive (negative) effects of cash flow on intangible assets (tangible assets) investments. When we split the data on the basis of listing status, we observe that cash flow is positively (negatively) and significantly related to intangible assets (tangible assets) investments for private firms but not so for public firms. In addition, we further observe that both public and private firms' investments follow a similar pattern when we split our data based on the availability of internal funds. Moreover, we also find that the sensitivity of investment (identifiable intangible assets) to cash flow is higher for young and large private firms but lower for small and old ones. Our results remain similar to other econometric specifications, which account for possible endogeneity issues. [ABSTRACT FROM AUTHOR]

This paper shows how to use results of statistical learning theory and stochastic algorithms to have a better understanding of the convergence of Reinforcement Learning (RL) once it is formulated as a fixed point problem. This can be used to propose improvement of RL learning rates. First, our analysis shows that the classical asymptotic convergence rate O(1/N)$O(1/\sqrt {N})$ is pessimistic and can be replaced by O((log(N)/N)β)$O((\log (N)/N)^{\beta })$ with 12≤β≤1$\frac{1}{2}\le \beta \le 1$, and N$N$ the number of iterations. Second, we propose a dynamic optimal policy for the choice of the learning rate used in RL. We decompose our policy into two interacting levels: the inner and outer levels. In the inner level, we present the PASS algorithm (for "PAst Sign Search") which, based on a predefined sequence of learning rates, constructs a new sequence for which the error decreases faster. The convergence of PASS is proved and error bounds are established. In the outer level, we propose an optimal methodology for the selection of the predefined sequence. Third, we show empirically that our selection methodology of the learning rate outperforms significantly standard algorithms used in RL for the three following applications: the estimation of a drift, the optimal placement of limit orders, and the optimal execution of a large number of shares. [ABSTRACT FROM AUTHOR]

Background: Alpha‐synuclein (α‐Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA‐binding Protein 43 (TDP‐43) monomers in vitro, supporting the idea that TDP‐43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α‐Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed‐competent α‐Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease. Methods: Based on the finding that α‐Syn has been found to be a prion‐like protein, we have utilized a validated α‐Synuclein seed amplification assay to determine if seed‐competent α‐Syn could be detected in the spinal fluid of patients with ALS. Results: Toxic species of α‐Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed‐amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects. Conclusions: Our findings suggest that a sub‐group of ALS occurs in which self‐replicating α‐Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder. [ABSTRACT FROM AUTHOR]

Background and purpose: According to the latest European guidelines, discontinuation of monoclonal antibodies against calcitonin gene‐related peptide (anti‐CGRP MAb) may be considered after 12–18 months of treatment. However, some patients may worsen after discontinuation. In this study, we assessed the response following treatment resumption. Methods: This was a prospective study conducted in 14 Headache Units in Spain. We included patients with response to anti‐CGRP MAb with clinical worsening after withdrawal and resumption of treatment. Numbers of monthly migraine days (MMD) and monthly headache days (MHD) were obtained at four time points: before starting anti‐CGRP MAb (T‐baseline); last month of first treatment period (T‐suspension); month of restart due to worsening (T‐worsening); and 3 months after resumption (T‐reintroduction). The response rate to resumption was calculated. Possible differences among periods were analysed according to MMD and MHD. Results: A total of 360 patients, 82% women, with a median (interquartile range [IQR]) age at migraine onset of 18 (12) years. The median (IQR) MHD at T‐baseline was 20 (13) and MMD was 5 (6); at T‐suspension, the median (IQR) MHD was 5 (6) and MMD was 4 (5); at T‐worsening, the median (IQR) MHD was 16 (13) and MMD was 12 (6); and at T‐reintroduction, the median (IQR) MHD was 8 (8) and MHD was 5 (5). In the second period of treatment, a 50% response rate was achieved by 57.4% of patients in MHD and 65.8% in MMD. Multivariate models showed significant differences in MHD between the third month after reintroduction and last month before suspension of first treatment period (p < 0.001). Conclusion: The results suggest that anti‐CGRP MAb therapy is effective after reintroduction. However, 3 months after resumption, one third of the sample reached the same improvement as after the first treatment period. [ABSTRACT FROM AUTHOR]

Background and Purpose: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)‐hydroxycholesterol (24(S)‐HC), which is an N‐methyl‐d‐aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. Experimental Approach: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE‐718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. Key Results: SAGE‐718 potentiated GluN1/GluN2A‐D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE‐718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine‐evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE‐718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)‐HC depletion caused by 7‐dehydrocholesterol reductase inhibition. Finally, SAGE‐718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. Conclusions and Implications: These findings provide strong evidence that SAGE‐718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction. [ABSTRACT FROM AUTHOR]

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p‐22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22‐A identified using FISH, MLPA, and/or array‐CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence. [ABSTRACT FROM AUTHOR]

Uplifted Pleistocene marine terrace sequences are used to quantify uplift rates along active margins by knowing terrace age and elevation, and sea level (SL) position at the time of terrace formation. When terraces are undated, ages are assigned by correlating terraces at progressively higher elevations with progressively older highstands. Uplift at convergent margins can be constant over time or occur coseismically during upper plate earthquakes. We explore the formation of terrace sequences under conditions of constant and earthquake‐driven uplift by using a forward numerical model. The modeling reveals that terraces are generally abandoned at SL highstands but they are carved during all stands, depending on the time spent within the sea erosional‐depth‐range. Therefore sea reoccupation of a same platform after formation is a common occurrence that decreases with increasing uplift rates, suggesting that most platforms in nature may be in fact polygenetic. Furthermore, the model run time influences the terrace sequences: terraces formed at the beginning of longer runs constitute an 'inherited morphology' affecting subsequent sequences. When coseismic uplift is applied, the formation and preservation of terraces for a given average uplift rate depend stochastically on the coseismic displacement ‐ recurrence interval combination in relation to the SL position at the time of the earthquake. These factors significantly contribute to a higher likelihood of non‐preserved terraces along a terrace sequence, which may affect age correlation and, consequently, the resulting uplift rates. Further research is needed to explore the effect of the full seismic cycle in shaping a terrace sequence. Plain Language Summary: The topography of the upper plate in a subduction zone is subject to uplift over time. The action of the sea on the coast creates marine terraces, horizontal erosional platforms that, if uplifted, form a staircase morphology. Terrace staircase sequences are used to calculate the average uplift rate of the coast if the terrace age is known. In absence of datable material, the terrace age is inferred by assuming that terraces are preserved in chronological order of formation along the sequence. We use numerical models to explore the generation of subsequent marine terraces forming a staircase sequence on coastal margins subject to constant uplift over time or to instantaneous uplift caused by earthquakes occurring at a certain frequency (recurrence interval). We observe that: terraces are carved as long as they lie within the sea erosional depth; sea reoccupation of previously formed terraces occurs frequently, increasing with decreasing uplift rates; running the model for longer or shorter periods of time has changes morphology of the sequence; varying the earthquake recurrence interval results in different staircase morphologies even if the average uplift rate remains unchanged. The potential absence of terraces increases the chance of assigning, through cross correlation, wrong terrace ages, resulting in inexact uplift rates. Key Points: Terraces form during all sea‐level stands, and sea reoccupation is common at uplift rates ≤0.5 mm/yr; most natural terraces may be polygeneticEarthquake‐driven uplift may cause non‐preservation of individual terraces, depending on the recurrence interval ‐ coseismic uplift valuesBy keeping parameters constant and varying the model run time, terrace sequences with different morphology are created [ABSTRACT FROM AUTHOR]

Studies of stream macroinvertebrates traditionally use sampling methods that target benthic habitats. These methods could underestimate biodiversity if important assemblage components exist outside of the benthic zone. To test the efficacy of different sampling methods, we collected paired reach‐wide benthic and edge samples from up to 10 study reaches in nine basins spanning an aridity gradient across the United States. Edge sampling targeted riparian‐adjacent microhabitats not typically sampled, including submerged vegetation, roots, and overhanging banks. We compared observed richness, asymptotic richness, and assemblage dissimilarity between benthic samples alone and different combinations of benthic and edge samples to determine the magnitude of increased diversity and assemblage dissimilarity values with the addition of edge sampling. We also examined how differences in richness and assemblage composition varied across an aridity gradient. The addition of edge sampling significantly increased observed richness (median increase = 29%) and asymptotic richness (median increase = 173%). Similarly, median Bray–Curtis dissimilarity values increased by as much as 0.178 when benthic and edge samples were combined. Differences in richness metrics were generally higher in arid basins, but assemblage dissimilarity either increased or decreased across the aridity gradient depending on how benthic and edge samples were combined. Our results suggest that studies that do not sample stream edges may significantly underestimate reach diversity and misrepresent assemblage compositions, with effects that can vary across climates. We urge researchers to carefully consider sampling methods in field studies spanning climatic zones and the comparability of existing data sets when conducting data synthesis studies. [ABSTRACT FROM AUTHOR]

Although CH2FCl (HCFC‐31) recently became of great atmospheric importance, studies concerning its excited states are almost nonexistent. Several excited singlet states were studied (valence nσ* and Rydberg n3s, n3p, σ3s, and σ3p) through highly correlated multireference configuration interaction with singles and doubles, including extensivity correction. Comparison with the states of CH3Cl indicates a strong influence of the F atom. Potential energy curves suggest formation of an electrostatically bound complex that relaxes to a hydrogen‐bonded contact ion‐pair (HBCIP) which can decay yielding CH2F + Cl or to the ground state minimum of CH2FCl. The HBCIP has a dipole moment of 9.57 D, a CI wavefunction described as 0.65ionic + 0.20biradical and it is strongly bonded by 4.72 eV. Its H bond has characteristics of moderate and strong H bonds. The simulated absorption spectrum confirms the nσ* assignment for the first and suggests the n3s + n3pσ assignment for the second band. [ABSTRACT FROM AUTHOR]