As they develop into mature speakers of their native language, infants must not only learn words but also the sounds that make up those words. To do so, they must strike a balance between accepting ...speaker-dependent variation (e.g., mood, voice, accent) but appropriately rejecting variation when it (potentially) changes a word's meaning (e.g., cat vs. hat). This meta-analysis focuses on studies investigating infants' ability to detect mispronunciations in familiar words, or mispronunciation sensitivity. Our goal was to evaluate the development of infants' phonological representations for familiar words as well as explore the role of experimental manipulations related to theoretical questions and of analysis choices. The results show that although infants are sensitive to mispronunciations, they still accept these altered forms as labels for target objects. Interestingly, this ability is not modulated by age or vocabulary size, suggesting that a mature understanding of native language phonology may be present in infants from an early age, possibly before the vocabulary explosion. These results support several theoretical assumptions made in the literature, such as sensitivity to mispronunciation size and position of the mispronunciation. We also shed light on the impact of data analysis choices that may lead to different conclusions regarding the development of infants' mispronunciation sensitivity. Our article concludes with recommendations for improved practice in testing infants' word and sentence processing online.
Infants start learning words, the building blocks of language, at least by 6 months. To do so, they must be able to extract the phonological form of words from running speech. A rich literature has ...investigated this process, termed word segmentation. We addressed the fundamental question of how infants of different ages segment words from their native language using a meta‐analytic approach. Based on previous popular theoretical and experimental work, we expected infants to display familiarity preferences early on, with a switch to novelty preferences as infants become more proficient at processing and segmenting native speech. We also considered the possibility that this switch may occur at different points in time as a function of infants' native language and took into account the impact of various task‐ and stimulus‐related factors that might affect difficulty. The combined results from 168 experiments reporting on data gathered from 3774 infants revealed a persistent familiarity preference across all ages. There was no significant effect of additional factors, including native language and experiment design. Further analyses revealed no sign of selective data collection or reporting. We conclude that models of infant information processing that are frequently cited in this domain may not, in fact, apply in the case of segmenting words from native speech.
In a meta‐analysis, we addressed how infants across different ages segment words from continuous speech in their native language. Based on previous popular theoretical and experimental work, we expected infants to display familiarity preferences early on, with a switch to novelty preferences as infants become more proficient at processing and segmenting native speech. The combined results from 168 experiments reporting on data gathered from 3774 infants revealed a persistent familiarity preference across all ages. There was no significant effect of additional factors, including native language and experiment design. Further analyses revealed no sign of selective data collection or reporting. We conclude that models of infant information processing that are frequently cited in this domain may not, in fact, apply in the case of segmenting words from native speech.
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including ...systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.
Older children with online schooling requirements, unsurprisingly, were reported to have increased screen time during the first COVID-19 lockdown in many countries. Here, we ask whether younger ...children with no similar online schooling requirements also had increased screen time during lockdown. We examined children's screen time during the first COVID-19 lockdown in a large cohort (n = 2209) of 8-to-36-month-olds sampled from 15 labs across 12 countries. Caregivers reported that toddlers with no online schooling requirements were exposed to more screen time during lockdown than before lockdown. While this was exacerbated for countries with longer lockdowns, there was no evidence that the increase in screen time during lockdown was associated with socio-demographic variables, such as child age and socio-economic status (SES). However, screen time during lockdown was negatively associated with SES and positively associated with child age, caregiver screen time, and attitudes towards children's screen time. The results highlight the impact of the COVID-19 lockdown on young children's screen time.
Online testing holds great promise for infant scientists. It could increase participant diversity, improve reproducibility and collaborative possibilities, and reduce costs for researchers and ...participants. However, despite the rise of platforms and participant databases, little work has been done to overcome the challenges of making this approach available to researchers across the world. In this paper, we elaborate on the benefits of online infant testing from a global perspective and identify challenges for the international community that have been outside of the scope of previous literature. Furthermore, we introduce ManyBabies-AtHome, an international, multi-lab collaboration that is actively working to facilitate practical and technical aspects of online testing and address ethical concerns regarding data storage and protection, and cross-cultural variation. The ultimate goal of this collaboration is to improve the method of testing infants online and make it globally available.
Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced ...JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.
Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways ...capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
Timely diagnosis and treatment are essential in the effective management of inflammatory rheumatic diseases (IRDs). Symptom checkers (SCs) promise to accelerate diagnosis, reduce misdiagnoses, and ...guide patients more effectively through the health care system. Although SCs are increasingly used, there exists little supporting evidence.
To assess the diagnostic accuracy, patient-perceived usability, and acceptance of two SCs: (1) Ada and (2) Rheport.
Patients newly presenting to a German secondary rheumatology outpatient clinic were randomly assigned in a 1:1 ratio to complete Ada or Rheport and consecutively the respective other SCs in a prospective non-blinded controlled randomized crossover trial. The primary outcome was the accuracy of the SCs regarding the diagnosis of an IRD compared to the physicians' diagnosis as the gold standard. The secondary outcomes were patient-perceived usability, acceptance, and time to complete the SC.
In this interim analysis, the first 164 patients who completed the study were analyzed. 32.9% (54/164) of the study subjects were diagnosed with an IRD. Rheport showed a sensitivity of 53.7% and a specificity of 51.8% for IRDs. Ada's top 1 (D1) and top 5 disease suggestions (D5) showed a sensitivity of 42.6% and 53.7% and a specificity of 63.6% and 54.5% concerning IRDs, respectively. The correct diagnosis of the IRD patients was within the Ada D1 and D5 suggestions in 16.7% (9/54) and 25.9% (14/54), respectively. The median System Usability Scale (SUS) score of Ada and Rheport was 75.0/100 and 77.5/100, respectively. The median completion time for both Ada and Rheport was 7.0 and 8.5 min, respectively. Sixty-four percent and 67.1% would recommend using Ada and Rheport to friends and other patients, respectively.
While SCs are well accepted among patients, their diagnostic accuracy is limited to date.
DRKS.de, DRKS00017642 . Registered on 23 July 2019.
The diagnosis of inflammatory rheumatic diseases (IRDs) is often delayed due to unspecific symptoms and a shortage of rheumatologists. Digital diagnostic decision support systems (DDSSs) have the ...potential to expedite diagnosis and help patients navigate the health care system more efficiently. The aim of this study was to assess the diagnostic accuracy of a mobile artificial intelligence (AI)–based symptom checker (Ada) and a web-based self-referral tool (Rheport) regarding IRDs. A prospective, multicenter, open-label, crossover randomized controlled trial was conducted with patients newly presenting to 3 rheumatology centers. Participants were randomly assigned to complete a symptom assessment using either Ada or Rheport. The primary outcome was the correct identification of IRDs by the DDSSs, defined as the presence of any IRD in the list of suggested diagnoses by Ada or achieving a prespecified threshold score with Rheport. The gold standard was the diagnosis made by rheumatologists. A total of 600 patients were included, among whom 214 (35.7%) were diagnosed with an IRD. Most frequent IRD was rheumatoid arthritis with 69 (11.5%) patients. Rheport’s disease suggestion and Ada’s top 1 (D1) and top 5 (D5) disease suggestions demonstrated overall diagnostic accuracies of 52%, 63%, and 58%, respectively, for IRDs. Rheport showed a sensitivity of 62% and a specificity of 47% for IRDs. Ada’s D1 and D5 disease suggestions showed a sensitivity of 52% and 66%, respectively, and a specificity of 68% and 54%, respectively, concerning IRDs. Ada’s diagnostic accuracy regarding individual diagnoses was heterogenous, and Ada performed considerably better in identifying rheumatoid arthritis in comparison to other diagnoses (D1: 42%; D5: 64%). The Cohen κ statistic of Rheport for agreement on any rheumatic disease diagnosis with Ada D1 was 0.15 (95% CI 0.08-0.18) and with Ada D5 was 0.08 (95% CI 0.00-0.16), indicating poor agreement for the presence of any rheumatic disease between the 2 DDSSs. To our knowledge, this is the largest comparative DDSS trial with actual use of DDSSs by patients. The diagnostic accuracies of both DDSSs for IRDs were not promising in this high-prevalence patient population. DDSSs may lead to a misuse of scarce health care resources. Our results underscore the need for stringent regulation and drastic improvements to ensure the safety and efficacy of DDSSs.
Prolonged activation of fibroblasts is a central hallmark of fibrosing disorders such as systemic sclerosis (SSc). Fibroblasts are the key effector cells. They differentiate into an activated ...myofibroblast phenotype. In contrast to normal wound healing with transient activation, myofibroblasts persist in fibrosing disorders. Current hypothesis suggests that profibrotic cytokines might trigger epigenetic changes which contribute to the persistently activated fibroblast phenotype. In the last years, several epigenetic alterations have been described in SSc and have been linked to different pathogenic aspects of the disease, in particular to aberrant fibroblast activation and tissue fibrosis, but also to vascular manifestations and inflammation. The focus of this review is the current knowledge on epigenetic changes in fibroblast activation in SSc.
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