Precursors to infant sensorimotor synchronization to speech and non-speech rhythms: A longitudinal study.

Impaired sensorimotor synchronization (SMS) to acoustic rhythm may be a marker of atypical language development. Here, Motion Capture was used to assess gross motor rhythmic movement at six time points between 5- and 11 months of age. Infants were recorded drumming to acoustic stimuli of varying linguistic and temporal complexity: drumbeats, repeated syllables and nursery rhymes. Here we show, for the first time, developmental change in infants' movement timing in response to auditory stimuli over the first year of life. Longitudinal analyses revealed that whilst infants could not yet reliably synchronize their movement to auditory rhythms, infant spontaneous motor tempo became faster with age, and by 11 months, a subset of infants decelerate from their spontaneous motor tempo, which better accords with the incoming tempo. Further, infants became more regular drummers with age, with marked decreases in the variability of spontaneous motor tempo and variability in response to drumbeats. This latter effect was subdued in response to linguistic stimuli. The current work lays the foundation for using individual differences in precursors of SMS in infancy to predict later language outcomes. RESEARCH HIGHLIGHT: We present the first longitudinal investigation of infant rhythmic movement over the first year of life Whilst infants generally move more quickly and with higher regularity over their first year, by 11 months infants begin to counter this pattern when hearing slower infant-directed song Infant movement is more variable to speech than non-speech stimuli In the context of the larger Cambridge UK BabyRhythm Project, we lay the foundation for rhythmic movement in infancy to predict later language outcomes.

Cortical tracking of visual rhythmic speech by 5- and 8-month-old infants: Individual differences in phase angle relate to language outcomes up to 2 years.

It is known that the rhythms of speech are visible on the face, accurately mirroring changes in the vocal tract. These low-frequency visual temporal movements are tightly correlated with speech output, and both visual speech (e.g., mouth motion) and the acoustic speech amplitude envelope entrain neural oscillations. Low-frequency visual temporal information ('visual prosody') is known from behavioural studies to be perceived by infants, but oscillatory studies are currently lacking. Here we measure cortical tracking of low-frequency visual temporal information by 5- and 8-month-old infants using a rhythmic speech paradigm (repetition of the syllable 'ta' at 2 Hz). Eye-tracking data were collected simultaneously with EEG, enabling computation of cortical tracking and phase angle during visual-only speech presentation. Significantly higher power at the stimulus frequency indicated that cortical tracking occurred across both ages. Further, individual differences in preferred phase to visual speech related to subsequent measures of language acquisition. The difference in phase between visual-only speech and the same speech presented as auditory-visual at 6- and 9-months was also examined. These neural data suggest that individual differences in early language acquisition may be related to the phase of entrainment to visual rhythmic input in infancy. RESEARCH HIGHLIGHTS: Infant preferred phase to visual rhythmic speech predicts language outcomes. Significant cortical tracking of visual speech is present at 5 and 8 months. Phase angle to visual speech at 8 months predicted greater receptive and productive vocabulary at 24 months.

Protecting Personhood: A Classic Grounded Theory.

The importance of perceiving and considering patients as healthcare partners has been increasingly promoted. Healthcare systems around the world are now highly interested in patient engagement, participation, collaboration, and partnership. Healthcare professionals are advised that patients, as autonomous beings, should be active in and responsible for a portion of their own care. The study presented here focused on patients' perceptions of interprofessional collaboration. It was conducted using the classic grounded theory methodology. The theory of protecting personhood emerged as the core concept of hospitalized patients, cared for by interprofessional healthcare teams. This theory encapsulates the process hospitalized patients go through to find balance in their sense of self, oscillating between personhood and patienthood in the unfamiliar hospital environment. The process consists of four stages: the stage of introspection, during which hospitalized patients become aware of their self as a person and as a patient; the stage of preservation, when patients find a balance between the sense of personhood and patienthood; the stage of rupture, wherein patients experience an imbalance between their sense of personhood and patienthood; and the stage of reconciliation, in which personhood is restored. The theory of protecting personhood offers insights into a better understanding of hospitalized patients' experiences and strategies, revealing the importance of relationships, and the driving force of empowerment. This study is about patients' perspectives of interprofessional healthcare teams. A grounded theory process allowed the emergence of patients' concerns and expectations, leading to a substantive theory grounded in the patients' data.

Delta- and theta-band cortical tracking and phase-amplitude coupling to sung speech by infants.

The amplitude envelope of speech carries crucial low-frequency acoustic information that assists linguistic decoding at multiple time scales. Neurophysiological signals are known to track the amplitude envelope of adult-directed speech (ADS), particularly in the theta-band. Acoustic analysis of infant-directed speech (IDS) has revealed significantly greater modulation energy than ADS in an amplitude-modulation (AM) band centred on ∼2 Hz. Accordingly, cortical tracking of IDS by delta-band neural signals may be key to language acquisition. Speech also contains acoustic information within its higher-frequency bands (beta, gamma). Adult EEG and MEG studies reveal an oscillatory hierarchy, whereby low-frequency (delta, theta) neural phase dynamics temporally organize the amplitude of high-frequency signals (phase amplitude coupling, PAC). Whilst consensus is growing around the role of PAC in the matured adult brain, its role in the development of speech processing is unexplored. Here, we examined the presence and maturation of low-frequency (<12 Hz) cortical speech tracking in infants by recording EEG longitudinally from 60 participants when aged 4-, 7- and 11- months as they listened to nursery rhymes. After establishing stimulus-related neural signals in delta and theta, cortical tracking at each age was assessed in the delta, theta and alpha [control] bands using a multivariate temporal response function (mTRF) method. Delta-beta, delta-gamma, theta-beta and theta-gamma phase-amplitude coupling (PAC) was also assessed. Significant delta and theta but not alpha tracking was found. Significant PAC was present at all ages, with both delta and theta -driven coupling observed.

Is massage an effective intervention in the management of post-operative scarring? A scoping review.

BACKGROUND: Scar massage is a widely used treatment modality in hand therapy. This intervention is thoroughly discussed in the literature relating to burns rehabilitation, however, the evidence for its use in treating linear scars following surgery is limited. PURPOSE OF STUDY: To collate the empirical literature on scar massage for the treatment of postsurgical cutaneous scars. STUDY DESIGN: Scoping review. METHODS: Medline, EMBASE, CINAHL, AMED, Scopus, ProQuest Dissertations & Theses Global, and the Joanna Briggs Institute were searched from inception to December 2020. Two researchers used a data extraction tool to record key demographic, intervention and outcome data, and to apply the Oxford Levels of Evidence for each study. RESULTS: Twenty-five studies met the inclusion criteria, reporting on a combined sample of 1515 participants. Only two papers addressed hand or wrist scars (92 participants). While all studies reported favorable outcomes for scar massage, there were 45 different outcome measures used and a propensity towards non-standardized assessment. Intervention protocols varied from a single session to three treatments daily for 6 months. The results from 13 studies were confounded by the implementation of additional rehabilitation interventions. CONCLUSIONS: The overall findings suggest that while there may be benefits to scar massage in reducing pain, increasing movement and improving scar characteristics; there is a lack of consistent research methods, intervention protocols and outcome measures. This scoping review highlights the heterogenous nature of research into scar massage following surgery and supports the need for further research to substantiate its use in the clinical setting.

A dual druggable genome-wide siRNA and compound library screening approach identifies modulators of parkin recruitment to mitochondria.

Genetic and biochemical evidence points to an association between mitochondrial dysfunction and Parkinson's disease (PD). PD-associated mutations in several genes have been identified and include those encoding PTEN-induced putative kinase 1 (PINK1) and parkin. To identify genes, pathways, and pharmacological targets that modulate the clearance of damaged or old mitochondria (mitophagy), here we developed a high-content imaging-based assay of parkin recruitment to mitochondria and screened both a druggable genome-wide siRNA library and a small neuroactive compound library. We used a multiparameter principal component analysis and an unbiased parameter-agnostic machine-learning approach to analyze the siRNA-based screening data. The hits identified in this analysis included specific genes of the ubiquitin proteasome system, and inhibition of ubiquitin-conjugating enzyme 2 N (UBE2N) with a specific antagonist, Bay 11-7082, indicated that UBE2N modulates parkin recruitment and downstream events in the mitophagy pathway. Screening of the compound library identified kenpaullone, an inhibitor of cyclin-dependent kinases and glycogen synthase kinase 3, as a modulator of parkin recruitment. Validation studies revealed that kenpaullone augments the mitochondrial network and protects against the complex I inhibitor MPP+. Finally, we used a microfluidics platform to assess the timing of parkin recruitment to depolarized mitochondria and its modulation by kenpaullone in real time and with single-cell resolution. We demonstrate that the high-content imaging-based assay presented here is suitable for both genetic and pharmacological screening approaches, and we also provide evidence that pharmacological compounds modulate PINK1-dependent parkin recruitment.

Independence of HIF1a and androgen signaling pathways in prostate cancer.

BACKGROUND: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. METHODS: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. RESULTS: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. CONCLUSIONS: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.

shRNA-mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth.

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy.

BACKGROUND: Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance. METHODS: EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and γH2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition. RESULTS: While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased γH2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls. CONCLUSIONS: Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance.

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.

The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer.

In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.

iCLIP identifies novel roles for SAFB1 in regulating RNA processing and neuronal function.

BACKGROUND: SAFB1 is a RNA binding protein implicated in the regulation of multiple cellular processes such as the regulation of transcription, stress response, DNA repair and RNA processing. To gain further insight into SAFB1 function we used iCLIP and mapped its interaction with RNA on a genome wide level. RESULTS: iCLIP analysis found SAFB1 binding was enriched, specifically in exons, ncRNAs, 3' and 5' untranslated regions. SAFB1 was found to recognise a purine-rich GAAGA motif with the highest frequency and it is therefore likely to bind core AGA, GAA, or AAG motifs. Confirmatory RT-PCR experiments showed that the expression of coding and non-coding genes with SAFB1 cross-link sites was altered by SAFB1 knockdown. For example, we found that the isoform-specific expression of neural cell adhesion molecule (NCAM1) and ASTN2 was influenced by SAFB1 and that the processing of miR-19a from the miR-17-92 cluster was regulated by SAFB1. These data suggest SAFB1 may influence alternative splicing and, using an NCAM1 minigene, we showed that SAFB1 knockdown altered the expression of two of the three NCAM1 alternative spliced isoforms. However, when the AGA, GAA, and AAG motifs were mutated, SAFB1 knockdown no longer mediated a decrease in the NCAM1 9-10 alternative spliced form. To further investigate the association of SAFB1 with splicing we used exon array analysis and found SAFB1 knockdown mediated the statistically significant up- and downregulation of alternative exons. Further analysis using RNAmotifs to investigate the frequency of association between the motif pairs (AGA followed by AGA, GAA or AAG) and alternative spliced exons found there was a highly significant correlation with downregulated exons. Together, our data suggest SAFB1 will play an important physiological role in the central nervous system regulating synaptic function. We found that SAFB1 regulates dendritic spine density in hippocampal neurons and hence provide empirical evidence supporting this conclusion. CONCLUSIONS: iCLIP showed that SAFB1 has previously uncharacterised specific RNA binding properties that help coordinate the isoform-specific expression of coding and non-coding genes. These genes regulate splicing, axonal and synaptic function, and are associated with neuropsychiatric disease, suggesting that SAFB1 is an important regulator of key neuronal processes.

The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis.

The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.

Scar massage as an intervention for post-surgical scars: A practice survey of Australian hand therapists.

Introduction: Scar massage is a commonly used treatment in hand therapy. The current empirical evidence that supports it is disparate and of variable quality, with no established effective dosage and method proposed. This study aimed to identify the current practice among Australian hand therapists using massage as an intervention for scarring following surgery to the hand and upper limb. Methods: A purposely designed self-report online survey was emailed to current members of the Australian Hand Therapy Association (n = 958). Data collected included demographics, intervention techniques, conditions treated and protocols, scar assessment and knowledge and training about scar massage as a clinical intervention. Results: A total of 116 completed questionnaires were received (a response rate of 12.1%). All respondents used scar massage as part of their clinical practice with 98% to improve soft tissue glide (n = 114), 92% for hypersensitivity (n = 107), and 84% to increase hand function (n = 97). Only 18% (n = 21) of respondents used standardised outcome measures, and most therapists had learned scar massage from a colleague (81%). Conclusions: Commonalities in how respondents implemented scar massage were found. Participants reported relying primarily on clinical experience to inform their practice. Whilst scar massage was widely used, few respondents had received formal skills training or completed outcome measures regularly to formally evaluate its clinical efficacy or impact. Replication of this study with a larger international sample of participants is warranted to determine if these findings reflect general practice.

Individual factors as predictors of secondary traumatic stress and burnout in forensic inpatient staff.

WHAT IS KNOWN ON THE SUBJECT: Secondary traumatic stress (STS) is the indirect traumatisation of a person through the stress of helping or knowing about other's trauma. Burnout is gradual exhaustion in response to long-term work-related stress. Both have negative psychological, physiological and/or organisational consequences; however, the existing research in forensic health care professionals (FHCPs) is limited. One study explored STS in FCHPs and found that lower psychological flexibility (ability to adapt) was a predictor of greater STS. Existing research on burnout in FHCPs suggests that individual differences, such as the ways in which we cope (talking to people vs. using substances), may predict burnout levels. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: Prevalence findings add to the recent evidence base, which also found moderate levels of burnout. However, this study is the first to find high levels of secondary traumatic stress in FHCPs. Similar to existing literature, the study's findings suggest that FHCP's with lower levels of psychological flexibility and more maladaptive coping strategies may experience greater STS and burnout symptoms, while staff who use more adaptive coping strategies may experience less burn-out. Unexpectedly, staff who reported a more anxious attachment style were burnt-out; however, there are limitations to this finding. WHAT ARE THE IMPLICATIONS FOR PRACTICE: Policies and practices in forensic settings should reflect the risk of STS and burnout. Practices or interventions should enhance adaptive coping strategies and psychological flexibility, such as Resilience Enhancement Programmes or Acceptance and Commitment Therapy (ACT). ABSTRACT: INTRODUCTION: Secondary traumatic stress (STS) and burnout literature in inpatient forensic health care professionals (FHCPs) is limited, despite the psychological, physiological and organisational consequences. AIMS: This study aimed to further this limited evidence base, investigating predictors of STS and burnout in FHCPs. METHOD: 98 healthcare professionals working in two UK forensic inpatient settings completed measures assessing: burnout, STS, psychological flexibility, coping style, attachment style and a demographic questionnaire recording length of service and the sex of staff. RESULTS: Results indicated high STS and moderate burnout levels. The main predictors of STS and burnout were poorer psychological flexibility and greater maladaptive coping styles, whereas lower burnout was predicted by greater adaptive coping styles and an anxious attachment style. DISCUSSION: This study has contributed towards a limited evidence base and indicates poorer psychological flexibility and greater maladaptive coping may be risk factors for STS and burnout in FHCPs, whereas greater maladaptive coping may be a protective factor. IMPLICATION FOR PRACTICE: The findings suggest that interventions such as Acceptance and Commitment Therapy (ACT) and coping skills interventions, may offer protective benefits to inpatient forensic healthcare professionals.

Measuring the Social Impact of Burn injuries in Australia: An Adaptation of the Life Impact Burn Recovery Evaluation - The Aus-LIBRE Profile.

Burn survivors can experience social participation challenges throughout their recovery. The aim of this study was to develop a novel Australian English translation of the Life Impact Burn Recovery Evaluation (LIBRE) Profile, the Aus-LIBRE Profile. This study consisted of three stages: 1) translation of the LIBRE Profile from American to Australian English by Australian researchers/burns clinicians; 2) piloting and cognitive evaluation of the Aus-LIBRE Profile with burn survivors to assess the clarity and consistency of the interpretation of each individual item, and 3) review of the Aus-LIBRE Profile by colleagues who identify as Aboriginal Australians for cross-cultural validation. In stage 2, investigators administered the translated questionnaire to 20 Australian patients with burn injuries in the outpatient clinic (10 patients from xx and 10 patients from yy). Face validity of the Aus-LIBRE Profile was tested in 20 burns survivors (11 females) ranging from 21 to 74 years (median age 43 years). The total body surface area (TBSA) burned ranged from 1% to 50% (median 10%). Twelve language changes were made based on the feedback from the burn clinicians/researchers, study participants and colleagues who identify as Aboriginal Australians. Using a formal translation process, the Aus-LIBRE Profile was adapted for use in the Australian burn population. The Aus-LIBRE Profile will require psychometric validation and testing in the Australian burn patient population before broader application of the scale.

Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Ensemble Detection of DNA Engineering Signatures.

Synthetic biology is creating genetically engineered organisms at an increasing rate for many potentially valuable applications, but this potential comes with the risk of misuse or accidental release. To begin to address this issue, we have developed a system called GUARDIAN that can automatically detect signatures of engineering in DNA sequencing data, and we have conducted a blinded test of this system using a curated Test and Evaluation (T&E) data set. GUARDIAN uses an ensemble approach based on the guiding principle that no single approach is likely to be able to detect engineering with perfect accuracy. Critically, ensembling enables GUARDIAN to detect sequence inserts in 13 target organisms with a high degree of specificity that requires no subject matter expert (SME) review.

Decoding speech information from EEG data with 4-, 7- and 11-month-old infants: Using convolutional neural network, mutual information-based and backward linear models.

BACKGROUND: Computational models that successfully decode neural activity into speech are increasing in the adult literature, with convolutional neural networks (CNNs), backward linear models, and mutual information (MI) models all being applied to neural data in relation to speech input. This is not the case in the infant literature. NEW METHOD: Three different computational models, two novel for infants, were applied to decode low-frequency speech envelope information. Previously-employed backward linear models were compared to novel CNN and MI-based models. Fifty infants provided EEG recordings when aged 4, 7, and 11 months, while listening passively to natural speech (sung or chanted nursery rhymes) presented by video with a female singer. RESULTS: Each model computed speech information for these nursery rhymes in two different low-frequency bands, delta and theta, thought to provide different types of linguistic information. All three models demonstrated significant levels of performance for delta-band neural activity from 4 months of age, with two of three models also showing significant performance for theta-band activity. All models also demonstrated higher accuracy for the delta-band neural responses. None of the models showed developmental (age-related) effects. COMPARISONS WITH EXISTING METHODS: The data demonstrate that the choice of algorithm used to decode speech envelope information from neural activity in the infant brain determines the developmental conclusions that can be drawn. CONCLUSIONS: The modelling shows that better understanding of the strengths and weaknesses of each modelling approach is fundamental to improving our understanding of how the human brain builds a language system.