The Association Between Stuttering Burden and Psychosocial Aspects of Life in Adults.

PURPOSE: Stuttering is a speech condition that can have a major impact on a person's quality of life. This descriptive study aimed to identify subgroups of people who stutter (PWS) based on stuttering burden and to investigate differences between these subgroups on psychosocial aspects of life. METHOD: The study included 618 adult participants who stutter. They completed a detailed survey examining stuttering symptomatology, impact of stuttering on anxiety, education and employment, experience of stuttering, and levels of depression, anxiety, and stress. A two-step cluster analytic procedure was performed to identify subgroups of PWS, based on self-report of stuttering frequency, severity, affect, and anxiety, four measures that together inform about stuttering burden. RESULTS: We identified a high- (n = 230) and a low-burden subgroup (n = 372). The high-burden subgroup reported a significantly higher impact of stuttering on education and employment, and higher levels of general depression, anxiety, stress, and overall impact of stuttering. These participants also reported that they trialed more different stuttering therapies than those with lower burden. CONCLUSIONS: Our results emphasize the need to be attentive to the diverse experiences and needs of PWS, rather than treating them as a homogeneous group. Our findings also stress the importance of personalized therapeutic strategies for individuals with stuttering, considering all aspects that could influence their stuttering burden. People with high-burden stuttering might, for example, have a higher need for psychological therapy to reduce stuttering-related anxiety. People with less emotional reactions but severe speech distortions may also have a moderate to high burden, but they may have a higher need for speech techniques to communicate with more ease. Future research should give more insights into the therapeutic needs of people highly burdened by their stuttering. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25582980.

Self-Reported Stuttering Severity Is Accurate: Informing Methods for Large-Scale Data Collection in Stuttering.

PURPOSE: To our knowledge, there are no data examining the agreement between self-reported and clinician-rated stuttering severity. In the era of big data, self-reported ratings have great potential utility for large-scale data collection, where cost and time preclude in-depth assessment by a clinician. Equally, there is increasing emphasis on the need to recognize an individual's experience of their own condition. Here, we examined the agreement between self-reported stuttering severity compared to clinician ratings during a speech assessment. As a secondary objective, we determined whether self-reported stuttering severity correlated with an individual's subjective impact of stuttering. METHOD: Speech-language pathologists conducted face-to-face speech assessments with 195 participants (137 males) aged 5-84 years, recruited from a cohort of people with self-reported stuttering. Stuttering severity was rated on a 10-point scale by the participant and by two speech-language pathologists. Participants also completed the Overall Assessment of the Subjective Experience of Stuttering (OASES). Clinician and participant ratings were compared. The association between stuttering severity and the OASES scores was examined. RESULTS: There was a strong positive correlation between speech-language pathologist and participant-reported ratings of stuttering severity. Participant-reported stuttering severity correlated weakly with the four OASES domains and with the OASES overall impact score. CONCLUSIONS: Participants were able to accurately rate their stuttering severity during a speech assessment using a simple one-item question. This finding indicates that self-report stuttering severity is a suitable method for large-scale data collection. Findings also support the collection of self-report subjective experience data using questionnaires, such as the OASES, which add vital information about the participants' experience of stuttering that is not captured by overt speech severity ratings alone.

Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40.

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

Reduced stuttering for school-age children: A systematic review.

BACKGROUND: Treatment of school-age children (6-12 years of age) who stutter is a public health priority. Their clinical needs include a psychosocial focus and stuttering reduction. For the latter clinical need, there is a critical window of opportunity for these children warranting research attention. PURPOSE: The purpose of the review is to guide future clinical research by establishing (a) what interventions are associated with stuttering reduction for school-age children (b) the reported immediate and longer-term effects of those interventions, and (c) the level of evidence for these interventions in terms of study design. METHODS: Fourteen databases and three conference proceedings were searched for interventions used to reduce stuttering in school-age children. Primary outcomes were mean stuttering reductions pre-treatment, immediately post-treatment, and any follow-up assessments. RESULTS: Of the 4305 studies identified from the databases, 67 studies met inclusion criteria. Five different treatment approaches were reported in the literature that might reduce stuttering for a school-age child, but with varying effect sizes. These include (a) operant methods, (b) speech restructuring, (c) combined operant methods and speech restructuring, (d) machine-driven treatments, and (e) treatments with a cognitive behaviour therapy component. CONCLUSIONS: Operant methods warrant investigation in future clinical trial research, as do variants of speech restructuring. Hybrid approaches showed encouraging results, including speech restructuring variants combined with operant methods or with cognitive behaviour therapy. However, evidence is preliminary only at Phase I and II trials. Several treatments with reported clinical promise have been overlooked for decades and require further investigation.

Diagnostic Accuracy and economic value of a Tiered Assessment for Fetal Alcohol Spectrum Disorder (DATAforFASD): Protocol.

INTRODUCTION: Australian practices for diagnosing fetal alcohol spectrum disorder (FASD) are lengthy and require specialist expertise. Specialist teams are based in urban locations; they are expensive and have prolonged waitlists. Innovative, flexible solutions are needed to ensure First Nations children living in rural/remote communities have culturally appropriate and equitable access to timely diagnosis and support. This study compares the accuracy of rapid assessments (index tests) that can be administered by a range of primary healthcare practitioners to specialist standardised FASD assessments (reference tests). The cost-efficiency of index tests will be compared with reference tests. METHODS AND ANALYSIS: At least 200 children aged 6-16 years at-risk of FASD will be recruited across at least seven study sites. Following standards for reporting diagnostic accuracy study (STARD) guidelines, all children will complete index and reference tests. Diagnostic accuracy statistics (including receiver operating curves, sensitivity, specificity, positive and negative predictive values and likelihood ratios) will identify whether rapid assessments can accurately identify: (1) the presence of an FASD diagnosis and (2) impairment in each neurodevelopmental domain, compared to comprehensive assessments. Direct and indirect healthcare costs for index tests compared to reference tests will be collected in primary healthcare and specialist settings. ETHICS AND DISSEMINATION OF RESULTS: Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/20/QCHQ/63173); Griffith University Human Research Ethics Committee (2020/743). Results will assist in validating the use of index tests as part of a tiered neurodevelopmental assessment process that was co-designed with First Nations community and primary healthcare practitioners. Outcomes will be summarised and provided to participating practitioners and sites, and disseminated to community health services and consumers. Findings will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12622000498796.

Effects of an Artificial Intelligence Platform for Behavioral Interventions on Depression and Anxiety Symptoms: Randomized Clinical Trial.

BACKGROUND: The need for scalable delivery of mental health care services that are efficient and effective is now a major public health priority. Artificial intelligence (AI) tools have the potential to improve behavioral health care services by helping clinicians collect objective data on patients' progress, streamline their workflow, and automate administrative tasks. OBJECTIVE: The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an AI platform for behavioral health in facilitating better clinical outcomes for patients receiving outpatient therapy. METHODS: The study was conducted at a community-based clinic in the United States. Participants were 47 adults referred for outpatient, individual cognitive behavioral therapy for a main diagnosis of a depressive or anxiety disorder. The platform provided by Eleos Health was compared to a treatment-as-usual (TAU) approach during the first 2 months of therapy. This AI platform summarizes and transcribes the therapy session, provides feedback to therapists on the use of evidence-based practices, and integrates these data with routine standardized questionnaires completed by patients. The information is also used to draft the session's progress note. Patients were randomized to receive either therapy provided with the support of an AI platform developed by Eleos Health or TAU at the same clinic. Data analysis was carried out based on an intention-to-treat approach from December 2022 to January 2023. The primary outcomes included the feasibility and acceptability of the AI platform. Secondary outcomes included changes in depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7) scores as well as treatment attendance, satisfaction, and perceived helpfulness. RESULTS: A total of 72 patients were approached, of whom 47 (67%) agreed to participate. Participants were adults (34/47, 72% women and 13/47, 28% men; mean age 30.64, SD 11.02 years), with 23 randomized to the AI platform group, and 24 to TAU. Participants in the AI group attended, on average, 67% (mean 5.24, SD 2.31) more sessions compared to those in TAU (mean 3.14, SD 1.99). Depression and anxiety symptoms were reduced by 34% and 29% in the AI platform group versus 20% and 8% for TAU, respectively, with large effect sizes for the therapy delivered with the support of the AI platform. No group difference was found in 2-month treatment satisfaction and perceived helpfulness. Further, therapists using the AI platform submitted their progress notes, on average, 55 hours earlier than therapists in the TAU group (t=-0.73; P<.001). CONCLUSIONS: In this randomized controlled trial, therapy provided with the support of Eleos Health demonstrated superior depression and anxiety outcomes as well as patient retention, compared with TAU. These findings suggest that complementing the mental health services provided in community-based clinics with an AI platform specializing in behavioral treatment was more effective in reducing key symptoms than standard therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05745103; https://classic.clinicaltrials.gov/ct2/show/NCT05745103.

Psychiatry's Obligation to Promote Voting Among Patients With Mental Illness.

The American Medical Association adopted a resolution in June 2022 recognizing voting as a social determinant of health. As psychiatric professionals and trainees with experience in civic health, the authors argue that psychiatrists must consider the relationship between voting and mental health as part of care delivery. People with psychiatric illness can experience unique barriers to voting and garner mental health benefits from civic engagement. Provider-led activities to promote voting are accessible and simple. Given the benefits of voting, and the availability of interventions to foster voter engagement, psychiatrists have an obligation to promote voting access among their patients.

Psychosocial features of stuttering for school-age children: A systematic review.

BACKGROUND: Contemporary clinical and empirical perspectives indicate that management of the psychosocial features of stuttering is fundamental for effective treatment. Interventions that improve psychosocial outcomes for school-age children who stutter are, therefore, needed. AIMS: This systematic review identifies what psychosocial outcomes have been explored in existing school-age clinical research, the measures used and the potential treatment effects. This will provide guidance for developing interventions that reflect contemporary perspectives of stuttering management. METHODS & PROCEDURES: A total of 14 databases and three conference proceedings were searched for clinical reports of psychosocial outcomes of children aged 6-12 years. The review did not include pharmacological interventions. Psychosocial measures and outcomes were analysed in each study based on data recorded pre-treatment, immediately post-treatment and for any follow-up assessments. MAIN CONTRIBUTIONS: Of the 4051 studies identified from the databases, a total of 22 studies met criteria for inclusion in the review. From these 22 studies, the review identified four prominent psychosocial domains that have been explored in school-age clinical research to date: Impact of stuttering, communication attitude, anxiety and speech satisfaction. These domains vary in measurement and effect sizes. Two behavioural treatments were associated with anxiety reduction, even though they did not contain anxiolytic procedures. No evidence of potential treatment effects emerged for communication attitudes. Quality of life-an important psychosocial domain pertinent to health economics-did not feature in school-age clinical reports. CONCLUSIONS & IMPLICATIONS: The psychosocial features of stuttering need to be managed during the school years. Three psychosocial domains-impact of stuttering, anxiety and speech satisfaction-show evidence of potential treatment effects. This review provides direction for future clinical research so that speech-language pathologists can effectively and holistically manage school-age children who stutter. WHAT THIS PAPER ADDS: What is already known on the subject Elevated levels of anxiety are apparent for children and adolescents who stutter. Therefore, the need to assess and manage psychosocial features of stuttering are expertly regarded as clinical priorities. Clinical trials of such psychosocial features of stuttering for children aged 6-12 years are not well advanced and, therefore, do not reflect current best practice management of this disorder. What this study adds to existing knowledge This systematic review identifies four different psychosocial domains measured and reported in the literature for school-age stuttering management. For three psychosocial domains, some evidence of potential treatment effects emerged with participant numbers greater than 10: Impact of stuttering, anxiety and speech satisfaction. Though treatment effect sizes varied, there is a suggestion that cognitive behaviour therapy can improve anxiety of school-age children who stutter. There is also suggestion that two other behavioural treatments can improve anxiety of school-age children who stutter. What are the potential or actual clinical implications of this work? Given the essential need for school-age children who stutter to receive management of any speech-related anxiety they may experience, it would be productive to discover in future clinical research what interventions could contribute to that goal-behavioural or psychosocial, or both. This review reveals that cognitive behaviour therapy, and other behavioural treatments, are associated with anxiety reductions. Such approaches should be considered for future clinical trial research to help advance the evidence base for managing school-age stuttering.

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.

Enhancing interprofessional practice through the co-design of a holistic culturally and developmentally informed First Nations child health assessment.

BACKGROUND: This qualitative study explored staff experiences of co-designing and implementing a novel interprofessional (IP) First Nations child health assessment (the helpful check), developed in partnership with a remote North-Queensland Aboriginal CommunityControlled Health Organisation. METHOD: Eleven staff across two teams (family health and allied health) were involved in co-designing and implementing the child health assessment and associated IP practices. Interviews were undertaken using a semi-structured interview template and were audio recorded and transcribed verbatim. Data were analysed using thematic analysis. RESULTS: Three overarching themes were developed: (1) connect teams by building strong relationships; (2) leave space for helpful check processes to evolve; and (3) integrate helpful check processes into routine practice to sustain change. CONCLUSIONS: Results demonstrate how the incorporation of IP practices into a remote primary healthcare setting led to perceived benefits for both the health service staff and clients.

Praying for More Time: Mexican Immigrants' Pandemic Eldercare Dilemmas.

Based on longitudinal research conducted with 21 Mexican immigrants between 2018 and 2021, this article examines the challenges the COVID-19 pandemic posed to undocumented immigrants in the United States attempting to provide care for aging parents in Mexico. As the United States excluded undocumented immigrants from pandemic support, the pandemic undermined their ability to provide health care for their parents even as the Mexican public health care system crumbled. Meanwhile, as the pandemic hastened their parents' demise, it thwarted immigrants' ability to time returns to see their parents before they died. While scholars have amply documented how spatial disparities exacerbated the impact of the pandemic among marginalized groups, few have examined the temporal disruptions caused by the pandemic. This article suggests that the pandemic provoked particular distress by desynchronizing the temporalities of family life across borders and preventing immigrants' abilities to coordinate care for their parents in time. [COVID-19, transnational families, eldercare, death, time].

Self-reported impact of developmental stuttering across the lifespan.

AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.

Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease.

Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease This phase 1b/2a, randomized, double-blind, placebo-controlled, dose-escalation trial tested low-dose subcutaneous aldesleukin (recombinant IL-2) in patients with ischemic heart disease. Low-dose IL-2 expanded Tregs, without adverse events of major concern. Single-cell RNA-sequencing of circulating immune cells was used to provide mechanistic assessment of the treatment's effects.

On Pandemic Privilege: Reflections on a "Home-Bound Pandemic Ethnography".

This essay examines the experience of conducting a "home-bound pandemic ethnography"-one that toggles back and forth between the ethnographer's own experience of the pandemic while in quarantine and the very different pandemic experiences of her Latina immigrant essential worker interviewees. Maintaining a split gaze between one's own experience and those of one's interviewees, a home-bound pandemic ethnography lends itself to a kind of reflexivity and comparison that traditional ethnographic "immersion" does not. Involving the disjunctive knowledge of "being here" while listening to the very different experience of "being there," it throws into stark relief asymmetries built deep into the ethnographic relationship. While ethnographic immersion rests on the illusion of ethnographers' acculturation so they become a kind of insider-outsider, a "home-bound" ethnography refuses the claims of traditional ethnography to "truly understand" the plight of the marginalized populations with whom we work. Just as critiques have emerged of anthropologists' silence regarding our relative immunity from climate catastrophes (Jobson, Am Anthropol, 122, 2020, 259) and from state violence (Gomberg-Muñoz, J Anthropol N Am, 21, 2018, 36) in comparison to those whom we research, the pandemic also demands an honest reckoning with the chasm that has widened anew between the lived realities of ethnographers and those of our research "subjects." Highlighting the discomfort of disjunctive lived realities, a home-bound pandemic ethnography creates a careful ledger of the ethnographer's comparative privilege, and questions the very premises of ethnographic immersion.

Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression.

Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional DNA topology is unknown. Here, we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML: Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with mutations in Npm1c to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a previously unknown superenhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members.

Cardiovascular effects of biological versus conventional synthetic disease-modifying antirheumatic drug therapy in treatment-naïve, early rheumatoid arthritis.

OBJECTIVES: To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy. METHODS: Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV). RESULTS: Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10-3 mm Hg-1 (2.7-3.3) vs 4.4×10-3 mm Hg-1 (3.7-5.2), p<0.001); LV mass significantly lower (78.2 g (74.0-82.7), n=81 vs 92.9 g (84.8-101.7), n=30, p<0.01); and ECV increased (27.1% (26.4-27.9), n=78 vs 24.9% (23.8-26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10-3 mm Hg-1 (2.7-3.4) to 3.6×10-3 mm Hg-1 (3.1-4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders. CONCLUSION: We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151.

Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial.

OBJECTIVES: We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX. METHODS: Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints. RESULTS: We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX. CONCLUSIONS: Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested. Trial registration number NCT02433184.

Adalimumab in Juvenile Idiopathic Arthritis-Associated Uveitis: 5-Year Follow-up of the Bristol Participants of the SYCAMORE Trial.

PURPOSE: To determine longer-term outcomes of participants enrolled from a single center in the SYCAMORE trial, a randomized placebo-controlled trial of adalimumab vs placebo in children with juvenile idiopathic arthritis-associated uveitis (JIA-U) uncontrolled on methotrexate. DESIGN: Retrospective interventional case series. METHODS: Medical records of all 28 SYCAMORE participants recruited at the Bristol Eye Hospital were reviewed at approximately 3-monthly intervals up to 5 years from the trial randomization date. Uveitis activity, treatment course, visual outcomes, ocular complications, and adverse events were recorded. Data are presented using summary statistics. RESULTS: Following withdrawal of the investigational medicinal product (IMP), 25 of the 28 participants were started on adalimumab for active JIA-U. Of the 12 participants in the active treatment arm of the SYCAMORE study, 11 (92%) were restarted on adalimumab after withdrawal of the IMP for active JIA-U (median time to flare 188 days [range 42-413 days). Two participants stopped adalimumab for uncontrolled JIA-U. One participant had a reduction in vision to 0.3 owing to cataract. Mean visual acuity for the remaining 27 participants was -0.04 (right eye) and -0.05 (left eye). CONCLUSIONS: Drug-induced remission of JIA-U did not persist when adalimumab was withdrawn after 1-2 years of treatment. Adalimumab was well tolerated and visual acuity outcomes were excellent.

Kinase Networks Regulate Metabolism: I'D(H1) Never Have Guessed!

Mutations in isoforms of isocitrate dehydrogenase (IDH) enzymes are described in multiple cancers and both mutant and wild-type IDH are important for the generation and maintenance of tumors, but how their activity is regulated is poorly understood. An article in this issue of Cancer Discovery identifies a novel posttranslational mechanism of IDH1 regulation involving phosphorylation of specific tyrosine residues by a network of kinases that alter the specificity of substrate and cofactor binding, dimer formation, and ultimately enzyme activity.See related article by Chen et al., p. 756.

A Theory-Driven Investigation of the Association Between Emotion Dysregulation and Suicide Risk in a Clinical Adolescent Sample.

OBJECTIVE: Emotion dysregulation has been consistently linked to suicide ideation and attempt, but an explanatory model for this relationship has not been adequately investigated in adolescents. This study examined the concurrent relationship among emotion dysregulation, variables from the Interpersonal-Psychological Theory of Suicide (IPTS), and suicide risk (operationalized as a continuous variable that increases in intensity from nonspecific to active suicide ideation to suicide ideation with a plan) in a clinical adolescent sample. METHOD: A total of 151 adolescents (aged 12-17) were recruited from an inpatient psychiatry unit. Cross-sectional analyses were conducted to determine whether the relationship between emotion dysregulation and suicide risk was explained by the variables of perceived burdensomeness (PB), thwarted belongingness, and capability for suicide, as proposed by the IPTS. RESULTS: As hypothesized, the relationship between emotion dysregulation and suicide risk was explained by PB and capability for suicide. Depressive symptoms had an independent relationship with suicide risk after controlling for IPTS variables. CONCLUSIONS: The results from this study suggest that effective treatment strategies that reduce negative cognition tied to PB and depressive symptoms would address the most proximal variables related to suicide risk in adolescents. Enhancing emotion management would serve to maintain low levels of proximal influences on risk.