Multiple-community-based epidemiological study of stuttering among 3-year-old children in Japan.

INTRODUCTION: Many epidemiological studies of the disorder of stuttering have been conducted during the 20th century, continuing during the current one. Unfortunately, only a few were carried out in Japan. This study aimed at assessing (1) the incidence and prevalence of stuttering in 3-year-old children in multiple Japanese communities, and (2) factors associated with the onset of stuttering among these children. METHODS: A questionnaire aimed at screening for the presence of stuttering was employed for 2,055 children aged 3 years, who underwent a standard nationwide health checkup. Positive responses were confirmed in several ways: (1) direct interviews and assessment of the child's speech, (2) confirmatory questionnaire, or (3) telephone interviews by licensed Speech Language Hearing Therapists. RESULTS: Approximately 6.5% of the children were found to exhibit stuttering at the time of their health checkup. This figure rose to 9.0% after including individuals who previously, but not currently, were reported to have exhibited stuttering. Among the putative risk factors, higher stuttering odds (odds ratio, OR = 3.26) were detected in those with a family history of stuttering, those whose guardians had concerns about their child's development (OR = 1.77), and those with diagnosed diseases or disabilities (OR = 2.14). DISCUSSION/CONCLUSIONS: It was concluded that, in Japan, both the risk of stuttering incidence (8.9%) in children up to, and including, the age of 3 years, as well as its prevalence (6.5%) in this population, was similar to those reported by recent studies in other countries. Additionally, our findings also confirmed that an increased risk for stuttering at age 3 is associated with a family history of stuttering.

Therapeutic potential of robots for people who stutter: a preliminary study.

Introduction: Growing anecdotal evidence suggests the feasibility of robotic intervention for people who suffer from disorders related to state anxiety. Few studies have been conducted on utilizing robots for persons who stutter (PWS). The present study examines the feasibility of using a robot for speech therapy for PWS. Methods: We prepared four settings (i.e., interviews with unfamiliar persons, interviews with unfamiliar communication robots, reading sentences aloud with a tandem robot that can utter the same words as a user by repeating the user's voice after a short delay, and reading sentences aloud while being alone). We assessed the potential of the robots as both interlocutors and practice partners in training with delayed auditory feedback (DAF) for PWS. Moreover, we assessed the relationship between the trait of stuttering and the participants' affinity to the robots. Results: Eleven PWS participated in the study. Eight (72.7%) participants had fewer stuttering-related psychological symptoms when they communicated with robots than when they communicated with humans. Spearman's rank correlation analysis revealed that there was a significant negative correlation between the Modified Erickson Communication Attitude scale (S-24) and the difference between the scores for stuttering-related psychological symptoms pertaining to the communication robot and humans (p < 0.01). Six participants (54.5%) had fewer stuttering-related psychological symptoms when they read aloud with the tandem robot than when they read aloud alone. There were significant positive correlations between S-24 and the differences between the scores for stuttering-related psychological symptoms when reading aloud with the tandem robot and those when reading aloud alone (p < 0.01). Discussion: The communication robot and tandem utterance robot can sometimes be burdensome, although both robots were always easier to talk to for PWS in this preliminary study. The participants with positive speech-related attitudes were more inclined to decrease stuttering-related psychological symptoms when communicating with CommU than when communicating with humans. The participants whose speech-related attitudes were negative were more inclined to show a decrease in stuttering-related psychological symptoms when reading aloud with the tandem robot. Further studies are needed to provide more detailed information.

Subphthalocyanine-flipper dyads for selective membrane staining.

The design, synthesis and evaluation of a subphthalocyanine-flipper (SubPc-Flipper) amphiphilic dyad is reported. This dyad combines two fluorophores that function in the visible region (420-800 nm) for the simultaneous sensing of both ordered and disordered lipidic membranes. The flipper probes part of the dyad possesses mechanosensitivity, long fluorescence lifetimes (τ = 3.5-5 ns) and selective staining of ordered membranes. On the other hand, subphthalocyanines (SubPc) are short-lifetime (τ = 1-2.5 ns) fluorophores that are insensitive to membrane tension. As a result of a Förster Resonance Energy Transfer (FRET) process, the dyad not only retains the mechanosensitivity of flippers but also demonstrates high selectivity and emission in different kinds of lipidic membranes. The dyad exhibits high emission and sensitivity to membrane tension (Δτ = 3.5 ns) when tested in giant unilamellar vesicles (GUVs) with different membrane orders. Overall, the results of this study represent a significant advancement in the applications of flippers and dyads in mechanobiology.

Anion-π catalysis on carbon allotropes.

Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion-π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels-Alder reactions and autocatalytic ether cyclizations. Currently, anion-π catalysis on carbon allotropes gains momentum because the combination with electric-field-assisted catalysis promises transformative impact on organic synthesis.

Weight-loss Independent Clinical and Metabolic Biomarkers Associated with Type 2 Diabetes Remission Post-bariatric/metabolic Surgery.

PURPOSE: Remission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping. MATERIALS AND METHODS: Ten patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed. RESULTS: Remitters had significantly greater ß-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and ß-cell function was revealed. CONCLUSION: We highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in ß-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.

Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates.

In this study, we introduce phosphorus, a pnictogen, as an exchange center for dynamic covalent chemistry. Cascade exchange of neutral phosphorotri- and -tetrathioates with thiolates is demonstrated in organic solvents, aqueous micellar systems, and in living cells. Exchange rates increase with the pH value, electrophilicity of the exchange center, and nucleophilicity of the exchangers. Molecular walking of the dynamic phosphorus center along Hammett gradients is simulated by the sequential addition of thiolate exchangers. Compared to phosphorotrithioates, tetrathioates are better electrophiles with higher exchange rates. Dynamic phosphorotri- and -tetrathioates are non-toxic to HeLa Kyoto cells and participate in the dynamic networks that account for thiol-mediated uptake into living cells.

Electric field-assisted anion-π catalysis on carbon nanotubes in electrochemical microfluidic devices.

The vision to control the charges migrating during reactions with external electric fields is attractive because of the promise of general catalysis, emergent properties, and programmable devices. Here, we explore this idea with anion-π catalysis, that is the stabilization of anionic transition states on aromatic surfaces. Catalyst activation by polarization of the aromatic system is most effective. This polarization is induced by electric fields. The use of electrochemical microfluidic reactors to polarize multiwalled carbon nanotubes as anion-π catalysts emerges as essential. These reactors provide access to high fields at low enough voltage to prevent electron transfer, afford meaningful effective catalyst/substrate ratios, and avoid interference from additional electrolytes. Under these conditions, the rate of pyrene-interfaced epoxide-opening ether cyclizations is linearly voltage-dependent at positive voltages and negligible at negative voltages. While electromicrofluidics have been conceived for redox chemistry, our results indicate that their use for supramolecular organocatalysis has the potential to noncovalently electrify organic synthesis in the broadest sense.

Measuring response to treatment in axial spondyloarthritis using quantitative imaging biomarkers: a prospective observational cohort study.

OBJECTIVE: Objective assessments of disease activity and response to treatment in axial spondyloarthritis (axSpA) remain a challenge; quantitative imaging biomarkers (QIBs) of inflammation could enhance assessments of disease activity and therapeutic response. We aimed to determine the responsiveness of QIBs obtained from diffusion-weighted imaging (DW-MRI) and chemical shift-encoded MRI (CSE-MRI) using the partially automated Bone Edema and Adiposity Characterisation with Histograms (BEACH) software tool in axSpA patients undergoing biologic therapy. METHODS: We conducted a prospective longitudinal cohort study, including 30 patients with axSpA undergoing biologic therapy. Patients were scanned before and after biologic therapy using conventional MRI, DWI and CSE-MRI at 3T. Apparent diffusion coefficient (ADC) and proton density fat fraction (PDFF) were assessed using the BEACH tool (https://github.com/TJPBray/BEACH), and conventional MR images were assessed using established visual scoring methods by expert radiologists. Responsiveness - the ability of the MRI measurements to capture changes in disease occurring as a result of biologic therapy - was assessed using the standardized response mean (SRM). Inter-reader reliability of the ADC and PDFF maps was assessed using Bland-Altman limits of agreement analysis and the intraclass correlation coefficient. RESULTS: Responsiveness to therapy was moderate for ADC-based parameters (SRM 0.50) and comparable to established visual scoring methods for bone marrow oedema (SRM 0.53). Interobserver variability was lower for QIBs compared with conventional visual scores methods. CONCLUSIONS: QIBs measured using the BEACH tool are sensitive to changes in inflammation in axSpA following biologic therapy, with similar responsiveness and lower interobserver variability to visual scoring by expert radiologists. ADVANCES IN KNOWLEDGE: QIBs measured using the partially automated BEACH tool offer an objective measure of response to biologic therapy in axSpA.

Fluorogenic In Situ Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds.

Progress with fluorescent flippers, small-molecule probes to image membrane tension in living systems, has been limited by the effort needed to synthesize the twisted push-pull mechanophore. Here, we move to a higher oxidation level to introduce a new design paradigm that allows the screening of flipper probes rapidly, at best in situ. Late-stage clicking of thioacetals and acetals allows simultaneous attachment of targeting units and interfacers and exploration of the critical chalcogen-bonding donor at the same time. Initial studies focus on plasma membrane targeting and develop the chemical space of acetals and thioacetals, from acyclic amino acids to cyclic 1,3-heterocycles covering dioxanes as well as dithiolanes, dithianes, and dithiepanes, derived also from classics in biology like cysteine, lipoic acid, asparagusic acid, DTT, and epidithiodiketopiperazines. From the functional point of view, the sensitivity of membrane tension imaging in living cells could be doubled, with lifetime differences in FLIM images increasing from 0.55 to 1.11 ns. From a theoretical point of view, the complexity of mechanically coupled chalcogen bonding is explored, revealing, among others, intriguing bifurcated chalcogen bonds.

Anion-(π)n -π Catalytic Micelles.

Anion-π catalysis operates by stabilizing anionic transition states on π-acidic aromatic surfaces. In anion-(π)n -π catalysis, π stacks add polarizability to strengthen interactions. In search of synthetic methods to extend π stacks beyond the limits of foldamers, the self-assembly of micelles from amphiphilic naphthalenediimides (NDIs) is introduced. To interface substrates and catalysts, charge-transfer complexes with dialkoxynaphthalenes (DANs), a classic in supramolecular chemistry, are installed. In π-stacked micelles, the rates of bioinspired ether cyclizations exceed rates on monomers in organic solvents by far. This is particularly impressive considering that anion-π catalysis in water has been elusive so far. Increasing rates with increasing π acidity of the micelles evince operational anion-(π)n -π catalysis. At maximal π acidity, autocatalytic behavior emerges. Dependence on position and order in confined micellar space promises access to emergent properties. Anion-(π)n -π catalytic micelles in water thus expand supramolecular systems catalysis accessible with anion-π interactions with an inspiring topic of general interest and great perspectives.

Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.

Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

Fluorescent Flippers: Small-Molecule Probes to Image Membrane Tension in Living Systems.

Flipper probes have been introduced as small molecule fluorophores to image physical forces, that is, membrane tension in living systems. Their emergence over one decade is described, from evolution in design and synthesis to spectroscopic properties. Responsiveness to physical compression in equilibrium at the ground state is identified as the ideal origin of mechanosensitivity to image membrane tension in living cells. A rich collection of flippers is described to deliver and release in any subcellular membrane of interest in a leaflet-specific manner. Chalcogen-bonding cascade switching and dynamic covalent flippers are developed for super-resolution imaging and dual-sensing of membrane compression and hydration. Availability and broad use in the community validate flipper probes as a fine example of the power of translational supramolecular chemistry, moving from fundamental principles to success on the market.

Dynamic Covalent Michael Acceptors to Penetrate Cells: Thiol-Mediated Uptake with Tetrel-Centered Exchange Cascades, Assisted by Halogen-Bonding Switches.

Chalcogen-centered cascade exchange chemistry is increasingly understood to account for thiol-mediated uptake, that is, the ability of reversibly thiol-reactive agents to penetrate cells. Here, reversible Michael acceptors are shown to enable and inhibit thiol-mediated uptake, including the cytosolic delivery of proteins. Dynamic cyano-cinnamate dimers rival the best chalcogen-centered inhibitors. Patterns generated in inhibition heatmaps reveal contributions from halogen-bonding switches that occur independent from the thyroid transporter MCT8. The uniqueness of these patterns supports that the entry of tetrel-centered exchangers into cells differs from chalcogen-centered systems. These results expand the chemical space of thiol-mediated uptake and support the existence of a universal exchange network to bring matter into cells, abiding to be decoded for drug delivery and drug discovery in the broadest sense.

Decoded fingerprints of hyperresponsive, expanding product space: polyether cascade cyclizations as tools to elucidate supramolecular catalysis.

Simple enough to be understood and complex enough to be revealing, cascade cyclizations of diepoxides are introduced as new tools to characterize supramolecular catalysis. Decoded product fingerprints are provided for a consistent set of substrate stereoisomers, and shown to report on chemo-, diastereo- and enantioselectivity, mechanism and even autocatalysis. Application of the new tool to representative supramolecular systems reveals, for instance, that pnictogen-bonding catalysis is not only best in breaking the Baldwin rules but also converts substrate diastereomers into completely different products. Within supramolecular capsules, new cyclic hemiacetals from House-Meinwald rearrangements are identified, and autocatalysis on anion-π catalysts is found to be independent of substrate stereochemistry. Decoded product fingerprints further support that the involved epoxide-opening polyether cascade cyclizations are directional, racemization-free, and interconnected, at least partially. The discovery of unique characteristics for all catalysts tested would not have been possible without decoded cascade cyclization fingerprints, thus validating the existence and significance of privileged platforms to elucidate supramolecular catalysis. Once decoded, cascade cyclization fingerprints are easily and broadly applicable, ready for use in the community.

The Dynamic Range of Acidity: Tracking Rules for the Unidirectional Penetration of Cellular Compartments.

Labeled ammonium cations with pKa ∼7.4 accumulate in acidic organelles because they can be neutralized transiently to cross the membrane at cytosolic pH 7.2 but not at their internal pH<5.5. Retention in early endosomes with less acidic internal pH was achieved recently using weaker acids of up to pKa 9.8. We report here that primary ammonium cations with higher pKa 10.6, label early endosomes more efficiently. This maximized early endosome tracking coincides with increasing labeling of Golgi networks with similarly weak internal acidity. Guanidinium cations with pKa 13.5 cannot cross the plasma membrane in monomeric form and label the plasma membrane with selectivity for vesicles embarking into endocytosis. Self-assembled into micelles, guanidinium cations enter cells like arginine-rich cell-penetrating peptides and, driven by their membrane potential, penetrate mitochondria unidirectionally despite their high inner pH. The resulting tracking rules with an approximated dynamic range of pKa change ∼3.5 are expected to be generally valid, thus enabling the design of chemistry tools for biology research in the broadest sense. From a practical point of view, most relevant are two complementary fluorescent flipper probes that can be used to image the mechanics at the very beginning of endocytosis.

Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors.

Thiol-mediated uptake is emerging as a powerful method to penetrate cells. Cyclic oligochalcogenides (COCs) have been identified as privileged scaffolds to enable and inhibit thiol-mediated uptake because they can act as dynamic covalent cascade exchangers, i.e., every exchange produces a new, covalently tethered exchanger. In this study, our focus is on the essentially unexplored COCs of higher oxidation levels. Quantitative characterization of the underlying dynamic covalent exchange cascades reveals that the initial ring opening of cyclic thiosulfonates (CTOs) proceeds at a high speed even at a low pH. The released sulfinates exchange with disulfides in aprotic but much less in protic environments. Hydrophobic domains were thus introduced to direct CTOs into hydrophobic pockets to enhance their reactivity. Equipped with such directing groups, fluorescently labeled CTOs entered the cytosol of living cells more efficiently than the popular asparagusic acid. Added as competitive agents, CTOs inhibit the uptake of various COC transporters and SARS-CoV-2 lentivectors. Orthogonal trends found with different transporters support the existence of multiple cellular partners to account for the diverse expressions of thiol-mediated uptake. Dominant self-inhibition and high activity of dimers imply selective and synergistic exchange in hydrophobic pockets as distinguishing characteristics of thiol-mediated uptake with CTOs. The best CTO dimers with hydrophobic directing groups inhibit the cellular entry of SARS-CoV-2 lentivectors with an IC50 significantly lower than the previous best CTO, below the 10 µM threshold and better than ebselen. Taken together, these results identify CTOs as an intriguing motif for use in cytosolic delivery, as inhibitors of lentivector entry, and for the evolution of dynamic covalent networks in the broadest sense, with reactivity-based selectivity of cascade exchange emerging as a distinguishing characteristic that deserves further attention.

Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry.

Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 µM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry.

An Orthogonal Dynamic Covalent Chemistry Tool for Ring-Opening Polymerization of Cyclic Oligochalcogenides on Detachable Helical Peptide Templates.

A model system is introduced as a general tool to elaborate on orthogonal templation of dynamic covalent ring-opening polymerization (ODC-TROP). The tool consists of 310 helical peptides as unprecedented templates and semicarbazones as orthogonal dynamic covalent linkers. With difficult-to-control 1,2-dithiolanes, ODC-TROP on the level of short model oligomers occurs with high templation efficiency, increasing and diminishing upon helix stabilization and denaturation, respectively. Further, an anti-templated conjugate with mispositioned monomers gave reduced templation upon helix twisting. Even with the "unpolymerizable" 1,2-diselenolanes, initial studies already afford mild templation efficiency. These proof-of-principle results promise that the here introduced tool, recyclable and enabling late-stage side chain modification, will be useful to realize ODC-TROP of intractable or unknown cyclic dynamic covalent monomers for dynamer materials as well as cellular uptake and signaling applications.

HydroFlipper membrane tension probes: imaging membrane hydration and mechanical compression simultaneously in living cells.

HydroFlippers are introduced as the first fluorescent membrane tension probes that report simultaneously on membrane compression and hydration. The probe design is centered around a sensing cycle that couples the mechanical planarization of twisted push-pull fluorophores with the dynamic covalent hydration of their exocyclic acceptor. In FLIM images of living cells, tension-induced deplanarization is reported as a decrease in fluorescence lifetime of the dehydrated mechanophore. Membrane hydration is reported as the ratio of the photon counts associated to the hydrated and dehydrated mechanophores in reconvoluted lifetime frequency histograms. Trends for tension-induced decompression and hydration of cellular membranes of interest (MOIs) covering plasma membrane, lysosomes, mitochondria, ER, and Golgi are found not to be the same. Tension-induced changes in mechanical compression are rather independent of the nature of the MOI, while the responsiveness to changes in hydration are highly dependent on the intrinsic order of the MOI. These results confirm the mechanical planarization of push-pull probes in the ground state as most robust mechanism to routinely image membrane tension in living cells, while the availability of simultaneous information on membrane hydration will open new perspectives in mechanobiology.

Treatment for School-Age Children Who Stutter: A Systematic Review of Japanese Literature.

PURPOSE: This systematic review identified and synthesized published research articles, written in Japanese, on the clinical effectiveness of a broad range of nonpharmacological interventions for school-age children who stutter. METHOD: A systematic review of Japanese literature published between January 1, 1980, and July 7, 2020, reporting interventions for school-age children who stutter, was carried out through a search of two databases (CiNii Article database and Japan Medical Abstract Society database) using the key words "stuttering" and "school-age" or "child" or "primary school students" or "children" or "school child" in Japanese. To be included in the review, the articles must report studies where data were subjectively reported by clinicians, where school-age participants were treated for developmental stuttering, where participants received interventions conducted by clinicians, and where quantitative outcomes (pre- and/or posttreatment) were measured; and they must be published in Japanese. RESULTS: Forty articles met all the inclusion criteria. Most articles adopted a case series or single-case study design. A total of 179 intervention programs were identified from all the articles and broadly classified into speech therapy, psychological therapy, interventions for modifying the child's environment, and others. CONCLUSIONS: Our systematic review provided a broad overview of the treatments used for school-age children who stutter in Japan. Future research should focus on gathering more reliable, systematic, and rigorous evidence to establish the effectiveness of stuttering treatments for school-age children and thereby develop evidence-based practices.