Morbidity and mortality in adults with a Fontan circulation beyond the fourth decade of life.

AIMS: To evaluate the late outcomes of adults (above 35 years) with a Fontan-type circulation, for whom current data on morbidity and mortality are lacking. METHODS AND RESULTS: Data were collected retrospectively on consecutive patients with Fontan circulation above the age of 35 years followed in three European specialist centres. Overall, 115 Fontan patients were included [median age 35 (range 35-48) years, 47.8% female]. The most common underlying congenital heart disease diagnosis was tricuspid atresia (n = 58, 50.4%), and the age at first Fontan completion was 9.1 (interquartile range 5.0-15.8) years. Almost two-thirds (61.7%) of patients had undergone an atriopulmonary Fontan, and 23.5% had received a total cavopulmonary connection. One-third required repeat surgery or intervention. Most patients (55.9%) were in New York Heart Association functional class II or class I (30.6%), 76 (66.1%) patients had experienced at least one arrhythmia, and eight (7.0%) protein-losing enteropathy. At a median follow-up of 5.0 (2.4-10.3) years, 15 (13.0%) patients were referred for transplantation assessment and 19 (16.5%) patients died, mainly from heart failure (84.2%). Univariable predictors of death or transplantation included lower serum albumin level [hazard ratio (HR) 1.09 per g/L decrease, 95% confidence interval (CI): 1.04-1.15, P = 0.0009], prior heart failure admission (HR 4.28, 95% CI:1.75-10.44, P = 0.001), prior atrial tachycardia or flutter (HR 3.02, 95% CI: 1.23-7.38, P = 0.02), and baseline pulmonary vasodilator therapy (HR 8.59, 95% CI:1.05-70.13, P = 0.04). Lower serum albumin and prior atrial tachycardia or flutter remained significant on bivariable analysis. CONCLUSION: Our study highlights the significant morbidity and mortality in older adults with a Fontan-type circulation, emphasizing the need for lifelong specialist surveillance with frequent risk stratification, close monitoring, and early consideration for transplantation assessment.

This study sheds light on the complex medical journey of adults living with the outcomes of Fontan surgery­a procedure performed in early childhood. These individuals have reached the milestone of their forties and beyond, yet they confront an array of significant health challenges that necessitate lifelong, individualized congenital heart disease care. The key findings are as follows: While adults with Fontan circulation are living longer, they are at high risk of death, mainly due to heart failure. They also face a host of other health issues, including the need for additional surgeries or interventions. Nearly two-thirds have experienced some form of heart rhythm problem, and a substantial number eventually require evaluation for a heart transplant.Heart transplants within this group were rare, which may be linked to the various barriers to transplantation in the Fontan population. Moreover, those with multiple indicators of advanced disease have a heightened risk of life-threatening events, reinforcing the critical need for personalized and continuous specialist care designed to meet their distinct health requirements.

A scoping review of social media in child, adolescents and young adults: research findings in depression, anxiety and other clinical challenges.

BACKGROUND: Social media and other technologies are reshaping communication and health. AIMS: This review addresses the relationship between social media use, behavioural health conditions and psychological well-being for youth aged <25 years. METHOD: A scoping review of 11 literature databases from 2000 to 2020 explored research studies in youth in five areas: clinical depression and anxiety, quantitative use, social media mode, engagement and qualitative dimensions and health and well-being. RESULTS: Out of 2820 potential literature references, 140 met the inclusion criteria. The foci were clinical depression and anxiety disorders (n = 78), clinical challenges (e.g. suicidal ideation, cyberbullying) (n = 34) and psychological well-being (n = 28). Most studies focused on Facebook, Twitter, Instagram and YouTube. Few studies are longitudinal in design (n = 26), had comparison groups (n = 27), were randomised controlled trials (n = 3) or used structured assessments (n = 4). Few focused on different youth and sociodemographic populations, particularly for low-income, equity-seeking and deserving populations. Studies examined association (n = 120; 85.7%), mediating (n = 16; 11.4%) and causal (n = 4; 2.9%) relationships. Prospective, longitudinal studies of depression and anxiety appear to indicate that shorter use (≤3 h/day) and purposeful engagement is associated with better mood and psychological well-being. Depression may predict social media use and reduce perception of support. Findings provide families, teachers and providers ways to engage youth. CONCLUSIONS: Research opportunities include clinical outcomes from functional perspective on a health continuum, diverse youth and sociodemographic populations, methodology, intervention and privacy issues. More longitudinal studies, comparison designs and effectiveness approaches are also needed. Health systems face clinical, training and professional development challenges.

pH Controlled Nanostructure and Optical Properties of ZnO and Al-Doped ZnO Nanorod Arrays Grown by Microwave-Assisted Hydrothermal Method.

The low-temperature microwave-assisted hydrothermal method was used to successfully grow pure and Al-doped ZnO (AZO) nanorod (NR) arrays on glass substrates. The combined effects of doping and pH on the structural properties, surface chemistry, and optical properties of all samples were investigated. Thermodynamic-based simulations of the growth solution were performed and a growth mechanism, that considers the effects of both the pH and Al-doping, is proposed, and discussed. Tuning the solution pH is key parameter to grow well-aligned, single crystal, highly packed, and high aspect ratio nanorod arrays. Moreover, the optical absorption in the visible range is enhanced by controlling the pH value. The PL spectra reveal a shift of the main radiative emission from the band-to-band into a transition involving deep defect levels of Zinc interstitial Zni. This shift is caused by an enhancement of the non-radiative components (phonon relaxation) at high pH values. The production of well-ordered ZnO and AZO nanorod arrays with visible-active absorption/emission centers would increase their potential use in various applications.

VIVID: A Web Application for Variant Interpretation and Visualization in Multi-dimensional Analyses.

Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an individual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of diversity and selection, and 3D visualization of genotypic information encoded in Variant Call Format on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritizing targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum, revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.

Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.

Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.

Young stroke due to pulmonary arteriovenous malformation.

Young patients presenting with cryptogenic stroke should be investigated for cardiac and extra-cardiac sources of emboli. We present a patient who was investigated for a cardiac source of emboli, following multiple ischaemic strokes and migraine with aura over a period of 17 years. The events were initially thought to be related to a patent foramen ovale (PFO) on bubble contrast echocardiography, however, due to an unusual flow pattern to the left heart, she underwent a CT angiogram to exclude intrapulmonary shunting. This confirmed the presence of a moderate sized congenital pulmonary arteriovenous fistula in the left lung. Transcatheter occlusion of the vascular malformation has resolution of her symptoms. Bubble contrast echocardiography is routinely used to diagnose a PFO in these cases, but extreme caution is required during the procedure to differentiate the pattern of flow seen in patients with a pulmonary arteriovenous malformation.

Whole-genome analysis of Malawian Plasmodium falciparum isolates identifies possible targets of allele-specific immunity to clinical malaria.

Individuals acquire immunity to clinical malaria after repeated Plasmodium falciparum infections. Immunity to disease is thought to reflect the acquisition of a repertoire of responses to multiple alleles in diverse parasite antigens. In previous studies, we identified polymorphic sites within individual antigens that are associated with parasite immune evasion by examining antigen allele dynamics in individuals followed longitudinally. Here we expand this approach by analyzing genome-wide polymorphisms using whole genome sequence data from 140 parasite isolates representing malaria cases from a longitudinal study in Malawi and identify 25 genes that encode possible targets of naturally acquired immunity that should be validated immunologically and further characterized for their potential as vaccine candidates.

Prognostic Value of Cardiac Magnetic Resonance Imaging in Acute Coronary Syndrome Patients With Troponin Elevation and Nonobstructive Coronary Arteries.

OBJECTIVE: To define the diagnostic yield of cardiac magnetic resonance (CMR) in differentiating the underlying causes of myocardial infarction with nonobstructive coronary arteries (MINOCA) and to determine the long-term prognostic implications of such diagnoses. METHODS: Cardiac magnetic resonance evaluation was performed in 227 patients (mean age, 56.4±14.9 years; 120 [53%] female) with a "working diagnosis" of MINOCA as defined by presentation with a troponin-positive acute coronary syndrome (troponin I >0.04 µg/L) and nonobstructed coronary arteries between January 1, 2007, and February 28, 2013. Follow-up was performed to assess the primary composite end point of myocardial infarction, heart failure, and all-cause mortality. RESULTS: Cardiac magnetic resonance identified nonstructural cardiomyopathies in 97 (43%) patients, myocardial infarction in 55 (24%) patients, structural cardiomyopathies in 27 (12%) patients, and pulmonary embolism in 1 patient. No CMR abnormalities were identified in the remaining patients. Kaplan-Meier analysis demonstrated the ability of a CMR diagnosis to predict the risk of the primary composite end point (P=.005) at 5-year follow-up. Worse outcomes were seen among patients with "true" MINOCA and a normal CMR image compared with those with CMR-confirmed myocardial infarction (P=.02). Use of antiplatelets (78% [37/45] vs 95% [52/55]; P=.01), beta blockers (56% [25/45] vs 82% [45/55]; P=.004), and statins (64% [29/45] vs 85% [47/55]; P=.01) was significantly lower in patients with true MINOCA with normal CMR imaging compared with those with CMR-confirmed myocardial infarction. CONCLUSIONS: Cardiac magnetic resonance carries a high diagnostic yield in patients with MINOCA and predicts long-term prognosis. Patients with MINOCA with normal CMR imaging had an increased rate of major adverse cardiac events and lower use of guideline-recommended myocardial infarction therapy compared with those with CMR-confirmed myocardial infarction.

Sn2+ Doping: A Strategy for Tuning of Fe3O4 Nanoparticles Magnetization Dipping Temperature/Amplitude, Irreversibility, and Curie Point.

Doped magnetite (SnxFe3-2/3xO4) nanoparticles (NPs) (12-50 nm) with different amount of Sn2+ ions (x) were synthesized using co-precipitation method. Sn2+ doping reduces the anticipated oxidation of Fe3O4 NPs to maghemite (γ-Fe2O3), making them attractive in several magnetic applications. Detailed characterizations during heating-cooling cycles revealed the possibility of tuning the unusual observed magnetization dipping temperature/amplitude, irreversibility, and Curie point of these NPs. We attribute this dip to the chemical reduction of γ-Fe2O3 at the NPs surfaces. Along with an increase in the dipping temperature, we found that doping with Sn2+ reduces the dipping amplitude, until it approximately disappears when x = 0.150. Based on the core-shell structure of these NPs, a phenomenological expression that combines both modified Bloch law (M = M0[1 - γ(T/TC)]ß) and a modified Curie-Weiss law (M = - α[1/(T - TC)δ]) is developed in order to explain the observed M-T behavior at different applied external magnetic fields and for different Sn2+ concentrations. By applying high enough magnetic field, the value of the parameters γ and δ ≈ 1 which are the same in modified Bloch and Curie-Weiss laws. They do not change with the magnetic field and depend only on the material structure and size. The power ß for high magnetic field was 2.6 which is as expected for this size of nanoparticles with the core dominated magnetization. However, the ß value fluctuates between 3 and 10 for small magnetic fields indicating an extra magnetic contribution from the shell structure presented by Curie-Weiss term. The parameter (α) has a very small value and it turns to negative values for high magnetic fields.

Evaluation of Xpert® MTB/RIF assay as a diagnostic test for pulmonary tuberculosis in children in Myanmar.

BACKGROUND: The Xpert® MTB/RIF assay has been recommended for the diagnosis of pulmonary tuberculosis (PTB). However, there are limited data from the South-East Asian region. SETTING: This study was carried out at a tertiary-level children's hospital in Mandalay, Myanmar. OBJECTIVE: To evaluate the performance of Xpert as a diagnostic test for PTB in children. METHODS: A cross-sectional descriptive study of children with suspected PTB. Gastric lavage aspirate samples were tested using Xpert, solid culture and smear microscopy. The performance of Xpert, solid culture and smear microscopy were evaluated using the revised National Institute of Health classification for intrathoracic TB in children as the reference standard. RESULTS: TB was bacteriologically confirmed in 38 (16.5%) of 231 children with suspected PTB. Of the 38 children with confirmed TB, 36 cases were identified using Xpert, 16 using solid culture and 12 using smear microscopy. With confirmed TB as the reference standard, the sensitivity of Xpert, solid culture and smear microscopy was respectively 94.7% (95%CI 80.9-99.1), 42.1% (95%CI 26.7-59.1) and 31.6% (95%CI 18.0-48.8). CONCLUSION: Xpert has improved the bacteriological confirmation of PTB among hospitalised children in Myanmar.

Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis.

BACKGROUND: Rifampicin (RIF) plays a pivotal role in the treatment of tuberculosis due to its bactericidal effects. Because the action of RIF is on rpoB gene encoding RNA polymerase ß subunit, 95% of RIF resistant mutations are present in rpoB gene. The majority of the mutations in rpoB gene are found within an 81bp RIF-resistance determining region (RRDR). METHODOLOGY: Literatures on RIF resistant mutations published between 2010 and 2016 were thoroughly reviewed. RESULTS: The most commonly mutated codons in RRDR of rpoB gene are 531, 526 and 516. The possibilities of absence of mutation in RRDR of rpoB gene in MDR-TB isolates in few studies was due to existence of other rare rpoB mutations outside RRDR or different mechanism of rifampicin resistance. CONCLUSION: Molecular methods which can identify extensive mutations associated with multiple anti-tuberculous drugs are in urgent need so that the research on drug resistant mutations should be extended.

Influence of Atomic Hydrogen, Band Bending, and Defects in the Top Few Nanometers of Hydrothermally Prepared Zinc Oxide Nanorods.

We report on the surface, sub-surface (top few nanometers) and bulk properties of hydrothermally grown zinc oxide (ZnO) nanorods (NRs) prior to and after hydrogen treatment. Upon treating with atomic hydrogen (H*), upward and downward band bending is observed depending on the availability of molecular H2O within the structure of the NRs. In the absence of H2O, the H* treatment demonstrated a cleaning effect of the nanorods, leading to a 0.51 eV upward band bending. In addition, enhancement in the intensity of room temperature photoluminescence (PL) signals due to the creation of new surface defects could be observed. The defects enhanced the visible light activity of the ZnO NRs which were subsequently used to photocatalytically degrade aqueous phenol under simulated sunlight. On the contrary, in the presence of H2O, H* treatment created an electronic accumulation layer inducing downward band bending of 0.45 eV (~1/7th of the bulk ZnO band gap) along with the weakening of the defect signals as observed from room temperature photoluminescence spectra. The results suggest a plausible way of tailoring the band bending and defects of the ZnO NRs through control of H2O/H* species.

Analysis of the Caenorhabditis elegans innate immune response to Coxiella burnetii.

The nematode Caenorhabditis elegans is well established as a system for characterization and discovery of molecular mechanisms mediating microbe-specific inducible innate immune responses to human pathogens. Coxiella burnetii is an obligate intracellular bacterium that causes a flu-like syndrome in humans (Q fever), as well as abortions in domesticated livestock, worldwide. Initially, when wild type C. elegans (N2 strain) was exposed to mCherry-expressing C. burnetii (CCB) a number of overt pathological manifestations resulted, including intestinal distension, deformed anal region and a decreased lifespan. However, nematodes fed autoclave-killed CCB did not exhibit these symptoms. Although vertebrates detect C. burnetii via TLRs, pathologies in tol-1(-) mutant nematodes were indistinguishable from N2, and indicate nematodes do not employ this orthologue for detection of C. burnetii. sek-1(-) MAP kinase mutant nematodes succumbed to infection faster, suggesting that this signaling pathway plays a role in immune activation, as previously shown for orthologues in vertebrates during a C. burnetii infection. C. elegans daf-2(-) mutants are hyper-immune and exhibited significantly reduced pathological consequences during challenge. Collectively, these results demonstrate the utility of C. elegans for studying the innate immune response against C. burnetii and could lead to discovery of novel methods for prevention and treatment of disease in humans and livestock.

Evidence of soft dipole resonance in

The first conclusive evidence of a dipole resonance in ^{11}Li having isoscalar character observed from inelastic scattering with a novel solid deuteron target is reported. The experiment was performed at the newly commissioned IRIS facility at TRIUMF. The results show a resonance peak at an excitation energy of 1.03±0.03 MeV with a width of 0.51±0.11 MeV (FWHM). The angular distribution is consistent with a dipole excitation in the distorted-wave Born approximation framework. The observed resonance energy together with shell model calculations show the first signature that the monopole tensor interaction is important in ^{11}Li. The first ab initio calculations in the coupled cluster framework are also presented.

Screening for cardiovascular disease risk factors at baseline and post intervention among adults with intellectual disabilities in an urbanised Asian society.

BACKGROUND: Adults with intellectual disabilities (ID) face significant barriers to screening participation. We determined predictors for regular cardiovascular health screening at baseline among adults with ID in Singapore, and evaluated the effectiveness of a 3-month screening intervention. METHODS: The study population involved all adults with ID aged ≥40 years receiving services from the Movement for the Intellectually Disabled of Singapore (MINDS), the largest such provider in Singapore. Over 3 months in 2011, adult clients not screened regularly at baseline for hypertension, diabetes and dyslipidaemia were offered free and convenient blood pressure, fasting blood glucose and lipid testing; data on other cardiovascular disease risk factors were also collected. Chi-square and logistic regression identified predictors of regular screening at baseline. RESULTS: Participation was 95.0% (227/239). At baseline, among adults with ID, 61.8% (118/191), 24.8% (52/210) and 18.2% (34/187) had gone for regular hypertension, diabetes and dyslipidaemia screening respectively; post intervention, rates rose to 96.9%, 89.5% and 88.8% respectively. Prevalence of cardiovascular disease risk factors (22.5% with hypertension, 10.6% with diabetes, 34.8% with dyslipidaemia, 10.7% obese and 90.6% lacking regular exercise) was high compared against the general population. While receiving residential services was associated with regular hypertension screening, receiving non-residential services and being independently mobile were associated with regular participation in fasting blood tests (all P < 0.05). CONCLUSION: Cardiovascular disease risk factors are common among adults with ID and clinicians should proactively screen such populations. Provision of free and convenient screening for cardiovascular disease risk improved screening participation.

Transsynaptic progression of amyloid-ß-induced neuronal dysfunction within the entorhinal-hippocampal network.

The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-ß (Aß) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Aß overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Aß was observed in the dentate gyrus, and Aß deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aß expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD.

Arc regulates spine morphology and maintains network stability in vivo.

Long-term memory relies on modulation of synaptic connections in response to experience. This plasticity involves trafficking of AMPA receptors (AMPAR) and alteration of spine morphology. Arc, a gene induced by synaptic activity, mediates the endocytosis of AMPA receptors and is required for both long-term and homeostatic plasticity. We found that Arc increases spine density and regulates spine morphology by increasing the proportion of thin spines. Furthermore, Arc specifically reduces surface GluR1 internalization at thin spines, and Arc mutants that fail to facilitate AMPAR endocytosis do not increase the proportion of thin spines, suggesting that Arc-mediated AMPAR endocytosis facilitates alterations in spine morphology. Thus, by linking spine morphology with AMPAR endocytosis, Arc balances synaptic downscaling with increased structural plasticity. Supporting this, loss of Arc in vivo leads to a significant decrease in the proportion of thin spines and an epileptic-like network hyperexcitability.

Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.

Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

Distinct roles of GABAergic interneurons in the regulation of striatal output pathways.

Striatal GABAergic microcircuits are critical for motor function, yet their properties remain enigmatic due to difficulties in targeting striatal interneurons for electrophysiological analysis. Here, we use Lhx6-GFP transgenic mice to identify GABAergic interneurons and investigate their regulation of striatal direct- and indirect-pathway medium spiny neurons (MSNs). We find that the two major interneuron populations, persistent low-threshold spiking (PLTS) and fast spiking (FS) interneurons, differ substantially in their excitatory inputs and inhibitory outputs. Excitatory synaptic currents recorded from PLTS interneurons are characterized by a small, nonrectifying AMPA receptor-mediated component and a NMDA receptor-mediated component. In contrast, glutamatergic synaptic currents in FS interneurons have a large, strongly rectifying AMPA receptor-mediated component, but no detectable NMDA receptor-mediated responses. Consistent with their axonal morphology, the output of individual PLTS interneurons is relatively weak and sparse, whereas FS interneurons are robustly connected to MSNs and other FS interneurons and appear to mediate the bulk of feedforward inhibition. Synaptic depression of FS outputs is relatively insensitive to firing frequency, and dynamic-clamp experiments reveal that these short-term dynamics enable feedforward inhibition to remain efficacious across a broad frequency range. Surprisingly, we find that FS interneurons preferentially target direct-pathway MSNs over indirect-pathway MSNs, suggesting a potential mechanism for rapid pathway-specific regulation of striatal output pathways.