Diagnosis of ultrafast surface dynamics of thin foil targets irradiated by intense laser pulses.

The temporal modulation of an electron bunch train accelerated from a foil target irradiated by an intense laser pulse is studied by measuring the coherent transition radiation (CTR) from the rear surface of a target. We experimentally obtained CTR spectra from a 1 µm thick foil target irradiated at a maximum intensity of 6.5 × 1019 W/cm2. Spectral redshifts of the emitted radiation corresponding to increases in laser intensity were observed. These measurements were compared with the theoretical calculation of CTR spectra considering ultrafast surface dynamics, such as plasma surface oscillation and relativistically induced transparency. Plasma surface oscillations induce a spectral redshift, while relativistic transparency causes a spectral blueshift. Both effects are required to find reasonable agreement with the experiment over the entire range of laser intensities.

The efficacy and safety of rotavirus vaccines in countries in Africa and Asia with high child mortality.

Rotavirus remains a leading cause of diarrhoeal morbidity and mortality in young children and rotavirus vaccines are critical for reducing global disease burden. This report addresses the performance of rotavirus vaccines in countries with high child mortality. We performed a sensitivity analysis as part of a systematic review on rotavirus vaccines to inform development of World Health Organization vaccine recommendations. The efficacy of four prequalified vaccines against severe rotavirus gastroenteritis was similar across high mortality settings in Asia and Africa. Within the first year following vaccination, vaccine efficacy for the four vaccines ranged from 48% to 57% while in the second year, efficacy ranged from 29% to 54%. The four vaccines showed no increase in intussusception risk in these settings. All four vaccines appear to prevent significant numbers of severe rotavirus gastroenteritis episodes with no measurable increase in intussusception risk in high mortality settings in Africa and Asia.

Immunogenicity and safety of two monovalent rotavirus vaccines, ROTAVAC® and ROTAVAC 5D® in Zambian infants.

BACKGROUND AND AIMS: ROTAVAC® (frozen formulation stored at -20 °C) and ROTAVAC 5D® (liquid formulation stable at 2-8 °C) are rotavirus vaccines derived from the 116E human neonatal rotavirus strain, developed and licensed in India. This study evaluated and compared the safety and immunogenicity of these vaccines in an infant population in Zambia. METHODS: We conducted a phase 2b, open-label, randomized, controlled trial wherein 450 infants 6 to 8 weeks of age were randomized equally to receive three doses of ROTAVAC or ROTAVAC 5D, or two doses of ROTARIX®. Study vaccines were administered concomitantly with routine immunizations. Blood samples were collected pre-vaccination and 28 days after the last dose. Serum anti-rotavirus IgA antibodies were measured by ELISA, with WC3 and 89-12 rotavirus strains as viral lysates in the assays. The primary analysis was to assess non-inferiority of ROTAVAC 5D to ROTAVAC in terms of the geometric mean concentration (GMC) of serum IgA (WC3) antibodies. Seroresponse and seropositivity were also determined. Safety was evaluated as occurrence of immediate, solicited, unsolicited, and serious adverse events after each dose. RESULTS: The study evaluated 388 infants in the per-protocol population. All three vaccines were well tolerated and immunogenic. The post-vaccination GMCs were 14.0 U/mL (95% CI: 10.4, 18.8) and 18.1 U/mL (95% CI: 13.7, 24.0) for the ROTAVAC and ROTAVAC 5D groups, respectively, yielding a ratio of 1.3 (95% CI: 0.9, 1.9), thus meeting the pre-set non-inferiority criteria. Solicited and unsolicited adverse events were similar across all study arms. No death or intussusception case was reported during study period. CONCLUSIONS: Among Zambian infants, both ROTAVAC and ROTAVAC 5D were well tolerated and the immunogenicity of ROTAVAC 5D was non-inferior to that of ROTAVAC. These results are consistent with those observed in licensure trials in India and support use of these vaccines across wider geographical areas.

Short-term outcomes of pediatric laparoscopic inguinal hernia repair in Korea based on Korean Health Insurance Big Data: 2011-2015.

PURPOSE: For pediatric inguinal hernia repairs (IHRs), open IHR (high ligation) has long been a gold standard. Recently laparoscopic IHR (LIHR) was introduced as a new treatment modality and has been performed more frequently in Korea. Unlike adults, LIHR in children is still controversial. In the present study, we investigate the short-term outcomes of pediatric LIHR in Korea using nationwide inpatient data. METHODS: We analyzed clinical practice for IHRs from 2011 to 2015 using Korean Health Insurance Review and Assessment Service-National Inpatient Sample. RESULTS: A total of 5281 patients 15 years old or younger underwent 5356 IHRs: 4507 OIHRs and 849 LIHRs. M:F ratio was 2.4:1. The proportion of LIHRs was only 1.8% at the beginning but had been continuously increased up to 29.8% at the end of the study period. LIHRs were closely related to synchronous bilateral inguinal hernia repairs (SBIHRs). Overall, SBIHRs were performed in 10.9% of open and 49.2% of LIHRs. Metachronous contralateral IHRs (MCIHRs) after initial unilateral IHRs were significantly more frequent after OIHRs (1.7%, 69/3, 951) than after LIHRs (0.2%, 1/427). Recurrence rate per side during study period was 0.1% (6/4, 993) after OIHRs and 0.2% (2/1, 259) after LIHRs, respectively (statistically insignificant). CONCLUSION: Nationwide inpatient data showed that LIHRs in pediatric patients had recently been increasingly performed in Korea. LIHRs facilitated SBIHRs, which, in turn, decreased the needs of MCIHRs. However limited numbers of patients might actually have benefited from them. Early recurrence after primary IHRs in children is quite low regardless of way of approach.

Dissolving microneedle with high molecular weight hyaluronic acid to improve skin wrinkles, dermal density and elasticity.

OBJECTIVES: Dissolving microneedle patches have been extensively studied in the field of cosmetics comparison with topical cosmetics focusing on the delivery of active ingredients. Nevertheless, the skin improvement effect of hyaluronic acid, which is mainly used as a backbone material for dissolving microneedle, was not analyzed. In this study, adenosine encapsulated high and low molecular weight hyaluronic acid dissolving microneedle patch (Ad-HMN and Ad-LMN) were evaluated with respect to skin wrinkling, dermal density, elasticity, and safety in a clinical test on the crow's feet area. METHODS: Clinical efficacy and safety tests were performed for 12 weeks on twenty three female subjects with wrinkles around their eyes. The Ad-HMN and Ad-LMN patch were applied once every 3 days, in the evening, for 8 weeks to the designated crow's feet area. Skin wrinkling, dermal density, and elasticity were measured by using PRIMOS® premium, Dermascan® C, Cutometer® MPA580, and Corneometer® CM 825, respectively. RESULTS: Both Ad-HMN and Ad-LMN groups showed statistically significant efficacy for almost all parameters. The Ad-HMN patch had better effect on the mean depth of biggest wrinkles, maximum depth of biggest wrinkles, dermal density, and skin elasticity than the Ad-LMN patch. No adverse effects were observed in either group during the test period. CONCLUSION: In the clinical efficacy test of four skin-improvement parameters, the Ad-HMN patch showed the better effect than the Ad-LMN patch with the similar adenosine dose.

OBJECTIFS: Les patches à micro-aiguilles dissolvantes ont fait l'objet d'études approfondies dans le domaine de la cosmétique en comparaison avec la cosmétique topique axée sur la diffusion de principes actifs. Cependant, l'effet améliorant de l'acide hyaluronique sur la peau, principalement utilisée comme matière de base pour la dissolution des micro-aiguilles, n'a pas été analysé. Dans la présente étude, les patchs à micro-éguilles dissolvant l'acide hyaluronique à poids moléculaire élevé et faible, encapsulé dans l'adénosine (Ad-HMN et Ad-LMN) ont été analysés par rapport à la formation des rides, la densité cutanée, l'élasticité et la sécurité d'emploi lors d'un test clinique sur la zone de pattes d'oie. MÉTHODES: Des tests d'efficacité et de sécurité cliniques ont été réalisés pendant 12 semaines sur 23 sujets féminins ayant des rides autour des yeux. Les patchs Ad-HMN et Ad-LMN ont été appliqués une fois tous les trois jours, le soir, pendant huit semaines, dans la zone à pattes d'oie désignée. La formation de rides, la densité cutanée et l'élasticité ont été mesurées à l'aide de PRIMOS® premium, Dermascan® C, Cutometer® MPA580 et Corneometer® CM825, respectivement. RÉSULTATS: Les deux groupes Ad-HMN et Ad-LMN ont présenté une efficacité statistiquement significative pour la quasi-totalité des paramètres. Le patch Ad-HMN a eu un meilleur effet sur la profondeur moyenne des rides les plus importantes, la profondeur maximale des rides les plus importantes, la densité cutanée et l'élasticité de la peau par rapport au patch Ad-LMN. Aucun effet indésirable n'a été observé dans aucun des groupes pendant la période d'essai. CONCLUSION: Lors du test d'efficacité clinique des quatre paramètres d'amélioration de la peau, le patch Ad-HMN a eu un meilleur effet que le patch Ad-LMN avec la dose d'adénosine similaire.

Utility of Pre-Hematopoietic Cell Transplantation Sinus CT Screening in Children and Adolescents.

BACKGROUND AND PURPOSE: The clinical benefit of pre-hematopoietic cell transplantation sinus CT screening remains uncertain, while the risks of CT radiation and anesthesia are increasingly evident. We sought to re-assess the impact of screening sinus CT on pretransplantation patient management and prediction of posttransplantation invasive fungal rhinosinusitis. MATERIALS AND METHODS: Pretransplantation noncontrast screening sinus CTs for 100 consecutive patients (mean age, 11.9 ± 5.5 years) were graded for mucosal thickening (Lund-Mackay score) and for signs of noninvasive or invasive fungal rhinosinusitis (sinus calcification, hyperattenuation, bone destruction, extrasinus inflammation, and nasal mucosal ulceration). Posttransplantation sinus CTs performed for sinus-related symptoms were similarly graded. Associations of Lund-Mackay scores, clinical assessments, changes in pretransplantation clinical management (additional antibiotic or fungal therapy, sinonasal surgery, delayed transplantation), and subsequent development of sinus-related symptoms or invasive fungal rhinosinusitis were tested (exact Wilcoxon rank sums, Fisher exact test, significance P < .05). RESULTS: Mean pretransplantation screening Lund-Mackay scores (n = 100) were greater in patients with clinical symptoms (8.07 ± 6.00 versus 2.48 ± 3.51, P < .001) but were not associated with pretransplantation management changes and did not predict posttransplantation sinus symptoms (n = 21, P = .47) or invasive fungal rhinosinusitis symptoms (n = 2, P = .59). CONCLUSIONS: Pre-hematopoietic cell transplantation sinus CT does not meaningfully contribute to pretransplantation patient management or prediction of posttransplantation sinus disease, including invasive fungal rhinosinusitis, in children. The risks associated with CT radiation and possible anesthesia are not warranted in this setting.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

Long-term immunogenicity and immune persistence of live attenuated and inactivated hepatitis a vaccines: a report on additional observations from a phase IV study.

Both live attenuated (HA-L) and inactivated (HA-I) hepatitis A vaccine were licensed for routine use in China. Although phase 1, 2 and 3 clinical studies of both vaccines have been completed, further systematic evaluation of their immunogenicity and immunological persistence under phase 4 clinical studies in a wide range of conditions and involving large populations is necessary. A phase IV clinical trial (NCT02601040) was performed in 9000 participants over 18 months of age. Geometric mean concentrations (GMCs) and seroconversion rates (SRs) were compared at five time points during 3 years for 1800 individuals among them. The SRs of HA-L and HA-I were 98.08% (95% CI 95.59%-99.38%) and 99.64% (95% CI 98.93%-100.00%) respectively 28 days after administration of the first dose, and remained at 97.07% (95% CI 94.31%-98.73%) or above and 96.73% (95% CI 94.07%-98.42%) or above respectively during the following 3 years. The GMCs for both the HA-L and HA-I groups showed that both vaccines elicited high anti-HAV titres, considerably more than the threshold of protection needed against HAV infection in humans, and these titres were sustained. Hence, both HA-I and HA-L vaccines could provide an excellent long-term protective effect, and supported the routine use of both vaccines.

Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 alleviate allergic rhinitis in mice by restoring Th2/Treg imbalance and gut microbiota disturbance.

This study aimed to examine whether probiotics, which suppressed the differentiation of splenic T cells into type 2 helper T (Th2) cells and induced into regulatory T cells in vitro, alleviate allergic rhinitis (AR) and gut microbiota disturbance. We isolated Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 from human faecal microbiota and kimchi, respectively, and examined their effects on ovalbumin (OVA)-induced AR and gut microbiota disturbance in mice. Treatment with IM55, IM76, or their probiotic mixture (PM) significantly reduced OVA-induced allergic nasal symptoms and blood immunoglobulin E (IgE) levels in mice. These also reduced OVA-induced interleukin (IL)-4 and IL-5 levels in nasal tissues and bronchoalveolar lavage fluid (BALF) but increased OVA-suppressed IL-10 levels. Treatment with IM55, IM76, or PM reduced OVA-induced increase in the populations of mast cells, eosinophils, and Th2 cells and increased OVA-suppressed population of regulatory T cells in the BALF. Treatment with IM55, IM76, or PM also inhibited OVA-induced expression of IL-5 in lung and colon tissues and restored OVA-disturbed composition of gut microbiota Proteobacteria, Bacteroidetes, and Actinobacteria. These results suggest that IM55 and IM67 can alleviate AR by restoring Th2/Treg imbalance and gut microbiota disturbance.

Author Correction: Anti-angiogenic drug scheduling optimisation with application to colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Anti-angiogenic drug scheduling optimisation with application to colorectal cancer.

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by "normalizing" abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic treatment and chemotherapeutic treatment on tumour volume. Model predictions were validated using CRC xenografts which underwent treatment with a clinically relevant combinatorial anti-angiogenic regimen. Bayesian model selection revealed the most appropriate term for capturing the effect of treatments on the tumour size, and provided insights into a switch-like dependence of FOLFOX delivery on the tumour vasculature. Our experimental data and mathematical model suggest that delivering chemotherapy prior to bvz may be optimal in the colorectal cancer setting.

Seasonality and within-subject clustering of rotavirus infections in an eight-site birth cohort study.

Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens.

Diagnosis of warm dense conditions in foil targets heated by intense femtosecond laser pulses using Kα imaging spectroscopy.

Warm dense conditions in titanium foils irradiated with intense femtosecond laser pulses are diagnosed using an x-ray imaging spectroscopy technique. The line shapes of radially resolved titanium Kα spectra are measured with a toroidally bent GaAs crystal and an x-ray charge-coupled device. Measured spectra are compared with the K-shell emissions modeled using an atomic kinetics - spectroscopy simulation code. Kα line shapes are strongly affected by warm (5-40 eV) bulk electron temperatures and imply multiple temperature distributions in the targets. The spatial distribution of temperature is dependent on the target thickness, and a thin target shows an advantage to generate uniform warm dense conditions in a large area.

Adenosine-loaded dissolving microneedle patches to improve skin wrinkles, dermal density, elasticity and hydration.

OBJECTIVE: Although dissolving microneedle patches have been widely studied in the cosmetics field, no comparisons have been drawn with the topical applications available for routine use. In this study, two wrinkle-improving products, adenosine-loaded dissolving microneedle patches and an adenosine cream, were evaluated for efficacy, with respect to skin wrinkling, dermal density, elasticity, and hydration, and safety in a clinical test on the crow's feet area. METHODS: Clinical efficacy and safety tests were performed for 10 weeks on 22 female subjects with wrinkles around their eyes. The adenosine-loaded dissolving microneedle patch was applied once every 3 days, in the evening, for 8 weeks to the designated crow's feet area. The adenosine cream was applied two times per day, in the morning and evening, for 8 weeks to the other crow's feet area. Skin wrinkling, dermal density, elasticity, and hydration were measured by using PRIMOS® premium, Dermascan® C, Cutometer® MPA580, and Corneometer® CM 825, respectively. In addition, subjective skin irritation was evaluated by self-observation, and objective skin irritation was assessed through expert interviews. RESULTS: The adenosine-loaded dissolving microneedle patches had a similar or better efficacy than the adenosine cream. Both groups showed statistically significant efficacy for almost all parameters (P < 0.05). The dissolving microneedle patches had a long-lasting effect on the average wrinkle depth (P < 0.05), only showed efficacy in dermal density (P < 0.05), had an early improving effect on elasticity (P < 0.05), and demonstrated better hydration efficacy (P < 0.001). No adverse effects were observed in either group during the test period. CONCLUSIONS: In the clinical efficacy test of four skin-improvement parameters, adenosine-loaded dissolving microneedle patches showed the same or better effect than the adenosine cream, although the weekly adenosine dose was 140 times lower. The dissolving microneedle patches caused no adverse reactions. These adenosine-loaded dissolving microneedle patches are expected to be safe, effective, and novel cosmetics for skin improvement.

Polymerization-Induced Phase Separation Formation of Structured Hydrogel Particles via Microfluidics for Scar Therapeutics.

Excessive scar formation can form disabling contractures that result in a debilitating psychological outcome. Sustainable hydrophobic corticosteroid release in vivo is essential to regulate the wound healing process. Functional hydrogel particles are widely applied for sustainable release. However, due to the limited aqueous solubility of hydrophobic compounds, most of the corticosteroid is released from the hydrogels within seconds, causing undesirable scar formation and recurrence. In this study, a novel polymerization-induced phase separation is investigated to form well-defined polyethylene glycol diacrylate (PEGDA) core/alginate shell structured hydrogel particles using microfluidics without toxic organic solvents. Based on their wettability preference, hydrophobic corticosteroid-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles are compartmentalized in the PEGDA core during polymerization to control the corticosteroid release. The distribution of the PLGA nanoparticles is precisely regulated by the phase separation boundary and characterized using a fluorescent dye. The thickness of the shell and partition coefficients are determined using the UV intensity and irradiation period. Upon encapsulation of the PLGA nanoparticles within the poly(PEGDA) core, a long-term corticosteroid treatment is developed and effective scar therapeutic outcomes are evaluated using both in vitro and in vivo models.

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer.

Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6. In gastric cancer cells that express high GATA6 levels, a GATA2 CpG island is hypermethylated, repressing expression in these cells. In contrast, GATA6 expression is undetectable in GATA2-overexpressing gastric cancer cells, which lack GATA2 DNA methylation. Furthermore, PRC2 complex-mediated transcriptional silencing of GATA6 was observed in the GATA2-overexpressing cells. We also show that the GATA2 and PRC2 complexes are enriched within the GATA6 locus, and that the recruitment of the PRC2 complex is impaired by disrupting GATA2 expression, resulting in GATA6 upregulation. In addition, ectopic GATA2 expression significantly downregulates GATA6 expression, suggesting GATA2 directly represses GATA6. Furthermore, GATA6 downregulation showed antitumor activity by inducing growth arrest. Finally, we show that aberrant GATA2 methylation occurs early during the multistep process of gastric carcinogenesis regardless of Helicobacter pylori infection. Taken together, GATA2 dysregulation by epigenetic modification is associated with unfavorable phenotypes in human gastric cancer cells by allowing GATA6 expression.

Anterior cingulate cortex γ-aminobutyric acid deficits in youth with depression.

Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12-21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.