Top-down control of flight by a non-canonical cortico-amygdala pathway.

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

Bloom where you are planted: Hemangioma or malignancy?

Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.

Toward enhanced visible-light photocatalytic dye degradation and reusability of La3+ substituted ZnFe2O4 nanostructures.

The present work focused on the synthesis of novel ZnLaxFe2-xO4 catalysts (x = 0, 0.01, 0.03, 0.05) and their utilization for the photocatalytic degradation of Rhodamine B dye. Structurally, the band gap energy of the catalysts tended to decrease (1.94-1.70 eV) with increasing the amount of La3+ dopant. ZnLa0.05Fe1.95O4 had an average particle size (40 nm), high surface area (41.07 m2 g-1) and large pore volume (0.186 cm3 g-1). Moreover, the effect of doping ratio, reaction time, H2O2 concentration, catalyst loading on the treatment performance of La3+ substituted ZnFe2O4 nanocomposites was investigated. ZnLa0.05Fe1.95O4/H2O2 system exhibited the highest degradation efficiency of 99.5% and nonlinear pseudo first-order kinetic reaction rate (14.8 × 10-3 min-1) in the presence of visible light irradiation. The key role of reactive oxygen species involving •O2- and •OH radicals was well explained through the scavenger study. A plausible mechanism of the degradation of Rhodamine B dye was also proposed. Due to two advantageous points including high recyclability (up to 4 cycles) and stability, La3+ substituted ZnFe2O4 nanocomposites can be an effective and competitive catalyst for the visible light-driven photodegradation of toxic dyes in the real wastewaters.

Suppression of non-radiative recombination to improve performance of colloidal quantum-dot LEDs with a Cs2CO3 solution treatment.

We report a five-fold luminance increase of green-light-emitting CdSe@ZnS quantum-dot LEDs (QLEDs) in response to treatment with a 2-ethoxyethanol solution of cesium carbonate (Cs2CO3). The maximum luminous yield of Cs2CO3-treated QLED is as high as 3.41 cd A-1 at 6.4 V. To elucidate device-performance improvement, we model measured currents as the sum of radiative and non-radiative recombination components, which are respectively represented by modified Shockley equations. Variations in model parameters show that a shift in Fermi level, reduction of barrier heights, and passivation of mid-gap defect states are the main results of Cs2CO3 treatment. In spite of a large luminance difference, light-extraction efficiency remains the same at 9% regardless of Cs2CO3 treatment because of the similarity in optical structures.

Indicators for Assessing the Quality of Refractive Error Care.

SIGNIFICANCE: Quality refractive error care is essential for reducing vision impairment. Quality indicators and standardized approaches for assessing the quality of refractive error care need to be established. PURPOSE: This study aimed to develop a set of indicators for assessing the quality of refractive error care and test their applicability in a real-world setting using unannounced standardized patients (USPs). METHODS: Patient outcomes and three quality of refractive error care (Q.REC) indicators (1, optimally prescribed spectacles; 2, adequately prescribed spectacles; 3, vector dioptric distance) were developed using existing literature, refraction training standards, and consulting educators. Twenty-one USPs with various refractive errors were trained to visit optical stores across Vietnam to have a refraction, observe techniques, and order spectacles. Spectacles were assessed against each Q.REC indicator and tested for associations with vision and comfort. RESULTS: Overall, 44.1% (184/417) of spectacles provided good vision and comfort. Of the spectacles that met Q.REC indicators 1 and 2, 62.5 and 54.9%, respectively, provided both good vision and comfort. Optimally prescribed spectacles (indicator 1) were significantly more likely to provide good vision and comfort independently compared with spectacles that did not meet any indicator (good vision: 94.6 vs. 85.0%, P = .01; comfortable: 66.1 vs. 36.3%, P < .01). Adequately prescribed spectacles (indicator 2) were more likely to provide good comfort compared with spectacles not meeting any indicator (57.7 vs. 36.3%, P < .01); however, vision outcomes were not significantly different (85.9 vs. 85.0%, P = .90). Good vision was associated with a lower mean vector dioptric distance (P < .01) but not with comfort (P = .52). CONCLUSIONS: The optimally prescribed spectacles indicator is a promising approach for assessing the quality of refractive error care without additional assessments of vision and comfort. Using USPs is a practical approach and could be used as a standardized method for evaluating the quality of refractive error care.

Assessing the virulence of Cryptococcus neoformans causing meningitis in HIV infected and uninfected patients in Vietnam.

We previously observed a substantial burden of cryptococcal meningitis in Vietnam atypically arising in individuals who are uninfected with human immunodeficiency virus (HIV). This disease was associated with a single genotype of Cryptococcus neoformans (sequence type [ST]5), which was significantly less common in HIV-infected individuals. Aiming to compare the phenotypic characteristics of ST5 and non-ST5 C. neoformans, we selected 30 representative Vietnamese isolates and compared their in vitro pathogenic potential and in vivo virulence. ST5 and non-ST5 organisms exhibited comparable characteristics with respect to in vitro virulence markers including melanin production, replication at 37°C, and growth in cerebrospinal fluid. However, the ST5 isolates had significantly increased variability in cellular and capsular sizing compared with non-ST5 organisms (P < .001). Counterintuitively, mice infected with ST5 isolates had significantly longer survival with lower fungal burdens at day 7 than non-ST5 isolates. Notably, ST5 isolates induced significantly greater initial inflammatory responses than non-ST5 strains, measured by TNF-α concentrations (P < .001). Despite being generally less virulent in the mouse model, we hypothesize that the significant within strain variation seen in ST5 isolates in the tested phenotypes may represent an evolutionary advantage enabling adaptation to novel niches including apparently immunocompetent human hosts.

Multilocus sequence typing of Cryptococcus neoformans var. grubii from Laos in a regional and global context.

Cryptococcosis causes approximately 180 000 deaths each year in patients with human immunodeficiency virus (HIV). Patients with other forms of immunosuppression are also at risk, and disease is increasingly recognized in apparently immunocompetent individuals. Cryptococcus neoformans var. grubii, responsible for the majority of cases, is distributed globally. We used the consensus ISHAM Multilocus sequence typing (MLST) scheme to define the population structure of clinical C. neoformans var. grubii isolates from Laos (n = 81), which we placed into the global context using published MLST data from other countries (total N = 1047), including a reanalysis of 136 Vietnamese isolates previously reported. We observed a phylogeographical relationship in which the Laotian population was similar to its neighbor Thailand, being dominated (83%) by Sequence Types (ST) 4 and 6. This phylogeographical structure changed moving eastwards, with Vietnam's population consisting of an admixture of isolates dominated by the ST4/ST6 (35%) and ST5 (48%) lineages. The ST5 lineage is the predominant ST reported from China and East Asia, where it accounts for >90% of isolates. Analysis of genetic distance (Fst) between different populations of C. neoformans var. grubii supports this intermediate structure of the Vietnamese population. The pathogen and host diversity reported from Vietnam provide the strongest epidemiological evidence of the association between ST5 and HIV-uninfected patients. Regional anthropological genetic distances suggest diversity in the C. neoformans var. grubii population across Southeast Asia is driven by ecological rather than human host factors. Where the ST5 lineage is present, disease in HIV-uninfected patients is to be expected.

Impact of 1,2-ethanedithiol treatment on luminescence and charge-transport characteristics in colloidal quantum-dot LEDs.

We report on a substantial increase in luminance and luminous efficiency of green-light emitting devices (LEDs) that use colloidal CdSe@ZnS quantum dots (QDs) as a light-emitting material in response to treatment with 1,2-ethanedithiol (EDT). The maximum luminance increased from 1146 to 8075 cd m-2, and luminous yield from 0.15 to 1.41 cd A-1 as a result of treating an incomplete device with drops of EDT right after spin-coating QDs onto a ZnO-nanoparticle layer. Based on systematic studies on substrate-dependent change in photoluminescence, and current-voltage and luminance-voltage characteristics, we propose that passivation of intra-gap defect states and relative shifts of energy levels relevant to the operation of QD LEDs are two main results of EDT treatment. In particular, we argue that energy-level shift without emission-color change can be attributed to surface-dipole effects.

PD-L1 expression in inflammatory myofibroblastic tumors.

Inflammatory myofibroblastic tumor is a rare mesenchymal tumor occurring at many anatomic sites, with a predilection for children and young adults. Often indolent, they can be locally aggressive and can metastasize, resulting in significant morbidity and mortality. Therapeutic options are often limited. The identification of underlying kinase mutations has allowed the use of targeted therapy in a subset of patients. Unfortunately, not all tumors harbor mutations and resistance to tyrosine kinase inhibitor therapy is a potential problem. We hypothesized that these tumors may be amenable to PD-L1 therapy given the immune nature of the tumor. PD-L1 expression in inflammatory myofibroblastic tumors has not yet been defined. The purpose of this study was to explore PD-L1 expression in inflammatory myofibroblastic tumors, as adaptive PD-L1 expression is known to enrich for response to anti-PD-1/PD-L1 therapies. Expression of PD-L1 (clone SP142) was assessed in 35 specimens from 28 patients. Positivity was defined as membranous expression in ≥5% of cells and evaluated separately in tumor and immune cells. Adaptive vs. constitutive patterns of tumor cell PD-L1 expression were assessed. PD-L1 status was correlated with clinicopathologic features. CD8+ T cell infiltrates were quantified by digital image analysis. ALK status was assessed by immunohistochemistry and/or FISH. Twenty-four (69%) tumors had PD-L1(+) tumor cells and 28 (80%) showed PD-L1(+) immune cells. Most recurrent and metastatic tumors (80%) and ALK(-) tumors (88%) were PD-L1(+). Adaptive PD-L1 expression was present in 23 (96%) of PD-L1(+) tumors, which also showed a three-four fold increase in CD8+ T cell infiltration relative to PD-L1(-) tumors. Constitutive PD-L1 expression was associated with larger tumor size (p = 0.002). Inflammatory myofibroblastic tumors show frequent constitutive and adaptive PD-L1 expression, the latter of which is thought to be predictive of response to anti-PD-1. These data support further investigation into PD-1/PD-L1 blockade in this tumor type.

Photodetector Based on Multilayer SnSe2 Field Effect Transistor.

We demonstrate a high-performance photodetector with multilayer tin diselenide (SnSe2) exfoliated from a high-quality crystal which was synthesized by the temperature gradient growth method. This SnSe2 photodetector exhibits high photoresponsivity of 5.11 × 105 A W-1 and high specific detectivity of 2.79 × 1013 Jones under laser irradiation (λ = 450 nm). We also observed a reproducible and stable time-resolved photoresponse to the incident laser beam from this SnSe2 photodetector, which can be used as a promising material for future optoelectronic applications.

The importance of assessing out-of-pocket payments when the financing of antiretroviral therapy is transitioned to domestic funding: findings from Vietnam.

OBJECTIVE: To assess out-of-pocket payments and catastrophic health expenditures among antiretroviral therapy (ART) patients in Vietnam, and to model catastrophic payments under different copayment scenarios when the primary financing of ART changes to social health insurance. METHODS: Cross-sectional facility-based survey of 843 patients at 42 health facilities representative of 87% of ART patients in 2015. RESULTS: Because of donor and government funding, no payments were made for antiretroviral drugs. Other health expenditures were about $66 per person per year (95% CI: $30-$102), of which $15 ($7-$22) were directly for HIV-related health services, largely laboratory tests. These payments resulted in a 4.9% (95% CI: 3.1-6.8%) catastrophic payment rate and 2.5% (95% CI: 0.9-4.1%) catastrophic payment rate for HIV-related health services. About 32% of respondents reported, they were eligible for SHI without copayments. If patients had to pay 20% of costs of ART under social health insurance, the catastrophic payment rate would increase to 8% (95% CI: 5.5-10.0%), and if patients without health insurance had to pay the full costs of ART, the catastrophic payment rate among all patients would be 24% (95% CI: 21.1-27.4%). CONCLUSIONS: Health and catastrophic expenditures were substantially lower than in previous studies, although different methods may explain some of the discrepancy. The 20% copayments required by social health insurance would present a financial burden to an additional 0.6% to 5.1% of ART patients. Ensuring access to health insurance for all ART patients will prevent an even higher level of financial hardship.

NF-κB factors control the induction of NFATc1 in B lymphocytes.

In peripheral lymphocytes, the transcription factors (TFs) NF-κB, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of κB-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-κB seem neither to interact nor to collaborate. We show here that NF-κB1/p50 and c-Rel, the most prominent NF-κB proteins in BCR-induced splenic B cells, control the induction of NFATc1/αA, a prominent short NFATc1 isoform. In part, this is mediated through two composite κB/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/αA by BCR signals. In concert with coreceptor signals that induce NF-κB factors, BCR signaling induces a persistent generation of NFATc1/αA. These data suggest a tight connection between NFATc1 and NF-κB induction in B lymphocytes contributing to the effector function of peripheral B cells.

NFATc1 induction in peripheral T and B lymphocytes.

NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/αA whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGFß. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/αA RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/αA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/αA and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-κB factors, together with anti-IgM, these signals also support the generation of NFATc1/αA. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level.

Variability of MDCT dose due to technologist performance: impact of posteroanterior versus anteroposterior localizer image and table height with use of automated tube current modulation.

OBJECTIVE: The purpose of this study was to determine MDCT dose variability due to technologist variability in performing CT studies. MATERIALS AND METHODS: Fifty consecutive adult patients who underwent two portal venous phase CT examinations of the abdomen and pelvis on the same 64-MDCT scanner between January and December 2011 were retrospectively identified. Tube voltage (kVp), tube current (mA), use of automated tube current modulation (ATCM), dose-length product (DLP), volume CT dose index (CTDIvol), table height, whether the localizer image was obtained using the posteroanterior or the anteroposterior technique, arm position, and number of overscanned slices were recorded. RESULTS: For a given patient, the total examination DLP difference comparing the two MDCT studies ranged from 0.1% to 238.0%. For the same patient, total examination DLP was always higher when the localizer image was obtained with the posteroanterior compared with the anteroposterior technique. When table position was closer to the x-ray source, patients appeared magnified in the posteroanterior localizer image (8-29%; average, 14%) and higher tube currents were selected with ATCM. Localizer technique, table height, arm position, number of overscanned slices, and technologist were all significant predictors of dose. CONCLUSION: Patient off-centering closer to the x-ray source resulted in patient magnification in the posteroanterior localizer image, leading to higher tube currents with ATCM and increased DLP. Differences in technologist, arm position, and overscanning also resulted in dose variability.

Determining the impacts of hospital cost-sharing on the uninsured near-poor households in Vietnam.

OBJECTIVES: The study objective was to identify the size of different hospital financing sources for different hospital services and their impact on the uninsured. METHODS: A panel dataset of 84 public general hospitals (2005-2008) with cross-section data on hospital activity and hospital revenue was created and used to calculate unit costs of different hospital services by applying multiple regression models. The resulting risk of catastrophic health expenditure (CHE) was estimated based on official income statistics. RESULTS: Average user fees (UF) for outpatient visits and inpatient bed days were US$4.13 and US$20.27, while actual full costs (AFC) were US$8.41 and US$36.66, respectively. These unit costs were 2.5 times higher in hospitals at the central versus the provincial level. UF for surgical inpatient bed days were 3.6 times that of non-surgical treatments (US$47.50 vs. 12.87) and AFC 5.0 times (US$101.72 vs. 20.08). UF accounted for 44.6%-77.9% of the AFC, the rest (22.1%-55.4%) was provided by direct government support (DGS). One surgical inpatient treatment at either central or provincial hospital level and one non-surgical inpatient treatment at central hospital level, immediately pushed uninsured near-poor households at risk of CHE. CONCLUSIONS: Around 45% of hospital AFC was paid by DGS, the larger rest by UF. UF have become a great financial burden on the uninsured near-poor households, who have to pay for these out-of-pocket and therefore may not utilize even necessary services. If the rate of DGS were reduced, this would have the effect of increasing UF, but the savings to Government could be spent on subsidizing insurance to ensure that a larger part of the population can cover UF through insurance, especially the near-poor households.

Pharmacogenomic Analysis of CYP3A5*3 and Tacrolimus Trough Concentrations in Vietnamese Renal Transplant Outcomes.

Purpose: CYP3A5 polymorphisms have been associated with variations in the pharmacokinetics of tacrolimus (Tac) in kidney transplant patients. Our study aims to quantify how the CYP3A5 genotype influences tacrolimus trough concentrations (C0) in a Vietnamese outpatient population by selecting an appropriate population pharmacokinetic model of Tac for our patients. Patients and Methods: The external dataset was obtained prospectively from 54 data of adult kidney transplant recipients treated at the 103 Military Hospital. All published Tac population pharmacokinetic models were systematically screened from PubMed and Scopus databases and were selected based on our patient's available characteristics. Mean absolute prediction error (MAPE), mean prediction error, and goodness-of-fit plots were used to identify the appropriate model for finding the formula that identifies the influence of CYP3A5 genotype on the pharmacokinetic data of Vietnamese patients. Results: The model of Zhu et al had a good predictive ability with MAPE of 19.29%. The influence of CYP3A5 genotype on tacrolimus clearance was expressed by the following formulas: CL/F=27,2×[(WT/70)0,75]×[(HCT/0,35)-0,501]×[(POD/180)0,0306]×CYP3A5(L/h). The simulation result showed that Tac C0 was significantly higher in patients not expressing CYP3A5 (p< 0.001). Conclusion: The incorporation of the CYP3A5 phenotype into Zhu's structural model has significantly enhanced our ability to predict Tacrolimus trough levels in the Vietnamese population. This study's results underscore the valuable role of CYP3A5 phenotype in optimizing the forecast of Tac concentrations, offering a promising avenue to assist health-care practitioners in their clinical decision-making and ultimately advance patient care outcomes.

Financial burden of health care for HIV/AIDS patients in Vietnam.

OBJECTIVE: To assess the out-of-pocket (OOP) payments for health-care services of HIV/AIDS patients, and identify associated factors in Vietnam. METHODS: Cross-sectional multisite survey of 1016 HIV/AIDS patients attending 7 hospitals and health centres in Ha Noi, Hai Phong and Ho Chi Minh City in 2012. RESULTS: HIV/AIDS patients used inpatient and outpatient care on average 5.1 times (95% CI = 4.7-5.4) besides ART services. Inpatient care cost US$ 461 on average and outpatient care US$ 50. Mean annual health-care expenditure for HIV/AIDS patients was US$ 188 (95% CI = 148-229). 35.1% of households (95% CI = 32.2-38.1) experienced catastrophic health expenditure; 73.3% (95% CI = 70.6-76.1) of households would be affected if ART were not subsidised. Being a patient at a provincial clinic, male sex, unstable employment, being in the poorest income quintile, a CD4 count of <200 cells/mL and not yet receiving ART increased the likelihood of catastrophic medical expense. CONCLUSIONS: HIV/AIDS patients in Vietnam frequently use medical services and incur OOP payments for health care. Scaling up free-of-charge ART services, earlier access to and initiation of ART, and decentralisation and integration of HIV/AIDS-related services could reduce their financial burden.

Estimating the cost of inappropriate antibiotic prophylaxis prior to dental procedures.

Inappropriate dental antibiotic prescriptions to prevent infective endocarditis in the United States results in ∼$31 million in excess costs to the healthcare system and patients. This includes out-of-pocket costs ($20.5 million), drug costs ($2.69 million) and adverse event costs (eg, Clostridioides difficile and hypersensitivity) of $5.82 million (amoxicillin), $1.99 million (clindamycin), and $380,849 (cephalexin).

Female dominance hierarchies influence responses to psychosocial stressors.

Social species form dominance hierarchies to ensure survival and promote reproductive success. Traditionally studied in males, rodent hierarchies are considered despotic, and dominant social rank results from a history of winning agonistic encounters. By contrast, female hierarchies are thought to be less despotic, and rank is conferred by intrinsic traits. Both social buffering and elevated social status confer resilience to depression, anxiety, and other consequences of chronic stress. Here, we investigate whether female social hierarchies and individual traits related to social rank likewise influence stress resilience. We observe the formation of dyadic female hierarchies under varying conditions of ambient light and circadian phase and subject mice to two forms of chronic psychosocial stress: social isolation or social instability. We find that stable female hierarchies emerge rapidly in dyads. Individual behavioral and endocrinological traits are characteristic of rank, some of which are circadian phase dependent. Further, female social rank is predicted by behavior and stress status prior to social introduction. Other behavioral characteristics suggest that rank is motivation-based, indicating that female rank identity serves an evolutionarily relevant purpose. Rank is associated with alterations in behavior in response to social instability stress and prolonged social isolation, but the different forms of stress produce disparate rank responses in endocrine status. Histological examination of c-Fos protein expression identified brain regions that respond to social novelty or social reunion following chronic isolation in a rank-specific manner. Collectively, female rank is linked to neurobiology, and hierarchies exert context-specific influence upon stress outcomes.