Transition to Inpatient Telepsychiatry Services and Impact on Quality of Care.

Demands for telepsychiatry have increased due to the challenges of COVID-19. The global pandemic caused a significant increase in anxiety and depression and a worsening of eating disorder symptoms, while the implementation of social distancing both exacerbated these mental health issues and disrupted the in-person delivery of mental health services. Rapid adaptation of telepsychiatry in the acute inpatient setting has been reported with favorable outcomes in patient experiences. This article reports our experience with a transition to telepsychiatry services on an acute eating disorder unit and the impact on quality of care. Forty-two inpatients on an eating disorders unit completed 410 surveys evaluating their experience with telepsychiatry. Simultaneously, surveys were distributed to physicians to identify technical and connectivity issues. Our experience showed that patients on an eating disorder unit, who had an average length of stay of 22 days, were very satisfied with telepsychiatry, with few technical or safety issues.

Human embryonic stem cell-derived endothelial cell product injection attenuates cardiac remodeling in myocardial infarction.

Background: Mechanisms contributing to tissue remodeling of the infarcted heart following cell-based therapy remain elusive. While cell-based interventions have the potential to influence the cardiac healing process, there is little direct evidence of preservation of functional myocardium. Aim: The aim of the study was to investigate tissue remodeling in the infarcted heart following human embryonic stem cell-derived endothelial cell product (hESC-ECP) therapy. Materials and methods: Following coronary artery ligation (CAL) to induce cardiac ischemia, we investigated infarct size at 1 day post-injection in media-injected controls (CALM, n = 11), hESC-ECP-injected mice (CALC, n = 10), and dead hESC-ECP-injected mice (CALD, n = 6); echocardiography-based functional outcomes 14 days post-injection in experimental (CALM, n = 13; CALC, n = 17) and SHAM surgical mice (n = 4); and mature infarct size (CALM and CALC, both n = 6). We investigated ligand-receptor interactions (LRIs) in hESC-ECP cell populations, incorporating a publicly available C57BL/6J mouse cardiomyocyte-free scRNAseq dataset with naive, 1 day, and 3 days post-CAL hearts. Results: Human embryonic stem cell-derived endothelial cell product injection reduces the infarct area (CALM: 54.5 ± 5.0%, CALC: 21.3 ± 4.9%), and end-diastolic (CALM: 87.8 ± 8.9 uL, CALC: 63.3 ± 2.7 uL) and end-systolic ventricular volume (CALM: 56.4 ± 9.3 uL, CALC: 33.7 ± 2.6 uL). LRI analyses indicate an alternative immunomodulatory effect mediated via viable hESC-ECP-resident signaling. Conclusion: Delivery of the live hESC-ECP following CAL modulates the wound healing response during acute pathological remodeling, reducing infarct area, and preserving functional myocardium in this relatively acute model. Potential intrinsic myocardial cellular/hESC-ECP interactions indicate that discreet immunomodulation could provide novel therapeutic avenues to improve cardiac outcomes following myocardial infarction.

Prevalence of and Relationship Between Caregiver Adversity Scores and Child Client Eco-systemic Structural Family Therapy (ESFT) Outcome: Implications for Family Based Mental Health Services (FBMHS).

Adverse childhood experiences, especially with primary caregivers, impacts the mental, physical, and relational health of individuals (Felitti et al. in Am J Prev Med, 14(4):245-258. https://doi.org/10.1016/s0749-3797(98)00017-8 , 1998). Therefore, caregiver adversity is important to consider when delivering therapeutic interventions to children (Gardner et al. in Clin Soc Work J 42(1):81-89. https://doi.org/10.1007/s10615-012-0428-8 , 2014; Eslinger et al. in J Child Fam Stud 24(9):2757. https://doi.org/10.1007/s10826-014-0079-1 , 2015; Hagan et al. in J Trauma Stress 30(6):690-697, 2017). This study analyzed archival data to understand the role of caregiver adversity in Eco-Systemic Structural Family Therapy (ESFT) outcomes, within Family Based Mental Health Services. Results indicate caregiver lifetime adversity score did not predict treatment outcome. However, caregiver current adversity and family length of stay were negatively correlated as were length of stay and client discharge level of care. These findings suggest that ESFT benefits families regardless of caregiver childhood adversity level and that clinician attention to caregiver current adversity is important to ensure families receive the full benefits of ESFT. Implications for optimizing ESFT and future directions for ESFT clinical research are discussed.

Structural Insights on Microwave-Synthesized Antimony-Doped Germanium Nanocrystals.

Doped and alloyed germanium nanocrystals (Ge NCs) are potential candidates for a variety of applications such as photovoltaics and near IR detectors. Recently, bismuth (Bi) as an n-type group 15 element was shown to be successfully and kinetically doped into Ge NCs through a microwave-assisted solution-based synthesis, although Bi is thermodynamically insoluble in bulk crystalline Ge. To expand the composition manipulation of Ge NCs, another more common n-type group 15 element for semiconductors, antimony (Sb), is investigated. Oleylamine (OAm)- and OAm/trioctylphosphine (TOP)-capped Sb-doped Ge NCs have been synthesized by the microwave-assisted solution reaction of GeI2 with SbI3. Passivating the Ge surface with a binary ligand system of OAm/TOP results in formation of consistently larger NCs compared to OAm alone. The TOP coordination on the Ge surface is confirmed by 31P NMR and SEM-EDS. The lattice parameter of Ge NCs increases with increasing Sb concentration (0.00-2.0 mol %), consistent with incorporation of Sb. An increase in the NC diameter with higher content of SbI3 in the reaction is shown by TEM. XPS and EDS confirm the presence of Sb before and after removal of surface ligands with hydrazine and recapping the Ge NC surface with dodecanethiol (DDT). EXAFS analysis suggests that Sb resides within the NCs on highly distorted sites next to a Ge vacancy as well as on the crystallite surface. High Urbach energies obtained from photothermal deflection spectroscopy (PDS) of the films prepared from pristine Ge NC and Sb-doped Ge NCs indicate high levels of disorder, in agreement with EXAFS data. Electrical measurements on TiO2-NC electron- and hole-only devices show an increase in hole conduction, suggesting that the Sb-vacancy defects are behaving as a p-type dopant in the Ge NCs, consistent with the vacancy model derived from the EXAFS results.

STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer.

Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity.

Neuregulin 1 Type I Overexpression Is Associated with Reduced NMDA Receptor-Mediated Synaptic Signaling in Hippocampal Interneurons Expressing PV or CCK.

Hypofunction of N-methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 (NRG1), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK). Here, we investigated ErbB4 expression and synaptic transmission in interneuronal populations of the hippocampus of transgenic mice overexpressing NRG1 type I (NRG1tg-type-I mice). Immunohistochemical analyses confirmed that ErbB4 was coexpressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1tg-type-I mice. NMDAR-mediated currents in interneurons expressing PV (including PV+ basket cells) or CCK were reduced in NRG1tg-type-I mice compared to their littermate controls. We found no difference in AMPA receptor-mediated currents. Optogenetic activation (5 pulses at 20 Hz) of local glutamatergic fibers revealed a decreased NMDAR-mediated contribution to disynaptic GABAergic inhibition of pyramidal cells in the NRG1tg-type-I mice. GABAergic synaptic transmission from either PV+ or CCK+ interneurons, and glutamatergic transmission onto pyramidal cells, did not significantly differ between genotypes. The results indicate that synaptic NMDAR-mediated signaling in hippocampal interneurons is sensitive to chronically elevated NGR1 type I levels. This may contribute to the pathophysiological consequences of increased NRG1 expression in SZ.

Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo.

Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 ± 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.

Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.

Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity.

Pilot study of a web-based intervention for adolescents with type 1 diabetes.

We evaluated the feasibility and effectiveness of a website designed to improve compliance to treatment protocols in adolescents with type-1 diabetes. Fifty-nine adolescents, 13-18 years of age, were randomly assigned to a control or experimental group. The control group received standard medical care as usual. The experimental group participated in an interactive, 7-week web-based intervention, taking part in problem-solving through discussion forums, chat rooms and blogs. Fifty of the 59 participants (85%) completed measures assessing diabetes-related quality of life, self-efficacy and outcome expectations. These variables were expected to be interrelated and their combined effects were considered as mediators of compliance. There was a marginally significant difference between the two groups on these combined measures (P = 0.052), with the control group scoring significantly higher on Positive Outcome Expectations (P = 0.03) both pre- and post-treatment. Attrition in the period between recruitment and the beginning of the intervention reduced power. Self-Efficacy was significantly correlated with Positive Outcome Expectations (r = 0.30, P = 0.037) and Diabetes Self-Management and Diabetes Quality of Life for Youths (r = 0.43, P = 0.002). In an exit survey, 90% of participants indicated that they were more willing to comply with their treatment protocol after participating in the intervention. An online website is a promising tool to bring adolescents with a chronic disease together, providing problem solving activities and social support.

A surfactant-free strategy for synthesizing and processing intermetallic platinum-based nanoparticle catalysts.

Using Pt(3)Fe nanoparticles as an example, a surfactant-free Np-KCl matrix method (Np stands for nanoparticle) is developed for the synthesis of nanoparticles with controlled size and structure. In this method, the Np-KCl assembly is formed in a one-pot reduction in THF at room temperature. KCl is an insoluble byproduct of the reaction and serves as a matrix that traps the nanoparticles to avoid particle agglomeration and to control the coalescence of nanoparticles during thermal annealing up to 600 °C. By varying the molar ratio of metal precursors and KCl, as well as the time and temperature of annealing, the final particle sizes and crystalline order can be independently controlled. After thermal processing, nanoparticles were released from the KCl matrix and transferred in an ethylene glycol-water solution to support materials forming a uniform Np-support assembly. A detailed study of the synthesis of ordered intermetallic Pt(3)Fe nanoparticles with an average diameter of 4 nm, using this Np-KCl method, is provided as an example of a generally applicable method. This surfactant-free strategy has been extended to the synthesis of other bi- and trimetallic nanoparticles of Pt-transition metals.

Diagnosing endometrial hyperplasia: why is it so difficult to agree?

Current World Health Organization classification of endometrial hyperplasia is problematic because of poor diagnostic reproducibility. We sought to determine factors that cause diagnostic disagreement in a review of 2601 endometrial specimens. Blinded random specimens of normal endometrium, hyperplasias, and carcinoma were reviewed by 2 pathologists, with review by a third pathologist in cases with disagreement. All cases of endometrial hyperplasia or carcinoma were scored for degree of glandular crowding, architectural complexity, and cytologic atypia. Sample adequacy, hyperplasia volume, presence of metaplasia, or endometrial polyp were also scored. The overall kappa for agreement was 0.71, with a lower kappa of 0.36 when cases called "no hyperplasia" were excluded. The percent specific agreement was 90.3% for no hyperplasia, 31.1% for simple hyperplasia, 51.1% for complex hyperplasia, 49.8% for atypical hyperplasia, and 57.5% for adenocarcinoma. Cases categorized as "low volume hyperplasia" had more diagnostic disagreement than "high volume," (62% vs. 39%, P=0.003). Similarly, cases called "scant" had more diagnostic disagreement than "not scant" (65% vs. 57%, P=0.013). The histologic feature associated with the most diagnostic disagreement was cytologic atypia (P<0.0001). Architectural crowding, architectural complexity, or the presence of a polyp were all associated with diagnostic disagreement (P<0.0001). High diagnostic disagreement in endometrial hyperplasia is related to both sample adequacy and interpretation of histologic features present. Although obtaining additional tissue may increase diagnostic reproducibility, differences in interpretation of key histologic features like cytologic atypia remain major factors contributing to diagnostic disagreement.

Cdk1 is sufficient to drive the mammalian cell cycle.

Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.

Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations.

PC4- and SF2-interacting protein 1 (Psip1)-also known as lens epithelium-derived growth factor (Ledgf)-is a chromatin-associated protein that has been implicated in transcriptional regulation, mRNA splicing, and cell survival in vitro, but its biological function in vivo is unknown. We identified an embryonic stem cell clone with disrupted Psip1 in a gene trap screen. The resulting Psip1-betageo fusion protein retains chromatin-binding activity and the PWWP and AT hook domains of the wild-type protein but is missing the highly conserved C terminus. The majority of mice homozygous for the disrupted Psip1 gene died perinatally, but some survived to adulthood and displayed a range of phenotypic abnormalities, including low fertility, an absence of epididymal fat pads, and a tendency to develop blepharitis. However, contrary to expectations, the lens epithelium was normal. The mutant mice also exhibited motor and/or behavioral defects such as hind limb clenching, reduced grip strength, and reduced locomotor activity. Finally, both Psip1(-/-) neonates and surviving adults had craniofacial and skeletal abnormalities. They had brachycephaly, small rib cages, and homeotic skeletal transformations with incomplete penetrance. The latter phenotypes suggest a role for Psip1 in the control of Hox expression and may also explain why PSIP1 (LEDGF) is found as a fusion partner with NUP98 in myeloid leukemias.

A novel SR-related protein is required for the second step of Pre-mRNA splicing.

The SR family proteins and SR-related polypeptides are important regulators of pre-mRNA splicing. A novel SR-related protein of an apparent molecular mass of 53 kDa was isolated in a gene trap screen that identifies proteins which localize to the nuclear speckles. This novel protein possesses an arginine- and serine-rich domain and was termed SRrp53 (for SR-related protein of 53 kDa). In support for a role of this novel RS-containing protein in pre-mRNA splicing, we identified the mouse ortholog of the Saccharomyces cerevisiae U1 snRNP-specific protein Luc7p and the U2AF65-related factor HCC1 as interacting proteins. In addition, SRrp53 is able to interact with some members of the SR family of proteins and with U2AF35 in a yeast two-hybrid system and in cell extracts. We show that in HeLa nuclear extracts immunodepleted of SRrp53, the second step of pre-mRNA splicing is blocked, and recombinant SRrp53 is able to restore splicing activity. SRrp53 also regulates alternative splicing in a concentration-dependent manner. Taken together, these results suggest that SRrp53 is a novel SR-related protein that has a role both in constitutive and in alternative splicing.

Phenoloxidase and QX disease resistance in Sydney rock oysters (Saccostrea glomerata).

QX is a fatal disease in Sydney rock oysters (Saccostrea glomerata) that results from infection by the protistan parasite, Marteilia sydneyi. Since 1997, the New South Wales Fisheries Service has bred S. glomerata for resistance to QX disease. The current study shows that the QX resistance breeding program has selected oysters with enhanced phenoloxidase (PO) activities. The third generation of QX-selected oysters was compared to S. glomerata that had never been selected for disease resistance. PO enzyme assays showed that oysters bred for resistance had significantly higher PO activities than the non-selected population. There was no difference between populations in the activities of a variety of other enzymes. Native polyacrylamide gel electrophoresis identified a novel form of PO in QX-selected oysters that contributes to their enhanced PO activities. This novel form of PO may represent a specific QX disease resistance factor.

Fibrillarin is essential for early development and required for accumulation of an intron-encoded small nucleolar RNA in the mouse.

Fibrillarin, a protein component of C/D box small nucleolar ribonucleoproteins (snoRNPs), directs 2'-O-methylation of rRNA and is also involved in other aspects of rRNA processing. A gene trap screen in embryonic stem (ES) cells resulted in an insertion mutation in the fibrillarin gene. This insertion generated a fusion protein that contained the N-terminal 132 amino acids of fibrillarin fused to a beta-galactosidase-neomycin phosphotransferase reporter. As a result, the N-terminal GAR domain was present in the fusion protein but the methyltransferase-like domain was missing. The ES cell line with the targeted fibrillarin allele was transmitted through the mouse germ line, creating heterozygous animals. Western blot analyses showed a reduction in fibrillarin protein levels in the heterozygous knockout animals. Animals homozygous for the mutation were inviable, and massive apoptosis was observed in early Fibrillarin(-/-) embryos, showing that fibrillarin is essential for development. Fibrillarin(+/-) live-born mice displayed no obvious growth defect, but heterozygous intercrosses revealed a reduced ratio of +/- to +/+ mice, showing that some of the Fibrillarin heterozygous embryos die in utero. Analyses of tissue samples and cultured embryonic fibroblasts showed no discernible alteration in pre-rRNA processing or the level of the U3 snoRNA. However, the level of the intron-encoded box C/D snoRNA U76 was clearly reduced. This suggests a high requirement for snoRNA synthesis during an early stage in development.