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The effectiveness of collaborative care of mental health problems is clear for depression and growing but mixed for anxiety disorders, including posttraumatic stress disorder (PTSD). We know little about whether collaborative care can be effective in settings that serve low-income patients such as Federally Qualified Health Centers (FQHCs). We compared the effectiveness of minimally enhanced usual care (MEU) versus collaborative care for PTSD with a care manager (PCM). This was a multi-site patient randomized controlled trial of PTSD care improvement over 1 year. We recruited and enrolled 404 patients in six FQHCs from June 2010 to October 2012. Patients were eligible if they had a primary care appointment, no obvious physical or cognitive obstacles to participation, were age 18-65 years, planned to continue care at the study location for 1 year, and met criteria for a past month diagnosis of PTSD. The main outcomes were PTSD diagnosis and symptom severity (range, 0-136) based on the Clinician-Administered PTSD Scale (CAPS). Secondary outcomes were medication and counseling for mental health problems, and health-related quality of life assessed at baseline, 6 months, and 12 months. Patients in both conditions improved similarly over the 1-year evaluation period. At 12 months, PTSD diagnoses had an absolute decrease of 56.7 % for PCM patients and 60.6 % for MEU patients. PTSD symptoms decreased by 26.8 and 24.2 points, respectively. MEU and PCM patients also did not differ in process of care outcomes or health-related quality of life. Patients who actually engaged in care management had mental health care visits that were 14 % higher (p < 0.01) and mental health medication prescription rates that were 15.2 % higher (p < 0.01) than patients with no engagement. A minimally enhanced usual care intervention was similarly effective as collaborative care for patients in FQHCs.

Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming-TAM-populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, Fc gamma RIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment.

Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis.

Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.

The neuropeptide PDF promotes the normal sequencing of circadian behavioral rhythms in Drosophila, but its signaling mechanisms are not well understood. We report daily rhythmicity in responsiveness to PDF in critical pacemakers called small LNvs. There is a daily change in potency, as great as 10-fold higher, around dawn. The rhythm persists in constant darkness and does not require endogenous ligand (PDF) signaling or rhythmic receptor gene transcription. Furthermore, rhythmic responsiveness reflects the properties of the pacemaker cell type, not the receptor. Dopamine responsiveness also cycles, in phase with that of PDF, in the same pacemakers, but does not cycle in large LNv. The activity of RalA GTPase in s-LNv regulates PDF responsiveness and behavioral locomotor rhythms. Additionally, cell-autonomous PDF signaling reversed the circadian behavioral effects of lowered RalA activity. Thus, RalA activity confers high PDF responsiveness, providing a daily gate around the dawn hours to promote functional PDF signaling.

Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the hilus of the dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the dentate hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Background Assisted Reproductive Technology (ART) reports generated by the Centers for Disease Control and Prevention (CDC) exclude embryo banking cycles from outcome calculations. Methods We examined data reported to the CDC in 2013 for the impact of embryo banking exclusion on national ART outcomes by recalculating autologous oocyte ART live birth rates. Inflation of reported fresh ART cycle live birth rates was assessed for all age groups of infertile women as the difference between fresh cycle live births with reference to number of initiated fresh cycles (excluding embryo banking cycles), as typically reported by the CDC, and fresh cycle live births with reference to total initiated fresh ART cycles (including embryo banking cycles). Results During 2013, out of 121,351 fresh non-donor ART cycles 27,564 (22.7%) involved embryo banking. The proportion of banking cycles increased with female age from 15.5% in women <35 years to 56.5% in women >44 years. Concomitantly, the proportion of thawed cycles decreased with advancing female age (P < 0.0001). Exclusion of embryo banking cycles led to inflation of live birth rates in fresh ART cycles, increasing in size in parallel to advancing female age and utilization of embryo banking, reaching 56.3% in women age >44. The inflation of live birth rates in thawed cycles could not be calculated from the publically available CDC data but appears to be even greater. Conclusions Utilization of embryo banking increased during 2013 with advancing female age, suggesting a potential age selection bias. Exclusion of embryo banking cycles from national ART outcome reports significantly inflated national ART success rates, especially among older women. Precis Exclusion of embryo banking cycles from US National Assisted Reproductive Technology outcome reports significantly inflates reported success rates especially in older women.

A simultaneous fit of parton distribution functions (PDFs) and electroweak parameters to HERA data on deep inelastic scattering is presented. The input data are the neutral current and charged current inclusive cross sections which were previously used in the QCD analysis leading to the HERAPDF2.0 PDFs. In addition, the polarization of the electron beam was taken into account for the ZEUS data recorded between 2004 and 2007. Results on the vector and axial-vector couplings of the Z boson to u- and d-type quarks, on the value of the electroweak mixing angle and the mass of the W boson are presented. The values obtained for the electroweak parameters are in agreement with Standard Model predictions.

Neurons receive input from the outside world or from other neurons through neuronal receptive endings (NREs). Glia envelop NREs to create specialized microenvironments; however, glial functions at these sites are poorly understood. Here, we report a molecular mechanism by which glia control NRE shape and associated animal behavior. The C. elegans AMsh glial cell ensheathes the NREs of 12 neurons, including the thermosensory neuron AFD. KCC-3, a K/Cl transporter, localizes specifically to a glial microdomain surrounding AFD receptive ending microvilli, where it regulates K+ and Cl- levels. We find that Cl- ions function as direct inhibitors of an NRE-localized receptor-guanylyl-cyclase, GCY-8, which synthesizes cyclic guanosine monophosphate (cGMP). High cGMP mediates the effects of glial KCC-3 on AFD shape by antagonizing the actin regulator WSP-1/NWASP. Components of this pathway are broadly expressed throughout the nervous system, suggesting that ionic regulation of the NRE microenvironment may be a conserved mechanism by which glia control neuron shape and function.