The Effect of Intensive Implementation Support on Fidelity for Four Evidence‑Based Psychosis Treatments: A Cluster Randomized Trial

Abstract Purpose: Service providers need effective strategies to implement evidence-based practices (EBPs) with high fidelity. This study aimed to evaluate an intensive implementation support strategy to increase fidelity to EBP standards in treatment of patients with psychosis. Methods: The study used a cluster randomized design with pairwise assignment of practices within each of 39 Norwegian mental health clinics. Each site chose two of four practices for implementation: physical health care, antipsychotic medication management, family psychoeducation, illness management and recovery. One practice was assigned to the experimental condition (toolkits, clinical training, implementation facilitation, data-based feedback) and the other to the control condition (manual only). The outcome measure was fidelity to the EBP, measured at baseline and after 6, 12, and 18 months, analyzed using linear mixed models and effect sizes. Results: The increase in fidelity scores (within a range 1-5) from baseline to 18 months was significantly greater for experimental sites than for control sites for the combined four practices, with mean difference in change of 0.86 with 95% CI (0.21; 1.50), p = 0.009). Effect sizes for increase in group difference of mean fidelity scores were 2.24 for illness management and recovery, 0.68 for physical health care, 0.71 for antipsychotic medication management, and 0.27 for family psychoeducation. Most improvements occurred during the first 12 months. Conclusions: Intensive implementation strategies (toolkits, clinical training, implementation facilitation, data-based feedback) over 12 months can facilitate the implementation of EBPs for psychosis treatment. The approach may be more effective for some practices than for others. Keywords: Evidence-based practice; Fidelity scale; Implementation support; Mental health services; Psychoses. © 2021. The Author(s).publishedVersio

Occult axillary lymph node metastases are of no prognostic significance in breast cancer

The significance of occult metastases in axillary lymph nodes in patients with carcinoma of the breast is controversial. Additional sections were cut from the axillary lymph nodes of 477 women with invasive carcinoma of the breast, in whom no metastases were seen on initial assessment of haematoxylin and eosin stained sections of the nodes. One section was stained with haematoxylin and eosin, and one using immunohistochemistry with two anti-epithelial antibodies (CAM5.2 and HMFG2). Occult metastases were found in 60 patients (13%). The median follow-up was 18.9 years with 153 breast cancer related deaths. There was no difference in survival between those with and those without occult metastases. Multivariate analysis, however, showed that survival was related to tumour size and histological grade. This node-negative group was compared with a second group of 202 patients who had one involved axillary node found on initial assessment of the haematoxylin and eosin sections; survival was worse in the patients in whom a nodal metastasis was found at the time of surgery. Survival was not related to the size of nodal metastases in the occult metastases and single node positive groups. Some previous studies have found a worse prognosis associated with occult metastases on univariate analysis, but the evidence that it is an independent prognostic factor on multivariate analysis is weak. We believe that the current evidence does not support the routine use of serial sections or immunohistochemistry for the detection of occult metastases in the management of lymph node negative patients, but that the traditional factors of histological grade and tumour size are useful

Cholinergic Activation of M2 Receptors Leads to Context-Dependent Modulation of Feedforward Inhibition in the Visual Thalamus

The temporal dynamics of inhibition within a neural network is a crucial determinant of information processing. Here, the authors describe in the visual thalamus how neuromodulation governs the magnitude and time course of inhibition in an input-dependent way

A Positive Feedback Synapse from Retinal Horizontal Cells to Cone Photoreceptors

Cone photoreceptors and horizontal cells (HCs) have a reciprocal synapse that underlies lateral inhibition and establishes the antagonistic center-surround organization of the visual system. Cones transmit to HCs through an excitatory synapse and HCs feed back to cones through an inhibitory synapse. Here we report that HCs also transmit to cone terminals a positive feedback signal that elevates intracellular Ca2+ and accelerates neurotransmitter release. Positive and negative feedback are both initiated by AMPA receptors on HCs, but positive feedback appears to be mediated by a change in HC Ca2+, whereas negative feedback is mediated by a change in HC membrane potential. Local uncaging of AMPA receptor agonists suggests that positive feedback is spatially constrained to active HC-cone synapses, whereas the negative feedback signal spreads through HCs to affect release from surrounding cones. By locally offsetting the effects of negative feedback, positive feedback may amplify photoreceptor synaptic release without sacrificing HC-mediated contrast enhancement

A quantitative analysis of lymphatic vessels in human breast cancer, based on LYVE-1 immunoreactivity

This study was undertaken to determine the highly sensitive method for detecting tumour lymphatic vessels in all the fields of each slide (LV), lymphatic microvessel density (LMVD) and lymphatic vessel invasion (LVI) and to compare them with other prognostic parameters using immunohistochemical staining with polyclonal (PCAB) and monoclonal antibodies (MCAB) to the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), and the pan-endothelial marker factorVIII in a series of 67 human breast cancers. In all LYVE-1-stained sections, LV (some of which contained red blood cells) were frequently found localised in extralobular stroma, dermis, connective tissue stroma and adjacent to artery and vein, but were rare within the intralobular stroma or the tumour body (3/67 cases) or areas of widespread invasion. In contrast small blood vessels were observed in intra- and extralobular stroma in the factor VIII-stained sections. Quantitation of vessel numbers revealed that LYVE-1/PCAB detected a significantly larger number of LV than either H&E or LYVE-1/MCAB (P<0.0001). LYVE-1/PCAB detected LVI in 25/67 cases (37.3%) and their presence was significantly associated with both lymph node metastasis (χ2=4.698, P=0.0248) and unfavourable overall survival (OS) (P=0.0453), while not relapse- free survival (RFS) (P=0.2948). LMVD had no influence for RFS and OS (P=0.4879, P=0.1463, respectively). Our study demonstrates that immunohistochemistry with LYVE-1/PCAB is a highly sensitive method for detecting tumour LV/LVI in breast cancer and LVI is a useful prognostic indicator for lymphatic tumour dissemination

High-Pass Filtering of Input Signals by the Ih Current in a Non-Spiking Neuron, the Retinal Rod Bipolar Cell

Hyperpolarization–activated cyclic nucleotide–sensitive (HCN) channels mediate the If current in heart and Ih throughout the nervous system. In spiking neurons Ih participates primarily in different forms of rhythmic activity. Little is known, however, about its role in neurons operating with graded potentials as in the retina, where all four channel isoforms are expressed. Intriguing evidence for an involvement of Ih in early visual processing are the side effects reported, in dim light or darkness, by cardiac patients treated with HCN inhibitors. Moreover, electroretinographic recordings indicate that these drugs affect temporal processing in the outer retina. Here we analyzed the functional role of HCN channels in rod bipolar cells (RBCs) of the mouse. Perforated–patch recordings in the dark–adapted slice found that RBCs exhibit Ih, and that this is sensitive to the specific blocker ZD7288. RBC input impedance, explored by sinusoidal frequency–modulated current stimuli (0.1–30 Hz), displays band–pass behavior in the range of Ih activation. Theoretical modeling and pharmacological blockade demonstrate that high–pass filtering of input signals by Ih, in combination with low–pass filtering by passive properties, fully accounts for this frequency–tuning. Correcting for the depolarization introduced by shunting through the pipette–membrane seal, leads to predict that in darkness Ih is tonically active in RBCs and quickens their responses to dim light stimuli. Immunohistochemistry targeting candidate subunit isoforms HCN1–2, in combination with markers of RBCs (PKC) and rod–RBC synaptic contacts (bassoon, mGluR6, Kv1.3), suggests that RBCs express HCN2 on the tip of their dendrites. The functional properties conferred by Ih onto RBCs may contribute to shape the retina's light response and explain the visual side effects of HCN inhibitors

No common denominator for breast cancer lymph node metastasis

The axillary lymph node status is the most powerful prognostic factor for breast cancer patients to date. The molecular mechanisms that control lymph node metastasis, however, remain poorly understood. To define patterns of genes or gene regulatory pathways that drive breast cancer lymph node metastasis, we compared the gene expression profiles of 15 primary breast carcinomas and their matching lymph node metastases using microarrays. In general, primary breast carcinomas and lymph node metastases do not differ at the transcriptional level by a common subset of genes. No classifier or single gene discriminating the group of primary tumours from those of the lymph node metastases could be identified. Also, in a series of 295 breast tumours, no classifier predicting lymph node metastasis could be developed. However, subtle differences in the expression of genes involved in extracellular-matrix organisation and growth factor signalling are detected in individual pairs of matching primary and metastatic tumours. Surprisingly, however, different sets of these genes are either up- or downregulated in lymph node metastases. Our data suggest that breast carcinomas do not use a shared gene set to accomplish lymph node metastasis

Contrast Adaptation Contributes to Contrast-Invariance of Orientation Tuning of Primate V1 Cells

BACKGROUND: Studies in rodents and carnivores have shown that orientation tuning width of single neurons does not change when stimulus contrast is modified. However, in these studies, stimuli were presented for a relatively long duration (e. g., 4 seconds), making it possible that contrast adaptation contributed to contrast-invariance of orientation tuning. Our first purpose was to determine, in marmoset area V1, whether orientation tuning is still contrast-invariant with the stimulation duration is comparable to that of a visual fixation. METHODOLOGY/PRINCIPAL FINDINGS: We performed extracellular recordings and examined orientation tuning of single-units using static sine-wave gratings that were flashed for 200 msec. Sixteen orientations and three contrast levels, representing low, medium and high values in the range of effective contrasts for each neuron, were randomly intermixed. Contrast adaptation being a slow phenomenon, cells did not have enough time to adapt to each contrast individually. With this stimulation protocol, we found that the tuning width obtained at intermediate contrast was reduced to 89% (median), and that at low contrast to 76%, of that obtained at high contrast. Therefore, when probed with briefly flashed stimuli, orientation tuning is not contrast-invariant in marmoset V1. Our second purpose was to determine whether contrast adaptation contributes to contrast-invariance of orientation tuning. Stationary gratings were presented, as previously, for 200 msec with randomly varying orientations, but the contrast was kept constant within stimulation blocks lasting >20 sec, allowing for adaptation to the single contrast in use. In these conditions, tuning widths obtained at low contrast were still significantly less than at high contrast (median 85%). However, tuning widths obtained with medium and high contrast stimuli no longer differed significantly. CONCLUSIONS/SIGNIFICANCE: Orientation tuning does not appear to be contrast-invariant when briefly flashed stimuli vary in both contrast and orientation, but contrast adaptation partially restores contrast-invariance of orientation tuning