Glial activation in pain and emotional processing regions in the nitroglycerin mouse model of chronic migraine.

OBJECTIVE: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. BACKGROUND: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. METHODS: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. RESULTS: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. CONCLUSIONS: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.

Person with Heart Failure and Care Partner Dyads: Current Knowledge, Challenges, and Future Directions: State-of-the-Art Review.

Over the past decade, there has been substantial growth in heart failure (HF) research that focuses on persons with HF and their care partners (family members or other close friends that provide unpaid support) as an interdependent team, or care dyad. In this state-of-the-art review, we use a dyadic lens to identify and summarize current research on HF care dyads, from qualitative studies, to nonexperimental quantitative studies, to randomized controlled trials. Although much work has been done, this literature is younger and less well-developed than care dyad literatures from other conditions (eg, cancer, Alzheimer's disease). We discuss the substantial challenges and limitations in this body of work, with an eye toward addressing common issues that impact rigor. We also look toward future directions, and discuss the promise dyadic research holds for improving patient, care partner, and relationship health.

Cognitive, Disability, and Treatment Outcome Implications of Symptom-Based Phenotyping in Late-Life Depression.

OBJECTIVE: Late-life depression is associated with substantial heterogeneity in clinical presentation, disability, and response to antidepressant treatment. We examined whether self-report of severity of common symptoms, including anhedonia, apathy, rumination, worry, insomnia, and fatigue were associated with differences in presentation and response to treatment. We also examined whether these symptoms improved during treatment with escitalopram. DESIGN: Eighty-nine older adults completed baseline assessments, neuropsychological testing and providing self-reported symptom and disability scales. They then entered an 8-week, placebo-controlled randomized trial of escitalopram, and self-report scales were repeated at the trial's end. Raw symptom scale scores were combined into three standardized symptom phenotypes and models examined how symptom phenotype severity was associated with baseline measures and depression improvement over the trial. RESULTS: While rumination/worry appeared independent, severity of apathy/anhedonia and fatigue/insomnia were associated with one another and with greater self-reported disability. Greater fatigue/insomnia was also associated with slower processing speed, while rumination/worry was associated with poorer episodic memory. No symptom phenotype severity score predicted a poorer overall response to escitalopram. In secondary analyses, escitalopram did not improve most phenotypic symptoms more than placebo, aside for greater reductions in worry and total rumination severity. CONCLUSION: Deeper symptom phenotype characterization may highlight differences in the clinical presentation of late-life depression. However, when compared to placebo, escitalopram did not improve many of the symptoms assessed. Further work is needed to determine whether symptom phenotypes inform longer-term course of illness, and which treatments may best benefit specific symptoms.

Migraine and peripheral pain models show differential alterations in neuronal complexity.

OBJECTIVE: Our laboratory has recently shown that there is a decrease in neuronal complexity in head pain processing regions in mouse models of chronic migraine-associated pain and aura. Importantly, restoration of this neuronal complexity corresponds with anti-migraine effects of known and experimental pharmacotherapies. The objective of the current study was to expand this work and examine other brain regions involved with pain or emotional processing. We also investigated the generalizability of our findings by analyzing neuronal cytoarchitectural changes in a model of complex regional pain syndrome (CRPS), a peripheral pain disorder. METHODS: We used the nitroglycerin (NTG) model of chronic migraine-associated pain in which mice receive 10 mg/kg NTG every other day for 9 days. Cortical spreading depression (CSD), a physiological corelate of migraine aura, was evoked in anesthetized mice using KCl. CRPS was induced by tibial fracture followed by casting. Neuronal cytoarchitecture was visualized with Golgi stain and analyzed with Simple Neurite Tracer. RESULTS: In the NTG model, we previously showed decreased neuronal complexity in the trigeminal nucleus caudalis (TNC) and periaqueductal gray (PAG). In contrast, we found increased neuronal complexity in the thalamus and no change in the amygdala or caudate putamen in this study. Following CSD, we observed decreased neuronal complexity in the PAG, in line with decreases in the somatosensory cortex and TNC reported with this model previously. In the CRPS model there was decreased neuronal complexity in the hippocampus, as reported by others; increased complexity in the PAG; and no change within the somatosensory cortex. CONCLUSIONS: Collectively these results demonstrate that alterations in neuronal complexity are a feature of both chronic migraine and chronic CRPS. However, each type of pain presents a unique cytoarchitectural signature, which may provide insight on how these pain states differentially transition from acute to chronic conditions.

The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.

Recovery and concordance in a secure forensic psychiatry hospital - the self rated DUNDRUM-3 programme completion and DUNDRUM-4 recovery scales.

BACKGROUND: Detention in a secure forensic psychiatric hospital may inhibit engagement and recovery. Having validated the clinician rated DUNDRUM-3 (programme completion) and DUNDRUM-4 (recovery) in a forensic hospital, we set out to draft and validate scales measuring the same programme completion and recovery items that patients could use to self-rate. Based on previous work, we hypothesised that self-rating scores might be predictors of objective progress including conditional discharge. We hypothesised also that the difference between patients' and clinicians' ratings of progress in treatment and other factors relevant to readiness for discharge (concordance) would diminish as patients neared discharge. We hypothesised also that this difference in matched scores would predict objective progress including conditional discharge. METHOD: In a prospective naturalistic observational cohort study in a forensic hospital, we examined whether scores on the self-rated DUNDRUM-3 programme completion and DUNDRUM-4 recovery scales or differences between clinician and patient ratings on the same scales (concordance) would predict moves between levels of therapeutic security and conditional discharge over the next twelve months. RESULTS: Both scales stratified along the recovery pathway of the hospital, but clinician ratings matched the level of therapeutic security more accurately than self ratings. The clinician rated scales predicted moves to less secure units and to more secure units and predicted conditional discharge but the self-rated scores did not. The difference between clinician and self-rated scores (concordance) predicted positive and negative moves and conditional discharge, but this was not always an independent predictor as shown by regression analysis. In regression analysis the DUNDRUM-3 predicted moves to less secure places though the HCR-20 C & R score dominated the model. Moves back to more secure places were predicted by lack of concordance on the DUNDRUM-4. Conditional discharge was predicted predominantly by the DUNDRUM-3. CONCLUSIONS: Patients accurately self-rate relative to other patients however their absolute ratings were consistently lower (better) than clinicians' ratings and were less accurate predictors of outcomes including conditional discharge. Quantifying concordance is a useful part of the recovery process and predicts outcomes but self-ratings are not accurate predictors.

Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression.

E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions. In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine, if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95 % CI = 1.08-1.56) than with E-cadherin high tumors [OR = 1.06, 95 % CI = 0.95-1.18; case-only p-heterogeneity (p-het) = 0.05]. Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations.

HER-2 assessment in formalin-fixed paraffin-embedded breast cancer tissue by well-based reverse phase protein array.

BACKGROUND: The human epidermal growth factor receptor-2 (HER-2) expression level is a critical element for determining the prognosis and management of breast cancer. HER-2 targeted therapy in breast cancer depends on the reliable assessment of HER-2 expression status but current standard methods are lacking a rigorous quantitative assay. To address this challenge, we developed an assessment of HER-2 expression method by well-based reverse phase protein array (RPPA). RESULTS: Well-based RPPA is based on a robust protein isolation methodology paired with a novel electrochemiluminescence detection system. HER-2 value of well-based RPPA significantly correlated with dot blotting results (R(2) = 0.939). By well-based RPPA, we successfully detected HER-2 expression in 76 human breast formalin-fixed paraffin-embedded tissue samples. We observed 93.4% (71/76) concordance between well-based RPPA and current HER-2 immunohistochemical assessment guideline. When the cutoff level of HER-2 value was set to 0.689 (HER-2/GAPDH) on the basis of receiver-operating characteristic curve, the area under the curve was 0.975 (95% CI, 0.941-1.000). Sensitivity and specificity of well-based RPPA was 92.1% and 94.7%, respectively. CONCLUSIONS: HER-2 value by well-based RPPA was correlated with the current HER-2 status guideline, suggesting that this normalized HER-2 assessment may offer advantages over unnormalized current immunohistochemical assessment methods.

Financial Stressors for Parents of Children and Emerging Adults With Congenital Heart Disease: A Qualitative Study.

INTRODUCTION: Congenital heart disease (CHD) is the most prevalent congenital disability globally. This study aimed to describe parents' perspectives on financial stressors related to having a child with CHD using a descriptive qualitative approach. METHOD: Qualitative data were obtained from parents of children with CHD in a cross-sectional web-based survey study. Iterative data analysis was used to develop essential themes that enabled a rich description of 147 parents' perspectives. RESULTS: Parents identified five financial stressors: perpetual worries about health insurance, facing the dilemma of "making too much money," struggling to balance work, worrying over having an emerging adult with CHD, and constant constraints because of financial needs. DISCUSSION: As experts in pediatric care, pediatric advanced practice providers need to work with policymakers to provide further financial assistance and sufficient insurance coverage for families that struggle to balance finances for the whole family and children with CHD.

Assessment of endoscope reprocessing at World Gastroenterology Organisation training centers using adenosine triphosphate testing.

Background and study aims Adequacy of endoscope disinfection in resource-limited settings is unknown. Adenosine triphosphate (ATP) testing is useful for evaluation of endoscope reprocessing, and ATP <200 relative light units (RLUs) after manual endoscope cleaning has been associated with adequacy of endoscope disinfection. Methods Consecutive endoscopes undergoing reprocessing at five World Gastroenterology Organisation (WGO) training centers underwent ATP testing before and after an on-site educational intervention designed to optimize reprocessing practices. Results A total of 343 reprocessing cycles of 65 endoscopes were studied. Mean endoscope age was 5.3 years (range 1-13 years). Educational interventions, based on direct observation of endoscope reprocessing practices at each site, included refinements in pre-cleaning, manual cleaning, high-level disinfection, and endoscope drying and storage. The percentage of reprocessing cycles with post-manual cleaning ATP ≧200 decreased from 21.4% prior to educational intervention to 14.8% post-intervention ( P =0.11). In multivariable logistic modelling, gastroscopes were significantly less likely (odds ratio [OR] 0.04, 95% confidence interval [CI] 0.01-0.19; P <0.001) than colonoscopes to achieve post-manual cleaning ATP < 200. No other factor (educational intervention, study site, endoscope age) was significantly associated with improved outcomes. Endoscope ID was not significantly associated with ATP values, and sites that performed manual versus automated HLD did not have significantly different likelihood of post-manual cleaning ATP <200 (OR 1.18, 95% CI 0.56-2.50; P =0.67). Conclusions In resource-limited settings, approximately 20% of endoscope reprocessing cycles may result in inadequate disinfection. This was not significantly improved by a comprehensive educational intervention. Alternative approaches to endoscope reprocessing are needed.

Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry.

BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome. METHODS: The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated. RESULTS: HIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer. CONCLUSIONS: We demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

Shared care between specialised psychiatric services and primary care: the experiences and expectations of General Practitioners in Ireland.

Objective. The study aims to explore the views of General Practitioners in Ireland on shared care between specialised psychiatric services and primary care. Method. A self-administered questionnaire was designed and posted to 400 randomly selected General Practitioners working in Ireland. Results. Of the respondents, 189 (94%) reported that they would support a general policy on shared care between primary care and specialised psychiatric services for patients who are stable on their treatment. However, 124 (61.4%) reported that they foresaw difficulties for patients in implementing such a policy including: a concern that primary care is not adequately resourced with allied health professionals to support provision of psychiatric care (113, 53.2%); a concern this would result in increased financial burden on some patients (89, 48.8%); a lack of adequate cooperation between primary care and specialised mental health services (84, 41.8%); a concern that some patients may lack confidence in GP care (55, 27.4%); and that primary care providers are not adequately trained to provide psychiatric care (29, 14.4% ). Conclusion. The majority of GPs in Ireland would support a policy of shared care of psychiatric patients; however they raise significant concerns regarding practical implications of such a policy in Ireland.

The role of generalized linear models in handling cost and count data.

Scientists from nursing and allied health disciplines frequently examine data with complex distributions. Key examples include data on cost that typically are skewed, and count data like the number of hospitalizations that regularly have greater variation than expected and a majority of observations at zero. Common approaches to handling complex data involve transformations that can interfere with interpretation, or force-fitting of data into linear or logistic regression. In this article, worked examples of generalized linear models, which allow for flexibility in the distribution of data, involving cost and count outcomes, are presented to help expose researchers to their nuances.

The Effects of Exercise-Based Interventions on Fluid Overload Symptoms in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

Patients with heart failure are subjected to a substantial burden related to fluid overload symptoms. Exercise can help the lymphatic system function more effectively to prevent fluid build-up in tissues and interstitium, thus potentially mitigating the symptoms due to fluid overload. The objective of this systematic review was to examine the effects of exercise-based interventions on fluid overload symptoms among patients with heart failure. MEDLINE, Embase, Cochrane Library, and CINAHL databases were systematically searched for relevant studies published from inception to August 2021. We included randomized controlled trials that compared exercise-based interventions of different modalities and usual medical care for adult patients with heart failure and reported the effects of interventions on any symptoms related to fluid overload. A random-effects meta-analysis was used to estimate the effectiveness, and a subgroup analysis and univariate meta-regression analysis were used to explore heterogeneity. Seventeen studies covering 1086 participants were included. We found robust evidence indicating the positive effect of exercises in dyspnea relief (SMD = -0.48; 95%CI [-0.76, -0.19]; p = 0.001); the intervention length also influenced the treatment effect (ß = 0.033; 95%CI [0.003, 0.063]; p = 0.04). Initial evidence from existing limited research showed that exercise-based intervention had positive effect to alleviate edema, yet more studies are needed to verify the effect. In contrast, the exercise-based interventions did not improve fatigue compared with usual care (SMD = -0.27; 95%CI [-0.61, 0.06]; p = 0.11). Findings regarding the effects of exercises on bodily pain, gastro-intestinal symptoms, and peripheral circulatory symptoms were inconclusive due to limited available studies. In conclusion, exercise-based interventions can be considered as an effective nonpharmacological therapy for patients with heart failure to promote lymph flow and manage fluid overload symptoms. Exercise-based interventions seem to have very limited effect on fatigue. More research should investigate the mechanism of fatigue related to heart failure. Future studies with high methodological quality and comprehensive assessment of symptoms and objective measure of fluid overload are warranted.

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition.

Migraine is the sixth most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Migraines are a common brain disorder that affects 14% of the world's population. For many people the main symptom of a migraine is a painful headache, often on one side of the head. Other symptoms include increased sensitivity to light or sound, disturbed vision, and feeling sick. These sensory disturbances are called aura and they often occur before the headache begins. One particularly debilitating subset of migraines are chronic migraines, in which patients experience more than 15 headache days per month. Migraine therapies are often only partially effective or poorly tolerated, making it important to develop new drugs for this condition, but unfortunately, little is known about the molecular causes of migraines. To bridge this gap, Bertels et al. used two different approaches to cause migraine-like symptoms in mice. One approach consisted on giving mice nitroglycerin, which dilates blood vessels, produces hypersensitivity to touch, and causes photophobia in both humans and mice. In the second approach, mice underwent surgery and potassium chloride was applied onto the dura, a thick membrane that surrounds the brain. This produces cortical spreading depression, an event that is linked to migraine auras and involves a wave of electric changes in brain cells that slowly propagates across the brain, silencing brain electrical activity for several minutes. Using these approaches, Bertels et al. studied whether causing chronic migraine-like symptoms in mice is associated with changes in the structures of neurons, focusing on the effects of migraines on microtubules. Microtubules are cylindrical protein structures formed by the assembly of smaller protein units. In most cells, microtubules assemble and disassemble depending on what the cell needs. Neurons need stable microtubules to establish connections with other neurons. The experiments showed that provoking chronic migraines in mice led to a reduction in the numbers of connections between different neurons. Additionally, Bertels et al. found that inhibiting HDAC6 (a protein that destabilizes microtubules) reverses the structural changes in neurons caused by migraines and decreases migraine symptoms. The same effects are seen when a known migraine treatment strategy, known as CGRP receptor blockade, is applied. These results suggest that chronic migraines may involve decreased neural complexity, and that the restoration of this complexity by HDAC6 inhibitors could be a potential therapeutic strategy for migraine.

Image analysis as an adjunct to manual HER-2 immunohistochemical review: a diagnostic tool to standardize interpretation.

AIMS: Accurate determination of HER-2 status is critical to identify patients for whom trastuzumab treatment will be of benefit. Although the recommended primary method of evaluation is immunohistochemistry, numerous reports of variability in interpretation have raised uncertainty about the reliability of results. Recent guidelines have suggested that image analysis could be an effective tool for achieving consistent interpretation, and this study aimed to assess whether this technology has potential as a diagnostic support tool. METHODS AND RESULTS: Across a cohort of 275 cases, image analysis could accurately classify HER-2 status, with 91% agreement between computer-aided classification and the pathology review. Assessment of the continuity of membranous immunoreactivity in addition to intensity of reactivity was critical to distinguish between negative and equivocal cases and enabled image analysis to report a lower referral rate of cases for confirmatory fluorescence in situ hybridization (FISH) testing. An excellent concordance rate of 95% was observed between FISH and the automated review across 136 informative cases. CONCLUSIONS: This study has validated that image analysis can robustly and accurately evaluate HER-2 status in immunohistochemically stained tissue. Based on these findings, image analysis has great potential as a diagnostic support tool for pathologists and biomedical scientists, and may significantly improve the standardization of HER-2 testing by providing a quantitative reference method for interpretation.

Academy of Nutrition and Dietetics: Revised 2020 Standards of Practice and Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Intellectual and Developmental Disabilities.

Intellectual and developmental disabilities (IDD) encompass both intellectual disabilities (ID) and developmental disabilities (DD). In 2016, 7.37 million people in the United States and 200 million worldwide were identified with an ID or DD. Approximately 1 in 6 (17.8%) children have been identified with a DD in the United States, which is up from 16.2% in 2009-2011. Globally, 52.9 million children from birth to 5 years of age have been identified with a DD. Registered dietitian nutritionists (RDNs) have an important role in the treatment of this population, as optimizing nutrition status improves cognition and quality of life. The Behavioral Health Nutrition Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has revised the Standards of Practice (SOP) and Standards of Professional Performance (SOPP) for RDNs in Intellectual and Developmental Disabilities for 3 levels of practice-competent, proficient, and expert. The SOP uses the Nutrition Care Process and clinical workflow elements for care of individuals with an ID or DD. The SOPP describes 6 domains that focus on professionalism. Indicators outlined in the SOP and SOPP depict how these standards apply to practice. The SOP and SOPP are complementary resources for RDNs caring for individuals with an ID or DD. The SOP and SOPP are intended to be used by RDNs for self-evaluation to assure competent practice and for determining potential education and training needs for advancement to a higher practice level in a variety of settings.

Axonal blockage with microscopic magnetic stimulation.

Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted electrode holds promise in the treatment of these conditions. However, there are several limitations to its application, including poor bio-compatibility and decreased efficacy during chronic implantation. A magnetic coil of miniature size can mitigate some of these problems, by coating it with biocompatible material for chronic implantation. However, it is unknown if miniature coils could be effective in axonal blockage and, if so, what the underlying mechanisms are. Here we demonstrate that a submillimeter magnetic coil can reversibly block action potentials in the unmyelinated axons from the marine mollusk Aplysia californica. Using a multi-compartment model of the Aplysia axon, we demonstrate that the miniature coil causes a significant local depolarization in the axon, alters activation dynamics of the sodium channels, and prevents the traveling of the invading action potentials. With improved biocompatibility and capability of emitting high-frequency stimuli, micro coils provide an interesting alternative for electric blockage of axonal conductance in clinical settings.

Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial.

CONTEXT: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected. OBJECTIVE AND DESIGN: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue. RESULTS: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison's patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects. CONCLUSION: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.