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Psychiatric symptoms are frequently reported in Wilson disease (WD); however, systematic assessments with validated measures are lacking.We aim to report the prevalence and clinical correlates for major depressive disorder (MDD) as resulting from a multisite international WD registry.All patients enrolled in the WD registry received structured psychiatric evaluations (MINI International Neuropsychiatric Interview, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 scale, Perceived Stress Scale), laboratory tests, hepatology, and neurological assessments. We present the analysis of the data collected at enrollment for the first 3 years (N = 62).Thirty-seven percent (23) had a lifetime history (MDD), and 6% (4) met the criteria for an active major depressive episode. Depression was self-reported in 30.51% (19) at WD diagnosis. Patients with MDD had worse mental health quality-of-life (QOL) scores (median 43 vs 53.6, P = 0.006), higher severe anxiety (13.04% vs 0), higher perceived stress (median 18 vs 9, P0.003), and higher levels of neuroticism (median 8 vs 5.0, P = 0.002). We found no significant difference in physical health QOL and severity of neurological or liver disease. There was no significant difference in copper parameters or liver tests in those with MDD and without. The limitations of our study consist the small sample size, the cross-sectional report, and the lack of brain copper measurements.Lifetime MDD is highly prevalent in WD and associated with worse mental health QOL. We did not find a significant association among liver disease, neurological disease laboratory tests, and MDD. Screening for depression should be considered in patients with WD.

ABSTRACT Mental imagery is the mental re-creation of perceptual experiences, events and scenarios, and motor acts. In our previous study, we assessed whether motor imagery (MI) training combined with functional magnetic resonance imaging-based neurofeedback could improve the motor function of nondemented subjects with mild Parkinson’s disease (PD) (N=22). We used visual imagery (VI) (e.g., of scenes or events, but not of self-movements) training without neurofeedback for the control group (N=22). Notably, both groups showed significant and comparable improvement in motor function after four weeks of daily imagery practice. In this study, we further examined the neural correlates of the motor enhancement as a result of the VI training by analyzing the self-reported VI content during daily practice and relating its quality to the functional connectivity characteristics of the same subjects. We demonstrated that the VI practice encompassed multisensory, spatial, affective, and executive processes all of which are also important for motor function in real life. Subjects with worse global disease severity also showed poorer quality of the VI content. Finally, the quality of the VI content showed significant positive correlations with the functional connectivity changes during the VI tasks in brain areas supporting visuospatial and sensorimotor processes. Our findings suggest that mental imagery training combining VI and MI may enhance motor function in patients with mild PD, and more broadly, underline the importance of incorporating self-reports of thoughts and experiences in neuroimaging studies that examine the brain mechanisms of complex cognitive processes especially in neuropsychiatric patient populations.

Introduction: For patients diagnosed with central retinal artery occlusion (CRAO), timely screening for underlying risk factors to prevent secondary stroke and other cardiovascular events is required. Given the profound impact on vision, there is also great interest in the potential to treat CRAO. Thrombolytic therapy is the current standard of care in acute ischemic cerebral stroke, but the window for administration is short. As part of a larger pilot to investigate the prospect of intravenous thrombolysis for patients presenting with acute CRAO in our institution, we set out to evaluate the specific presentation patterns of this population within our system. Methods: Retrospective study performed on 804 patients correctly diagnosed with CRAO from 2011-2020. From this cohort of patients, we identified 484 for whom we could accurately determine the time of first symptoms, the time of first contact with the healthcare system, and the time of evaluation by an ophthalmologist. Results: While 18.0% (87/484) of patients waited over 24 hours from time of vision loss to contact the health care system, 50.2% of patients did connect in under 4.5 hours (243/484). However, only 16.7% (81/484) of patients saw an ophthalmologist within that window, and 35.5% (172/484) did not have any ophthalmologic evaluation within 24 hours of vision loss. Conclusion: Half of CRAO patients within our institution connect with the health care system within a potential window for intravenous thrombolytic treatment, but the majority do not receive ophthalmic diagnosis within that time frame. In conclusion, public health education efforts to speed up presentation times and system-based strategies to decrease the time to ophthalmic diagnosis are needed if thrombolytic treatment either via compassionate use or within a clinical trial setting is to be more widely offered.

Background: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. Methods: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18–75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25–150 μg/L), 24 h urinary copper excretion (100–900 μg/24 h), and alanine aminotransferase (ALT

Wilson disease (WD) is a chronic disorder of copper metabolism which may affect patient's quality of life (QOL).Our aim was to assess the relationship between mental QOL (M-QOL) and physical QOL (P-QOL) and severity of the liver, neurological disease and mental health in patients with WD.At enrollment into our multisite international WD registry, adults (n = 62) were administered examinations assessing QOL (Short-Form 12-Item Health Survey), cognition, and mood. Patients also underwent hepatology and neurological assessments.Patients had lower M-QOL than P-QOL scores, P = 0.0006. Patients with major depressive disorder (n = 22) had worse M-QOL scores, P = 0.0017 but not P-QOL. We found no association with impaired cognition (n = 37) and QOL. The P-QOL scores have a moderate negative association with neurological disease severity based on the Unified Wilson Disease Rating Scale score (total [r = -0.38, P0.003], part 2 [r = -0.50, P0.0001], and part 3 [r = -0.37, P = 0.004]). M-QOL was not associated with Unified Wilson Disease Rating Scale scores. Worse P-QOL, but not M-QOL, was found in higher cirrhosis severity indicated by Child-Pugh (r = -0.80, P = 0.002) and Model for End Stage Liver Disease scores (r = -0.64, P = 0.03).M-QOL was associated with depression but not cognitive impairment, neurological disease, or liver disease severity, suggesting that mental health issues may affect overall QOL independent of the degree of liver or neurological disease. P-QOL was affected by the severity of neurological and liver disease but not mental health but also contributes to overall QOL in WD. An appreciation of the range of problems that affect QOL in adults with WD will help health care providers address issues that could improve overall well-being. The Short-Form 12-Item Health Survey may provide a useful instrument for QOL surveillance in WD.

Increased competition in market has forced small and medium scale industries to re-examine ways of manufacturing. For many years large scale industries have implemented lean to sustain in the business. Small and medium scale productions avoided to use lean tools due to monetary factors. The fruitfulness of lean execution in large scale sector now realized benefits focusing extreme need in small scale industries also. In this work it is aimed to present a framework of lean implementation using primary lean tools. Future state Value Stream Map and proposed String Diagram are developed and implemented indicating the improvement proposal and possible time reductions as a result of modification. Efforts are made in eliminate wastes in production flow line using various lean tools. As a result it reduced waiting time from 645 min to 462 min, productivity increased from 50% to 70% and material movement reduced from 283.08 m to 153.92 m.

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.

Increased competition in market has forced small and medium scale industries to re-examine their methods of doing business. Corrosion cannot be eliminated completely and considered as major problem in industries. In Last decades industries have implemented corrosion prevention technique in order to sustain the competitive market. pH level of water used by customers based on geographic location and heating cycle affects most on metal parts of water heater. It results in pitting corrosion and reduction of life cycle with increased maintenance cost. Corrosion issues needs to be properly understood with prescribe necessary kind of treatment to ensure a long life span of the water heater. Many factor affects the material such as temperature, presence of moisture, reduced performance due to environmental effect and life of the water heater. Life cycle is improved when both inhibitor and protective coating method such as galvanizing, thermal spraying sacrificial method, impressed current, Zinc paint are used together or when protective coating is used together with cathodic protection. In present work authors have made an attempt to study Industrial economic aspects of corrosion issues in water heater and its prevention techniques analysis. Effect of galvanizing in various environments such as normal water, heated water and salty water is tested on metal parts and it has shown significant reduction in corrosion. Study of various corrosion prevention technique is focused on reduction in corrosion rate there by reducing the rework.

Background: Diabetes, hypertension, obesity, and dyslipidemia, all are the risk factors of metabolic syndrome (MS). Various studies have shown that each risk factor is associated with increased inflammation. hsCRP is a non-specific, sensitive inflammatory marker that is raised in various inflammatory conditions. Similarly, glutathione is an antioxidant which binds with ROS produced during inflammation and reduces damage caused by ROS. Aims and Objectives: This study has been planned to find the correlation between oxidative stress and metabolic risk factors in apparently healthy adults. Materials and Methods: We recruited apparently healthy adults (n = 120) and measured waist circumference, blood pressure, lipid profile, Fasting blood sugar, serum GSH, and hsCRP in all the subjects. Seventy-seven subjects were found to have at least one or more metabolic risk factors (Group A) according to NCEP ATP III criteria with waist circumference >90 cm for male and >80 cm for female and 43 were without any metabolic risk factors (Group B). Thereafter, we compared the serum levels of hsCRP and serum GSH with persons having one or more risk factors for MS. Results: In this study, we observed that subjects with metabolic risk factors were having more oxidative stress indicated by increased hsCRP (4783.1 ± 2060.21) and low serum GSH (3.17 ± 0.81) in comparison to controls (1640.5 ± 547.47 and 4.79 ± 0.77, respectively). This increase in hsCRP and decrease in GSH in case group was statistically significant. We also found the higher basal hsCRP levels in control group as per AHA/CDC study. Conclusion: We observed in this study that Indians without any risk factors for MS have relatively higher CRP levels and are at intermediate risk for cardiovascular disease. It was also observed that as the number of metabolic risk factors increases, the levels of hsCRP increases, and serum GSH decreases. This indicates that more risk factors are associated with higher oxidative stress.

We aimed to determine suicide risk and lifetime suicidal ideation in Parkinson disease (PD) patients versus controls and how depression, demoralization, and insomnia are associated with suicidality. In this case–control study, PD patients and matched controls were recruited from movement disorder clinics, Michael J. Fox Foundation, and Research Match websites. Suicide risk and suicidal ideation were assessed using the Suicidal Behavior Questionnaire-revised (SBQ-R) and Columbia-Suicide Severity Rating Scale. Lifetime depression was assessed using the Brief Lifetime Depression Scale, sleep using Insomnia Severity Index (ISI), demoralization using Diagnostic Criteria for Psychosomatic Research and Kissane Demoralization Scales, and non-motor symptoms using UPDRS Non-Motor Aspects of Experiences of Daily Living scale (nM-EDL). 186 PD participants and 177 controls were matched for age (64.2 ± 7.7 years), sex (48.8% female), and socioeconomics. PD participants were not more likely than controls to have high suicide risk (SBQ-R ≥ 7) (7.5% vs. 11.3%; p = 0.22) or to have had a lifetime suicide plan or attempt (2.7% vs. 5.1%; p = 0.24), but were less likely to have had lifetime suicidal ideation (23.1% vs. 35.0%; p = 0.01). PD participants were more likely than controls to have lifetime depression history (34.4% vs. 20.9%; p = 0.004), and demoralization (19.9% vs. 10.7%; p = 0.02), and had higher ISI scores (8.7 ± 5.8 vs. 5.1 ± 4.5; p

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

Background: Human herpesvirus-6 (HHV-6) has been associated with various neurologic disorders, but movement disorders are rare. This case describes a patient who developed a choreoathetotic movement disorder in the setting of HHV-6 infection. Case Report: A 72-year-old woman with AML and recent HHV-6 encephalitis following stem cell transplant presented with involuntary movements. Neurologic examination demonstrated motor impersistence and irregular non-stereotyped writhing movements consistent with a choreoathetotic movement disorder secondary to HHV-6 infection. Discussion: This is the first literature reported case of adult-onset chorea associated with HHV-6 infection, though it remains unclear if the movement disorder was from the infection or a secondary autoimmune response.

e18529 Background: Cancer incidence is higher in AYA women compared to men and is increasing. National trends by race/ethnicity and region for AYA women in the U.S. are needed to improve health care outcomes. Methods: Data about the top ten cancers 2001-2017, race/ethnicity, and 9 CDC divisions were extracted from US Cancer Statistics Public databases encompassing 99% of US population. Age-adjusted incidence and its annual percent change (APC) were generated using SEER*Stat and trends analyzed via joinpoint regression. All statistical tests were two sided. Results: The top ten cancers in AYA women were: breast (incidence of 26.7 per 100,000), thyroid (16.0), melanoma (11.5), cervical (8.8), colorectal (4.1), uterine (3.5), non-Hodgkin lymphoma (3.6), Hodgkin lymphoma (4.0), and leukemia (3.1). Hispanic women had the highest incidence of uterine and cervical cancer and leukemia. Incidence of breast and colorectal cancer and non-Hodgkin lymphoma was highest in NH Black. Thyroid and colorectal cancer, melanoma, and Hodgkin lymphoma incidences were highest in NH White. Incidence trends included: 1) rise in breast (APC 0.5%), uterine (2.9%) in 2001-2017, and colorectal cancer (2.2% 2001-2013; 6.7% 2013-2017); 2) thyroid cancer (APC 2.1-7.2%) 2001-2015; (-5.7%) 2015-2017; 3) melanoma (-1%) 2005-2017; 4) cervical cancer (-1.4%) 2001-2013; 5) non-Hodgkin lymphoma (-0.5%) in 2007-2017; 5) Hodgkin lymphoma (-0.9%) 2007-2017; 6) leukemia (2.4%) 2001-2012 (p < 0.05). Incidence trends by race/ethnicity included: 1) breast cancer rise in all groups except for NH Black; 2) thyroid cancer rise in all 2001-2015; fall in NH White 2015-2017; 3) melanoma fall in Hispanic and NH Other, rise in NH White 2001-2005); 4) cervical cancer decline in all, Hispanic 2001-2013; 5) colorectal and uterine cancer rise in all; 6) fall in non-Hodgkin lymphoma in NH Black 2005-2017; rise in NH Other; 8) fall in Hodgkin lymphoma in NH White; 7) ovarian cancer rise in Hispanic; 8) leukemia rise in all, NH black 2001-2015 (p < 0.05). Division incidence trends included: 1) breast cancer rise in New England and Middle Atlantic (APC 0.7%); 2) colorectal cancer rise in New England (3.5%) and Mountain (4%); 3) melanoma fall in West South Central (-1.1%); 4) cervix cancer fall in West South Central (-0.3%) and South Atlantic (-0.7%); 5) uterine cancer rise in East North Central (2.3%), South Atlantic (3.0%), and West South Central (4.3%); 6) non-Hodgkin lymphoma rise (0.54%) in Pacific; 7) leukemia rise in South Atlantic (2.4%) and West South Central (0.9%) (p < 0.05). Conclusions: Breast, colorectal, uterine cancer, and leukemia incidence rose in AYA women, while thyroid and cervical (2001-2013) cancer, melanoma and lymphoma incidence fell, with variation by race/ethnicity and division. Research to describe environmental, lifestyle, and healthcare/policy factors and correlate them with outcomes is an urgent unmet need to improve equity in cancer outcomes.

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.

Injector well completions are typically carried out using two methods: simple and selective. The performance of injector wells has traditionally been evaluated using spinner-based injection logging tools (ILTs) or on-demand fiber optic distributed temperature and acoustic (DTS or DAS) sensing while logging the well performance every 3 months or once a year depending on the application. However, with such methods utilizing a snap shot approach, critical well performance information or possible anomalies are often missed due to measurements taken only during certain periods. Therefore, operators have explored the use of advanced fiber-optics methods such as permanent distributed temperature sensing (DTS) and permanent distributed acoustic sensing (DAS), that provide continuous, real-time measurements to enable understanding of dynamic well behavior at all times and mitigate any deferred or behavioral problems. Of relevance to this work is a vertical, injector well in a competent sandstone formation of the Heavy Oil Chichimene field in Llanos Basin, Colombia. As a first step of the fiber-optics monitoring strategy, a careful evaluation of DTS and DAS based fiber-optics methods was conducted. Based on the data analysis and operational history, DAS-based fiber optics monitoring was chosen as the most effective monitoring solution for this well. Subsequently, a proprietary DAS algorithm was developed to analyze the data and estimate the flow allocation for all the four zones. The results include waterfall acoustic energy maps, temporal flow allocation profiles and most importantly, the zonal flow allocation values. Predicted (DAS) zonal flow allocation data was compared with traditional injection logs (ILT) under different operational conditions (varied injection flow rates and valve choke settings). Based on comparable agreement between DAS and ILT data, the operator decided to replace ILT runs with DAS-based fiber optic monitoring, resulting in lower operational costs while enabling near real-time monitoring, and providing the continuous distributed data essential for the dynamic monitoring of the well. The successful application of fiber-optics monitoring to provide an injection profile in conjunction with a surface-controlled electric valve system demonstrates a significant potential to optimize the injection process in complex injector wells. Further, remotely controlling, monitoring and optimizing injection rates into the multi-segmented zones improves the service life of the injection operations, eliminates future intervention costs, and increases ultimate recovery.

Introduction: Demoralization is quite prevalent in patients with Parkinson disease (PD). Unrecognized or untreated, demoralization may progress, at times, to demands for euthanasia and the desire for suicide. Typically, patients with PD do not complain of being “demoralized”; rather, they report disruptions in the quality of their lives. Hence, early identification of disruptions in health-related quality of life (HRQoL) specifically associated with demoralization may prompt earlier recognition and treatment. Published data on such associations, however, could not be found. Alleviation of demoralization in PD is likely to improve treatment outcomes. Objective: This research aimed at identifying the disruptions of HRQoL specifically associated with the demoralization of patients with PD. Methods: Consecutive general hospital outpatients with PD (n = 95) were assessed for: demoralization, with the Diagnostic Criteria for Psychosomatic Research Demoralization Scale (DCPR-D) and the Demoralization Scale (DS); depression, with the Patient Health Questionnaire-9 (PHQ-9); HRQoL, with the Parkinson Disease Questionnaire-Short Form (PDQ-8); sociodemographic variables; medical comorbidities; PD severity; and types of treatment. Results: The prevalence of demoralization was 19%. Regression analyses showed that demoralization was significantly more likely to be experienced by participants who had difficulty with mobility and felt embarrassed in public due to having PD. Demoralization explained HRQoL over and above depression. Conclusions: Stigma and perceived difficulty with mobility are associated with demoralization of PD patients, and they may signal the need for psychotherapeutic and behavioral interventions to prevent the progression to helplessness, hopelessness, demands for euthanasia, and desire for suicide.

Background Wilson Disease (WD) can result in a number of physical and mental health issues due to copper toxicity affecting the liver and brain. It is no longer acceptable to look at survival alone as an outcome measure in chronic disease. Our aim was to a) assess quality of life (QOL) in WD b) assess the relationship between mental health QOL (M-QOL) and physical health QOL (P-QOL) and severity of liver and neurological disease and mental health issues (major depressive disorder (MDD) and cognitive impairment). Methods Adult WD patients in the WD registry study (n=52), were evaluated at enrollment over 1.5 y using questionnaires and administered exams assessing QOL (SF-12), cognition (MOCA) and mood (MINI-7). Patients also underwent hepatology and neurological assessments (UWDRS). Results Adult patients with WD had lower M-QOL scores compared to P-QOL scores median 50.2 (range 19.3–62.2) vs. 56.0 (range 23.9–64.7), p=0.0018 indicating that the burden of mental health issues in WD is greater than that of physical health issues on quality of life. Eleven patients had cirrhosis based on review of imaging, APRI and Fib4 scores. There was no significant difference in M-QOL scores in patients with cirrhosis vs. those without (median 54.5 (range 26.2–59.7) vs 46.5 (range 19.3–62.2), p = 0.11. Similarly, there was no significant difference in P-QOL in patients with cirrhosis vs. those without (median 55.7 (range 44.4–59.9) vs. 56.3 (range 23.9–64.7), p = 1.00. In those with cirrhosis, higher Child-Pugh scores were associated with a worse P-QOL (r=-0.84, p=-.0011) and M-QOL (r=-0.60, p=0.0488). Patients with lifetime MDD (n=22) had worse M-QOL scores compared to those without MDD (median 42.3 vs 54.6, p The P-QOL scores have a moderate negative association with the neurological UWDRS II Score (r=-0.44, p=0.001), UWDRS III Score (r=-0.42, p= 0.002) and total UWDRS score (r=-0.44, p=0.001). There are no associations with M-QOL and neurological UWDRS scores. Conclusions While overall QOL in WD is affected by both mental and physical health, patients with WD have worse M-QOL than P-QOL scores and mental health issues may affect WD patient’s QOL independent of their degree of liver or neurologic disease. Multivariate regression will be performed to evaluate if mental health issues are independently associated with QOL.

Introduction Mental health problems are underappreciated in Wilson disease (WD) (Schaefer et al. 2016). We aimed to determine: i) the prevalence and clinical features of major depressive disorder (MDD) in adults with WD ii) whether MDD correlates with liver and neurological disease and quality of life (QOL). Method A multi-site international WD registry was developed and initiated in December 2017. At enrolment adults (n=55) were evaluated using questionnaires and administered exams assessing cognition, mood, psychosis, substance use, anxiety, perceived stress, personality change and QOL. MDD was determined using the investigator led MINI-7 questionnaire. Patients also underwent hepatology and neurological assessments (UWDRS). We reviewed patient reported depression at first presentation and diagnosis. Statistical analysis using SAS9.4 (SAS Institute; Cary, NC) included summary statistics, Wilcoxon Rank Sum test and categorical comparisons using Chi-squared or Fisher’s exact test. Results Depression was reported in 26% at first presentation of WD (33% at diagnosis). At enrolment 35% had a lifetime history of MDD. At evaluation 5 patients with lifetime MDD took antidepressants; 1 without. At enrolment 36.33% were suffering from symptoms of current depression based on the PHQ-9 (self-administered). Cirrhosis was present in 24% based on imaging, APRI and Fib4 scores. There was no association between cirrhosis and depression symptomology (PHQ-9 score >9). In those with depression symptomology, 1 had cirrhosis and 6 did not. Liver disease severity did not differ in cirrhotics with MDD and those without (median Child-Pugh 5 (5–9) vs. 5 (5–9), p=0.13). Two patients (1 with MDD) took medication for hepatic encephalopathy. No significant difference in neurological total UWDRS scores was found in those with MDD vs. without (median 8 (0–73) vs. 4 (0–40), p=0.22). A neurological UWDRS total score >0 was not associated with lifetime MDD status (79% vs. 81%, p=1.00). Patients with MDD had worse mental health QOL (median 43 vs. 52.7 p=0.042), more suicidal ideation (32% vs. 8%, p=0.05), higher anxiety (p=0.008), higher perceived stress (median 19 vs. 9, p=0.007), and more neuroticism (median 7 vs. 4.5, p=0.006). We found no significant difference in physical health QOL in MDD (median 55.6 vs. 56.3, p=0.69). Conclusion MDD is highly prevalent in WD and associated with worse mental health QOL. The risk appears higher than other liver diseases (Lee et al. 2013. Psychosomatics, 4:52–9). We did not find an association between the severity of liver, neurological disease and MDD. Screening for depression should be considered in patients with WD.

Clinical Vignette: A 64-year-old man with essential tremor (ET) and Parkinson’s disease (PD) presented with medically refractory, large amplitude, debilitating rest and action tremor in his extremities. Clinical Dilemma: Ventral intermediate nucleus of the thalamus (VIM) deep brain stimulation (DBS) improves tremor in ET and PD but does not ameliorate bradykinesia and rigidity in PD. The comparative efficacy of subthalamic nucleus (STN) DBS in managing action ET tremor remains unclear. Clinical Solution: Bilateral STN was selected as the DBS target. Moderate improvement in rest tremor and mild improvement in action tremor were noted following initial programming. Gap In Knowledge: There are no head-to-head trials to guide DBS target selection in patients with both ET and PD. Current evidence is limited to a few small head-to-head trials that have demonstrated equivalent efficacy in tremor reduction in PD patients using VIM as DBS target and in ET patients using STN. Expert Commentary: Due to limited evidence, DBS treatment of complex cases, such as combined Parkinson’s disease and essential tremor, remains based on expert consensus at each institution. Further multi-approach efforts, using imaging, electrophysiologic, and animal data, will be needed to answer the identified gap in knowledge. Highlights: There is limited evidence to guide deep brain target selection in patients with essential tremor and Parkinson’s disease. We review existing literature and propose strategies to manage tremor in these patients.

Introduction In many neurology residency programs, outpatient neurology subspecialties are underrepresented. Trainee exposure to these subspecialties, including movement disorders, is limited by paucity and variability of clinical experiences. We designed a structured educational tool to address this variability and allow for standardization of elements of movement disorders teaching. Methods We designed and implemented a web-based curriculum in movement disorders for neurology housestaff, in order to improve participant knowledge. The curriculum includes an introduction with a structured framework for the description of abnormal movements and 10 interactive modules focusing on common movement disorders. The curriculum was piloted with nine neurology housestaff at Yale-New Haven Hospital. Evaluation of the curriculum was performed using pre- and post-tests, a survey, and semi-structured interviews. Results The mean pre-test score was 0.7 (±0.19), and the mean post-test score was 0.95 (±0.05) (t = 3.27). Surveys demonstrated mean Likert values >4/5 for all questions in all categories (knowledge acquisition, quantity, enthusiasm and technical). Semi-structured interviews revealed the following themes: 1) the modules increased participant comfort with the topic, 2) the format was engaging, and 3) the curriculum accommodated different learning styles. All participants remarked that the structured framework was a particular strength. Conclusion We have created, implemented, and evaluated a foundational curriculum in movement disorders for neurology trainees, using readily-available technology. Housestaff responded positively to the curriculum, both in terms of content and format. This curriculum can be implemented in a variety of educational settings, as a central component of a standardized approach to movement disorders teaching., Highlights • Neurology housestaff find interactive, online modules to be an acceptable and engaging supplement to their training. • Neurology housestaff learn from online modules as demonstrated by survey and by pre- and post-testing. • Neurology housestaff respond well to simple algorithms to approach movement disorders.

Clinical vignette: A 51-year-old man with essential tremor (ET) had bilateral ventralis intermedius nucleus deep brain stimulation (VIM-DBS) placed to address refractory tremor. Despite well-placed DBS leads and adequate tremor response, he subsequently experienced worsening. Re-programming of the device and reconfirming the electrical thresholds for benefits and side effects were both performed. Six years following DBS implantation, repeat imaging revealed brain atrophy and a measured lead position change with a coincident change in clinical response. Clinical dilemma: What do we know about brain atrophy affecting lead placement and long-term DBS effectiveness? What are the potential strategies to combat narrowed therapeutic thresholds and to maximize DBS therapeutic benefit? Clinical solution: Decreasing the electrical field of stimulation and programming in a bipolar configuration are strategies to provide symptomatic tremor control and to minimize stimulation-induced side effects. Gaps in knowledge: Currently, effects of brain atrophy, and factors underpinning emergence of side effects and/or loss of benefit in chronic VIM-DBS remain largely unexplored.

ObjectiveTo determine the prevalence and associated features of demoralization in Parkinson disease (PD).MethodsParticipants with PD and controls were prospectively recruited from outpatient movement disorder clinics and the community. Demoralization was defined as scoring positively on the Diagnostic Criteria for Psychosomatic Research, Demoralization questionnaire or Kissane Demoralization Scale score ≥24. Depression was defined as Patient Health Questionnaire-9 score ≥10. Forward stepwise logistic regression was used to determine the odds of having demoralization in the overall, control, and PD cohorts.ResultsDemoralization occurred in 18.1% of 94 participants with PD and 8.1% of 86 control participants (p = 0.05). These 2 groups were otherwise comparable in age, sex, education, economics, race, and marital status. Although demoralization was highly associated with depression, there were individuals with one and not the other. Among participants with PD, 7 of 19 (36.8%) depressed individuals were not demoralized, and 5 of 17 (29.4%) demoralized individuals were not depressed. In the overall cohort, having PD (odds ratio 2.60, 95% confidence interval 1.00–6.80, p = 0.051) was associated with demoralization, along with younger age and not currently being married. In the PD cohort, younger age and Unified Parkinson's Disease Rating Scale, part III score (per score 1) were associated with demoralization (odds ratio 1.06, 95% confidence interval 1.01–1.12, p = 0.02).ConclusionsDemoralization is common in PD and is associated with motor dysfunction. In demoralization, there is a prominent inability to cope, making it somewhat distinct from depression. Treatment approaches are also different, making it important to identify demoralization in patients with PD.

An oil and gas company's arc flash electrical safe operations program is a corporate initiative to prevent electrical arc flash injuries. The program implements the company general instruction—electrical arc flash hazard mitigation, which provides minimum safe work requirements for protection of personnel in the workplace against electrical arc flash hazards in accordance with the National Fire Protection Agency 70E. The program tracks five key performance indicators (KPIs) to protect employees from arc flash hazards in all company facilities, which are as follows: 1) technology deployment; 2) training and certification; 3) operation and maintenance delineation; 4) operation and maintenance unified procedures; and 5) arc flash analysis. To verify compliance, the company initiated field-based assessments conducted by a specialized team of Power Systems Compliance and Electrical Engineers. The assessments are designed to validate each facility's compliance as well as to identify any opportunities for improvement in the application of arc flash mitigation. The assessors utilized a standardized checklist to determine the level to which established KPIs have been implemented. The checklists are weighted and scored to validate compliance in a consistent manner. This paper demonstrates a structured approach to measure arc flash KPI compliance and highlights some findings and practical examples that can be applied at many oil and gas facilities.

Introduction : CD47, a cell-surface ligand overexpressed in various malignancies, binds to SIRPα on effector macrophages to promote tumor cell evasion of phagocytosis. Blockade of the CD47-SIRPα interaction provides a pro-phagocytic signal which enhances phagocytosis mediated by tumor-targeting antibodies such as rituximab. Agents targeting CD47 in combination with rituximab have demonstrated promising clinical activity in R/R NHL; however, the broad expression of CD47 leads to frequent on-target, off-tumor toxicities, including treatment-emergent hemolytic anemia. CC-95251 is a novel, fully human immunoglobulin G1 antibody that binds to SIRPα on monocytes and macrophages to potently block the CD47-SIRPα interaction. Here we report interim results from a phase 1 study evaluating CC-95251 combined with rituximab in patients (pts) with R/R NHL. Methods: CC-95251-ST-001 (NCT03783403) is a multicenter, open-label, phase 1, dose-escalation and expansion study of CC-95251 in pts with advanced solid tumors and CD20+ R/R NHL. The primary objectives of the dose-escalation stage presented here are to evaluate the safety and tolerability of escalating doses of CC-95251 combined with rituximab and to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose for the combination in pts with R/R NHL. Pts with CD20+ NHL who had progressed on standard anticancer therapy or for whom no approved conventional therapy was available were eligible for inclusion. Dose-escalation was conducted using an adaptive, 2-parameter Bayesian logistic regression model with overdose control. Pts were treated in 28-day cycles with CC-95251 administered intravenously at 3, 10, or 20 mg/kg every week (QW) and rituximab 375 mg/m 2 given on days 1, 8, 15, and 22 of cycle 1, on day 1 of cycles 2-5, and on day 1 of every other cycle from cycle 6 to 24 until disease progression or unacceptable toxicity. Results: As of April 30, 2021, 18 pts were enrolled and 17 had received ≥ 1 dose of CC-95251 and rituximab. Median age of the enrolled study population was 69 (range 30-84) years. Treated pts had received a median of 4 (range 1-7) prior systemic therapies, including 14/17 (82%) pts with confirmed prior rituximab exposure. Enrolled tumor types included R/R diffuse large B-cell lymphoma in 14 (78%) pts, follicular lymphoma in 2 (11%), and mantle cell lymphoma and marginal zone lymphoma in 1 (6%) pt each. Of the pts with available response data for prior lines of therapy (LOT), 7 (41%) had disease confirmed to be refractory to any prior LOT, including 5 (29%) refractory to rituximab-containing regimens, and 5 (29%) to their last LOT. Pts received a median of 3 (range 1-12) cycles of CC-95251, with a median duration of treatment of 14.1 (range 1.1-47.3) weeks. There were no CC-95251 dose reductions. Five (29%) pts experienced ≥ 1 treatment-emergent adverse events (TEAEs) leading to CC-95251 dose interruption. To date, the MTD has not been reached for the combination of CC-95251 and rituximab. The most common (≥ 30%) TEAEs of any grade were neutropenia (11/17 [65%]), infections (9/17 [53%]), hypokalemia (6/17 [35%]), and hypomagnesemia (6/17 [35%]; Table). Grade ≥ 3 TEAEs reported in ≥ 2 pts were neutropenia (9/17 [53%]) and infections (4/17 [24%]). No treatment-related anemia, a notable toxicity of some anti-CD47 therapies, was reported with CC-95251 and there were no treatment-related deaths. The overall response rate was 41% (7/17), with 2/17 (12%) pts achieving a complete response (Figure). The median time to response was 7.6 weeks. Median duration of response has not been reached as responses are ongoing. Pharmacokinetic (PK) analysis showed that CC-95251 exhibited dose-proportional increases in exposure at doses > 3 mg/kg QW indicating saturation of nonlinear clearance pathways or target saturation. Full receptor occupancy on peripheral monocytes was achieved at doses > 3 mg/kg QW. The estimated terminal half-life when in the linear range of clearance was approximately 12 days. No substantial differences in PK were observed at the given dose levels for CC-95251 monotherapy versus CC-95251 combined with rituximab. Conclusions: CC-95251, a novel anti-SIRPα antibody, demonstrated a manageable safety profile and promising efficacy in combination with rituximab in pts with heavily pretreated CD20+ R/R NHL. The study continues to enroll in the dose-expansion phase. Updated safety and efficacy data will be presented. Figure 1 Figure 1. Disclosures Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Hawkes: Regeneron: Speakers Bureau; Specialised Therapeutics: Consultancy; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Ghosh: Karyopharma: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genentech: Research Funding; AbbVie: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau. Tuscano: BMS, Seattle Genetics, Takeda, Achrotech, Genentech, Pharmacyclics, Abbvie: Research Funding. Chu: Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; BI: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Eli Lilly: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck KgaA: Other: DSMB. Patel: Bristol Myers Squibb: Current Employment. Burgess: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hege: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chhagan: Bristol Myers Squibb: Current Employment. Boyanapalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Day: Tracey Day: Current Employment. Shen: Bristol Myers Squibb: Current Employment. Mehta: Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy.