Microporous Ag/AgCl on a Titanium Scaffold for Use in Capillary Reference Electrodes.

AgCl-coated silver fabricated with the thermal-electrolytic method can be used to prepare more reproducible reference electrodes than Ag/AgCl prepared with alternative methods such as electrolytic and chemical AgCl deposition or thermal fabrication. However, thermal-electrolytic fabrication requires a scaffold material upon which to build the layers upon. Platinum and rhodium have been used for this purpose as they are mechanically strong and chemically inert, but their cost is prohibitive for wider application. Herein, we report the stability of Ag/AgCl reference electrodes built atop a titanium scaffold using the thermal-electrolytic method and the use of these Ti/Ag/AgCl constructs in capillary-based reference electrodes. Electrochemical characterization shows that the probable presence of small amounts of oxygen at the Ti/Ag interface does not affect the reference electrode performance; in particular, over a wide pH range, the half-cell potential is pH independent. The electrical resistance of the Ti/Ag/AgCl/KCl system is dominated by the charge transfer resistance at the interface of the AgCl to KCl solution but is kept very small by the large AgCl surface area and a high solution concentration of chloride. The resulting high exchange current minimizes the effect of system impurities on the reference half-cell potential. Capillary-based reference electrodes comprising Ti/Ag/AgCl show exceptionally low potential drifts (as low as 0.03 ± 2.01 µV/h) and standard deviations of the potential at or below ±0.5 mV over a 60 h period. These capillary-based reference electrodes are suitable for very small sample volumes while still providing a free-flowing liquid junction that prevents reference electrode contamination.

Improvement of the Upper Detection Limit of Ionophore-Based H+-Selective Electrodes: Explanation and Elimination of Apparently Super-Nernstian Responses.

The response range of an ion-selective electrode (ISE) has been described by counterion interference at the lower and Donnan failure at the upper detection limit. This approach fails when the potentiometric response at the upper detection limit exhibits an apparently super-Nernstian response, as has been reported repeatedly for H+-selective electrodes. While also observed when samples contain other anions, super-Nernstian responses at low pH are a problem in particular for samples that contain phthalate, a common component of commercial pH calibration solutions. This work shows that coextraction of H+ and a sample anion into the sensing membrane alone does not explain these super-Nernstian responses, even when membrane-internal diffusion potentials are taken into account. Instead, these super-Nernstian responses are explained by the formation of complexes between that anion and at least two protonated ionophore molecules. As demonstrated by experiments and explained with quantitative phase boundary models, the apparently super-Nernstian responses at low pH can be eliminated by restricting the molecular ratio of ionophore and ionic sites. Notably, this conclusion results in recommendations for the optimization of sensing membranes that, in some instances, will conflict with previously reported recommendations from the ionic site theory for the optimization of the lower detection limit. This mechanistic insight is key to maximizing the response range of these ionophore-based ISEs.

A System for In Vitro Generation of Mature Murine Plasma Cells Uncovers Differential Blimp-1/Prdm1 Promoter Usage.

Upon encounter with Ag, B cells undergo a sequential process of differentiation to become Ab-secreting plasma cells. Although the key drivers of differentiation have been identified, research has been limited by the lack of in vitro models recapitulating the full process for murine B cells. In this study, we describe methodology using BCR or TLR ligation to obtain plasma cells that are phenotypically mature, have exited cell cycle and express a gene signature concordant with long-lived plasma cells. Dependent on the initial stimuli, the transcriptomes also show variation including the enhanced expression of matrisome components after BCR stimulation, suggestive of unique functional properties for the resultant plasma cells. Moreover, using the new culture conditions we demonstrate that alternative promoter choice regulating the expression of the master transcription factor Blimp-1/Prdm1 can be observed; when the canonical B cell promoter for Prdm1 is deleted, differentiating B cells exhibit flexibility in the choice of promoter, dictated by the initiating stimulus, with preferential maintenance of expression following exposure to TLR ligation. Thus our system provides a readily tractable model for furthering our understanding of plasma cell biology.

Surveying nonvisual arrestins reveals allosteric interactions between functional sites.

Arrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell-signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modeling (ANM) together with our covariance compliment techniques to survey all the available structures of the nonvisual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain ß-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.

Functional movement disorder gender, age and phenotype study: a systematic review and individual patient meta-analysis of 4905 cases.

Functional movement disorder (FMD) is a common manifestation of functional neurological disorder presenting with diverse phenotypes such as tremor, weakness and gait disorder. Our current understanding of the basic epidemiological features of this condition is unclear. We aimed to describe and examine the relationship between age at onset, phenotype and gender in FMD in a large meta-analysis of published and unpublished individual patient cases. An electronic search of PubMed was conducted for studies from 1968 to 2019 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Individual patient data were collected through a research network. We described the distribution of age of onset and how this varied by gender and motor phenotype. A one-stage meta-analysis was performed using multilevel mixed-effects linear regression, including random intercepts for country and data source. A total of 4905 individual cases were analysed (72.6% woman). The mean age at onset was 39.6 years (SD 16.1). Women had a significantly earlier age of onset than men (39.1 years vs 41.0 years). Mixed FMD (23.1%), tremor (21.6%) and weakness (18.1%) were the most common phenotypes. Compared with tremor (40.7 years), the mean ages at onset of dystonia (34.5 years) and weakness (36.4 years) were significantly younger, while gait disorders (43.2 years) had a significantly later age at onset. The interaction between gender and phenotype was not significant. FMD peaks in midlife with varying effects of gender on age at onset and phenotype. The data gives some support to 'lumping' FMD as a unitary disorder but also highlights the value in 'splitting' into individual phenotypes where relevant.

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Pyrethroid insecticide and milkweed cardenolide interactions on detoxification enzyme activity and expression in monarch caterpillars.

Declines of the monarch butterfly population have prompted large-scale plantings of milkweed to restore the population. In North America, there are >73 species of milkweed to choose from for these nationwide plantings. However, it is unclear how different milkweed species affect monarch caterpillar physiology, particularly detoxification enzyme activity and gene expression, given the highly variable cardenolide composition across milkweed species. Here, we investigate the effects of a high cardenolide, tropical milkweed species and a low cardenolide, swamp milkweed species on pyrethroid sensitivity as well as detoxification enzyme activity and expression in monarch caterpillars. Caterpillars fed on each species through the fifth-instar stage and were topically treated with bifenthrin after reaching this final-instar stage. Esterase, glutathione S-transferase, and cytochrome P450 monooxygenase activities were quantified as well as the expression of selected esterase, glutathione S-transferase, ABC transporter, and cytochrome P450 monooxygenase transcripts. There were no significant differences in survival 24 h after treatment with bifenthrin. However, bifenthrin significantly increased glutathione S-transferase activity in caterpillars feeding on tropical milkweed and significantly decreased esterase activity in caterpillars feeding on tropical and swamp milkweed. Significant differential expression of ABC transporter, glutathione S-transferase, and esterase genes was observed for caterpillars feeding on tropical and swamp milkweed and not receiving bifenthrin treatment. Furthermore, significant differential expression of glutathione S-transferase and esterase genes was observed for bifenthrin-treated and -untreated caterpillars feeding on tropical milkweed relative to swamp milkweed. These results suggest that feeding on different milkweed species can affect detoxification and development mechanisms with which monarch caterpillars rely on to cope with their environment.

A multicenter randomized controlled trial indicates that paclitaxel-coated balloons provide no benefit for arteriovenous fistulas.

The role of paclitaxel-coated balloons has been established in the coronary and peripheral arterial circulations with recent interest in the use of paclitaxel-coated balloons to improve patency rates following angioplasty of arteriovenous fistulas. To assess the efficacy of paclitaxel-coated angioplasty balloons to prolong the survival time of target lesion primary patency in arteriovenous fistulas, we designed an investigator-led multi-center randomized controlled trial with follow up time variable for a minimum of one year. Patients with an arteriovenous fistula who were undergoing an angioplasty for a clinical indication were included but patients with one or more lesions outside the treatment segment were excluded. Following successful treatment with a high-pressure balloon, 212 patients were randomized. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. The primary endpoint was time to loss of clinically driven target lesion primary patency. Primary analysis showed no significant evidence for a difference in time to end of target lesion primary patency between groups: hazard ratio 1.18 with a 95% confidence interval of 0.78 to 1.79. There were no significant differences for any secondary outcomes, including patency outcomes and adverse events. Thus, our study demonstrated no evidence that paclitaxel-coated balloons provide benefit, following standard care high-pressure balloon angioplasty, in the treatment of arteriovenous fistulas. Hence, in view of the benefit suggested by other trials, the role of paclitaxel-coated angioplasty balloons remains uncertain.

Results from a prospective longitudinal survey of employment and work outcomes in newly diagnosed cancer patients during and after curative-intent chemotherapy: A Wisconsin Oncology Network study.

BACKGROUND: Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment. METHODS: A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated. RESULTS: A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full-time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12-month follow-up (78%). Work-related productivity loss due to health was high during treatment. CONCLUSIONS: This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at-risk patients.

Benign Breast Intraductal Papillomas Without Atypia at Core Needle Biopsies: Is Surgical Excision Necessary?

PURPOSE: The aim of this study was to determine the upgrade rate of image-guided core needle biopsy (CNB)-proven benign breast intraductal papillomas (IDPs) without atypia to high-risk benign lesions or malignancy after surgical excision. METHODS: A retrospective database search at a single institution identified 102 adult female patients with benign breast IDPs without atypia diagnosed on imaging-guided CNBs who subsequently had surgical excisions between 2011 and 2016. Patient characteristics, imaging features, biopsy techniques, and the pathology reports from imaging-guided CNBs and subsequent surgical excisions were reviewed. The upgrade rate to malignancies or high-risk benign lesions was determined at the patient level. RESULTS: The upgrade rate to malignancy was 2.9% (3/102), including two cases of ductal carcinoma in situ (DCIS) and one case of microinvasive (< 1 mm) ductal carcinoma arising from DCIS. The upgrade rate to high-risk benign lesions was 7.8% (8/102), with seven cases of atypical ductal hyperplasia and one case of atypical lobular hyperplasia. A personal history of breast cancer and a larger mean lesion size were significantly associated with an upgrade to malignancy (p < 0.05). CONCLUSIONS: The management of benign breast IDPs without atypia detected on imaging-guided CNBs is controversial. Our results suggest risk stratification is important in approaching these patients. Although surgical excision should be considered for all benign breast IDPs without atypia, observation with serial imaging may be appropriate in selected low-risk patients. This approach will save many women from surgeries and decrease the cost of medical care.

Psychological and demographic characteristics of 368 patients with dissociative seizures: data from the CODES cohort.

BACKGROUND: We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology. METHODS: Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic). RESULTS: Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men. CONCLUSIONS: Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.

Ketamine for Prehospital Pain Management Does Not Prolong Emergency Department Length of Stay.

BACKGROUND: Ketamine is gaining acceptance as an agent for prehospital pain control, but the associated risks of agitation, hallucinations and sedation have raised concern about its potential to prolong emergency department (ED) length of stay (LOS). This study compared ED LOS among EMS patients who received prehospital ketamine, fentanyl or morphine specifically for pain control. We hypothesized ED LOS would not differ between patients receiving the three medications. METHODS: This retrospective observational study utilized the 2018 ESO Research Database, which includes more than 7.5 million EMS events attended by more than 1,200 agencies. Inclusion criteria were a 9-1-1 scene response; age ≥ 18 years; a recorded pain score greater than 4; an initial complaint or use of a treatment protocol indicating a painful condition; prehospital administration of ketamine, fentanyl or morphine; and ED LOS data available. Patients were excluded if they received a combination of the medications, or if there were indications that medication administration could have been for airway management (i.e., altered mental status, head injury, respiratory distress/depression) or agitation control (e.g., behavioral complaints). Kruskal-Wallis test was used to compare ED LOS among patients receiving each of the three medications. Post-hoc evaluations of between-group differences were conducted using Wilcoxon Rank Sum test and a Bonferroni-corrected alpha value of 0.017. RESULTS: Of 9,548 patients who met the inclusion criteria, 119 received ketamine, 1,359 received morphine, and 8,070 received fentanyl. Patient and event characteristics did not significantly differ between the three groups. Median (IQR) ED LOS was 3.5 (2.5-6.1) hours for patients who received ketamine, 4.0 (2.7-6.1) hours for patients who received morphine, and 3.7 (2.6-5.4) hours for patients who received fentanyl (p = 0.002). In post-hoc pairwise comparisons, patients who received morphine had significantly longer ED LOS than patients who received fentanyl (p < 0.001); there was no significant difference in ED LOS for patients who received ketamine vs. morphine (p = 0.161) or for patients who received ketamine vs. fentanyl (p = 0.809). CONCLUSION: ED LOS is not longer for patients who receive prehospital ketamine, versus morphine or fentanyl, for management of isolated painful non-cardiorespiratory conditions.

Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used in spinal arthrodesis procedures to enhance bony fusion. Research has suggested that it is the most cost-effective fusion enhancer, but there are significant upfront costs for the healthcare system. The primary objective of this study was to determine whether intraoperative dosing and corresponding costs changed with surgeon cost awareness. The secondary objective was to describe surgical complications before and after surgeon awareness of rhBMP-2 cost. METHODS: A retrospective medical record review was conducted to identify patients who underwent spinal arthrodesis procedures performed by a single surgeon, supplemented with rhBMP-2, from June 2016 to June 2018. Collected data included rhBMP-2 dosage, rhBMP-2 list price, and surgical complications. Expected Medicare reimbursement was calculated. Data were analyzed before and after surgeon awareness of rhBMP-2 cost. RESULTS: Forty-eight procedures were performed using rhBMP-2, 16 before and 32 after surgeon cost awareness. Prior to cost awareness, the most frequent rhBMP-2 dosage level was x-small (38.9%, n = 7), followed by large (27.8%, n = 5) and small (22.2%, n = 4). After cost awareness, the most frequent rhBMP-2 dosage was xx-small (56.8%, n = 21), followed by x-small (21.6%, n = 8) and large (13.5%, n = 5). The rhBMP-2 average cost per surgery was $4116.56 prior to surgeon cost awareness versus $2268.38 after. Two complications were observed in the pre-cost awareness surgical group; 2 complications were observed in the post-cost awareness surgical group. CONCLUSIONS: Surgeon awareness of rhBMP-2 cost resulted in use of smaller rhBMP-2 doses, decreased rhBMP-2 cost per surgery, and decreased overall hospital admission charges, without a detectable increase in surgical complications.

Globalization of The Journal of Craniofacial Surgery Over The Last Decade: A Continent, Country, and State Level Analysis.

ABSTRACT: Craniofacial surgery continues to be a rapidly evolving field, due in part to interdisciplinary collaboration that has allowed for sharing of knowledge and methodologies, which has expanded greatly due to online journals and publications. The Journal of Craniofacial Surgery (JCS) is a highly regarded journal that has attracted attention for its mission to increase diversity and global representation in manuscript submissions and research publications. The purpose of this study is to provide an objective measurement of global participation in craniofacial research specifically as it pertains to the JCS. Through a bibliometric analysis, the country of origin of all articles published in the JCS from 2010 to 2019 was analyzed. In line with its mission, the JCS increased its overall production 1.9 times during the past decade and increased its global representation 1.6 times, as represented by the number of countries contributing (78). The journal produced 8147 articles with Turkey (1424), USA (1397), China (1178), South Korea (1023), and Italy (644) being the top producers. The highest represented states were Florida (156), New York (130), California (117), Massachusetts (112), and Pennsylvania (106). The Journal of Craniofacial Surgery has the greatest diversity of country representation of the major plastic and reconstructive journals compared. Overall the JCS has stayed true to its mission to foster craniofacial research and is a valuable resource for craniofacial surgeons across the world. This study provides an analysis of trends in global contributions to craniofacial research and highlights areas for further increasing global contributors to the field of craniofacial surgery.

Attitudinal and demographic factors associated with seeking help and receiving antidepressant medication for symptoms of common mental disorder.

BACKGROUND: Despite the increased attention given to improvement of mental health-related knowledge and attitudes, rates of help-seeking for mental illness remain low even in countries with well-developed mental health services. This study examines the relationships between attitudes to mental illness, symptoms of common mental disorder and seeking-help and receiving medication for a mental health problem. METHODS: We used data from the nationally representative Health Survey for England 2014 to design three logistic regression models to test for the effects of attitudes to mental illness (measured by a shortened version of the Community Attitudes toward the Mentally Ill, CAMI scale) on: recent contact with a doctor for a mental health problem; use of any type of mental health service in the last 12 months; and having antidepressants currently prescribed, while controlling for symptoms of common mental disorder (measured by the General Health Questionnaire, GHQ). We also tested for an interaction between attitudes to mental illness and symptoms of common mental disorder on the outcomes. RESULTS: A significant but very small effect of CAMI score was found on 'antidepressants currently prescribed' model (OR = 1.01(1.00, 1.02) but not on the two indicators of help-seeking. We also found a significant but very small interaction between CAMI and GHQ scores on recent contact with a doctor (OR = 0.99, 95% CI (0.990, 0.998); adjusted Wald test P = 0.01)). Knowing someone with a mental illness had a significant positive effect on help-seeking indicated by: (a) recent contact with a doctor (2.65 (1.01, 6.98)) and (b) currently prescribed antidepressant (2.67 (1.9, 3.75)) after controlling for attitudes to mental illness. CONCLUSIONS: Our results suggest that knowing someone with a mental health problem seems to have a further positive effect on help-seeking, beyond improving attitudes to mental illness. Furthermore, multiple different types and aspects of stigma may contribute to help-seeking behaviours, consequently multi-faceted approaches are likely to be most efficient.

Mindfulness-based crisis interventions (MBCI) for psychosis within acute inpatient psychiatric settings; a feasibility randomised controlled trial.

BACKGROUND: Inpatient psychiatric care is a scarce and expensive resource in the National Health Service (NHS), with chronic bed shortages being partly driven by high re-admission rates. Brief inpatient talking therapies for psychosis could help reduce re-admission rates. The primary aim was to assess feasibility and acceptability of a novel, brief, mindfulness-based intervention for inpatients with psychosis. The secondary aim was to collect pilot outcome data on readmission rate, at 6 and 12 months (m) post discharge, and self-report symptom measures at 6 m. METHODS: The amBITION study (BrIef Talking therapIes ON wards) was a parallel group, feasibility randomised controlled trial (RCT). In addition to treatment as usual (TAU), eligible inpatients with psychotic symptoms were randomly allocated to receive either (Mindfulness-Based Crisis Intervention; MBCI) or a control intervention (Social Activity Therapy; SAT), for 1-5 sessions. RESULTS: Fifty participants were recruited (26 MBCI; 24 SAT); all received at least 1 therapy session (mean = 3). Follow-up rates were 98% at 6 m and 96% at 12 m for service use data extracted from clinical notes, and 86% for self-report measures. At 6 m follow-up, re-admission rates were similar across groups (MBCI = 6, SAT = 5; odds ratio = 1.20, 95% CI: 0.312-4.61). At 12 m follow-up, re-admissions were lower in the MBCI group (MBCI = 7, SAT = 11; odds ratio = 0.46, 95% CI: 0.14-1.51). Three participants experienced adverse events; none was related to trial participation. CONCLUSIONS: Delivering a brief mindfulness-based inpatient intervention for psychosis is feasible and acceptable, and may reduce risk of short-term readmission. These promising findings warrant progression to a larger clinical effectiveness trial. TRIAL REGISTRATION: ISRCTN37625384.

Mental illness stigma after a decade of Time to Change England: inequalities as targets for further improvement.

BACKGROUND: England's Time to Change programme to reduce mental health-related stigma and discrimination included a social marketing campaign using traditional and social media, and targeted middle-income groups aged 25-45 between 2009 and 2016. From 2017, the same age group on low to middle incomes were targeted, and the content focused on men's mental health, by changing the advertising and adapting the 'key messages'. This study investigates changes in stigma-related public knowledge, attitudes and desire for social distance in England since Time to Change began in 2008-19 and for 2017-19. METHODS: Using data from a face-to-face survey of a nationally representative quota sample of adults for England, we evaluated longitudinal trends in outcomes with regression analyses and made assumptions based on a simple random sample. The pre-existing survey used a measure of attitudes; measures of knowledge and desire for social distance were added in 2009. RESULTS: Reported in standard deviation units (95% CI), the improvement for knowledge for 2009-19 was 0.25 (0.19, 0.32); for attitudes, 2008-19, 0.32 (0.26, 0.39) and for desire for social distance, 2009-19 0.29 (0.23, 0.36). Significant interactions between year and both region and age suggest greater improvements in London, where stigma is higher, and narrowing of age differences. There were significant improvements between 2017 and 2019 in knowledge [0.09 (0.02, 0.16)] and attitudes [0.08 (0.02, 0.14)] but not social distance. CONCLUSION: The positive changes support the effectiveness of Time to Change but cannot be definitively attributed to it. Inequalities in stigma by demographic characteristics present targets for research and intervention.

Public knowledge, attitudes, social distance and reporting contact with people with mental illness 2009-2017.

BACKGROUND: Our aim was to investigate patterns of change in public knowledge, attitudes, desire for social distance and reporting having contact with people with mental health problems in England during the Time to Change (TTC) programme to reduce stigma and discrimination 2009-2017. METHODS: Using data from an annual face-to-face survey of a nationally representative quota sample of adults, we evaluated longitudinal trends of the outcome measures with regression analyses and made assumptions on the basis of a simple random sample. We tested interactions between year and demographic subgroups. RESULTS: There were improvements in all outcomes in 2017 compared with baseline measures (2008 or 2009). Reported in s.d. units [95% confidence interval (CI)], the improvement for knowledge was 0.17 (0.10-0.23); for attitudes 0.25 (0.18-0.31); and for social distance 0.29 (0.23-0.35). A higher likelihood of reporting contact was also associated with most recent survey year (odds ratio 1.47, 95% CI 1.27-1.71). Statistically significant interactions between year and region of England suggest greatest improvements in attitudes and intended behaviour in London, where both outcomes were significantly worse in the early years of the survey. However, for attitudes, this interaction was only significant among women. Other significant interactions suggest that attitudes improved most in the target age group (25-44). CONCLUSIONS: The results provide support for the effectiveness of TTC across demographic groups. However, other societal changes may influence the results, such as the increasing prevalence of common mental disorder in young women.

Characteristics of 698 patients with dissociative seizures: A UK multicenter study.

OBJECTIVE: We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology. METHODS: We collected demographic and clinical data from 698 adults with dissociative seizures recruited to the screening phase of the CODES (Cognitive Behavioural Therapy vs Standardised Medical Care for Adults With Dissociative Non-Epileptic Seizures) trial from 27 neurology/specialist epilepsy clinics in the UK. We described the cohort in terms of age, age at onset of dissociative seizures, duration of seizure disorder, level of socioeconomic deprivation, and other social and clinical demographic characteristics and their associations. RESULTS: In what is, to date, the largest study of adults with dissociative seizures, the overall modal age at dissociative seizure onset was 19 years; median age at onset was 28 years. Although 74% of the sample was female, importantly the male:female ratio varied with age at onset, with 77% of female but only 59% of male participants developing dissociative seizures by the age of 40 years. The frequency of self-reported previous epilepsy was 27%; nearly half of these epilepsy diagnoses were retrospectively considered erroneous by clinicians. Patients with predominantly hyperkinetic dissociative seizures had a shorter disorder duration prior to diagnosis in this study than patients with hypokinetic seizures (P < .001); dissociative seizure type was not associated with gender. Predominantly hyperkinetic seizures were most commonly seen in patients with symptom onset in their late teens. Thirty percent of the sample reported taking antiepileptic drugs; this was more common in men. More than 50% of the sample lived in areas characterized by the highest levels of deprivation, and more than two-thirds were unemployed. SIGNIFICANCE: Females with dissociative seizures were more common at all ages, whereas the proportion of males increased with age at onset. This disorder was associated with socioeconomic deprivation. Those with hypokinetic dissociative seizures may be at risk for delayed diagnosis and treatment.

A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules.

The stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis is shown to be a general and powerful reaction sequence for the preparation of diverse polycyclic scaffolds from simple precursors. The modular strategy successfully constructs substructures prevalent in numerous bioactive natural product families, varying in substitution and carbocyclic composition. Several of the prepared compounds were shown to possess potent cytotoxic activity against a panel of tumor cell lines. The utility of this strategy was further demonstrated by a concise and highly convergent 17-step formal synthesis of the complex antimalarial marine diterpene, (+)-7,20-diisocyanoadociane.