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Smith’s chapter focuses on the continued influence of the idea of Weimar Berlin in contemporary popular culture. The chapter takes as its starting point recent cultural expressions, such as the television series Babylon Berlin, focusing on previously unexplored aspects of how Weimar is depicted as a modern Babylon. Smith identifies two particularly salient aspects in these depictions: first, that the portrait of right-wing political cultures within Weimar are given more depth and nuance than are afforded center-left and left-wing ones; and, second, how the depiction of sex and violence leads us back to Alfred Döblin’s Berlin Alexanderplatz and its apocalyptic vision of Weimar, along with Anglo-American visions of Weimar that have particularly long staying power, in particular Christopher Isherwood’s depiction of 1930s Berlin and its iterations and adaptations on stage and screen. The chapter demonstrates the ways in which Weimar retains its grip on aspects of our contemporary popular culture and how the particular forms these cultural expressions take may tell us about the lessons drawn from Weimar.
To determine if the high-level personal protective equipment used in the treatment of high-consequence infectious diseases is effective at stopping the spread of pathogens to healthcare personnel (HCP) while doffing.
Background:
Personal protective equipment (PPE) is fundamental to the safety of HCPs. HCPs treating patients with high-consequence infectious diseases use several layers of PPE, forming complex protective ensembles. With high-containment PPE, step-by-step procedures are often used for donning and doffing to minimize contamination risk to the HCP, but these procedures are rarely empirically validated and instead rely on following infection prevention best practices.
Methods:
A doffing protocol video for a high-containment PPE ensemble was evaluated to determine potential contamination pathways. These potential pathways were tested using fluorescence and genetically marked bacteriophages.
Results:
The experiments revealed existing protocols permit contamination pathways allowing for transmission of bacteriophages to HCPs. Updates to the doffing protocols were generated based on the discovered contamination pathways. This updated doffing protocol eliminated the movement of viable bacteriophages from the outside of the PPE to the skin of the HCP.
Conclusions:
Our results illustrate the need for quantitative, scientific investigations of infection prevention practices, such as doffing PPE.
Disasters exacerbate inequities in health care. Health systems use the Hospital Incident Command System (HICS) to plan and coordinate their disaster response. This study examines how 2 health systems prioritized equity in implementing the Hospital Incident Command System (HICS) during the coronavirus disease 2019 (COVID-19) pandemic and identifies factors that influenced implementation.
Methods:
This is a qualitative case comparison study, involving semi-structured interviews with 29 individuals from 2 US academic health systems. Strategies for promoting health equity were categorized by social determinants of health. The Consolidated Framework for Implementation Research (CFIR) guided analysis using a hybrid inductive-deductive approach.
Results:
The health systems used various strategies to incorporate health equity throughout implementation, addressing all 5 social determinants of health domains. Facilitators included HICS principles, external partnerships, community relationships, senior leadership, health equity experts and networks, champions, equity-stratified data, teaming, and a culture of health equity. Barriers encompassed clarity of the equity representative role, role ambiguity for equity representatives, tokenism, competing priorities, insufficient resource allocation, and lack of preparedness.
Conclusions:
These findings elucidate how health systems centered equity during HICS implementation. Health systems and regulatory bodies can use these findings as a foundation to revise the HICS and move toward a more equitable disaster response.
The Dunning-Krueger effect is a cognitive bias where individuals tend to overestimate their abilities in areas where they are less competent. The Cordoba Naming Test (CNT) is a 30-item confrontation naming task. Hardy and Wright (2018) conditionally validated a measure of perceived mental workload called the NASA Task Load Index (NASA-TLX). Researchers reported that workload ratings on the NASA-TLX increased with increased task demands on a cognitive task. Anxiety is known as an emotion that can make an individual more susceptible to develop a mental health condition. We examine if the Dunning-Krueger effect occurs in a Mexican population with and without current symptoms of anxiety and possible factors driving individuals to overestimate their abilities on the CNT. We predicted the abnormal symptoms of anxiety (ASA) group would report better CNT performance, report higher perceived workloads on the CNT, and underperform on the CNT compared to the normal symptoms of anxiety (NSA) group. We also predicted the low-performance group would report better CNT performance, report higher perceived workloads on the CNT, and underperform on the CNT compared to the high-performance group.
Participants and Methods:
The sample consisted of 192 Mexican participants with NSA (79 low-performance & 113 high-performance) and 74 Mexican participants with ASA (44 low-performance & 30 high-performance). Participants completed the CNT, NASA-TLX, and the Hospital Anxiety and Depression Scale (HADS) in Spanish. The NASA-TLX was used to evaluate perceived workloads after the completion of the CNT. Meanwhile, the HADS was used to create our anxiety groups. Finally, CNT raw scores were converted into T-scores, which then were averaged to create the following two groups: low-performance (CNT T-Score <50) and high-performance (CNT T-Score 50+). A series of 2x2 ANCOVAs, controlling for gender were used to evaluate CNT performance and perceived workloads.
Results:
We found a significant interaction where the low-performance ASA and the high-performance NSA groups demonstrated better CNT performance and reported higher perceived workloads (i.e., performance, temporal demand) on the CNT compared to their respective counterparts (i.e., low-performance NSA & high-performance ASA groups), p's<.05, ηp's2=.02. We found a main effect where the high-performance group outperformed the low-performance group on the CNT and reported lower perceived workloads on the CNT, p's<.05, ηp's2 =.04-.46.
Conclusions:
The Dunning-Krueger effect did not occur in our sample. Participants that demonstrated better CNT performance also reported higher perceived workloads regardless of their current symptoms of anxiety. A possible explanation can be our sample's cultural norms of what would be considered as abnormal symptoms of anxiety, is a normal part of life, decreasing the possibilities to experience self-efficacy distoritions. Future studies should investigate whether the Dunning-Kruger effect may be influencing other aspects of cognitive functioning subjectively in Mexicans residing in Mexico and the United States with and without current symptoms of anxiety.
Various water-based heater-cooler devices (HCDs) have been implicated in nontuberculous mycobacteria outbreaks. Ongoing rigorous surveillance for healthcare-associated M. abscessus (HA-Mab) put in place following a prior institutional outbreak of M. abscessus alerted investigators to a cluster of 3 extrapulmonary M. abscessus infections among patients who had undergone cardiothoracic surgery.
Methods:
Investigators convened a multidisciplinary team and launched a comprehensive investigation to identify potential sources of M. abscessus in the healthcare setting. Adherence to tap water avoidance protocols during patient care and HCD cleaning, disinfection, and maintenance practices were reviewed. Relevant environmental samples were obtained. Patient and environmental M. abscessus isolates were compared using multilocus-sequence typing and pulsed-field gel electrophoresis. Smoke testing was performed to evaluate the potential for aerosol generation and dispersion during HCD use. The entire HCD fleet was replaced to mitigate continued transmission.
Results:
Clinical presentations of case patients and epidemiologic data supported intraoperative acquisition. M. abscessus was isolated from HCDs used on patients and molecular comparison with patient isolates demonstrated clonality. Smoke testing simulated aerosolization of M. abscessus from HCDs during device operation. Because the HCD fleet was replaced, no additional extrapulmonary HA-Mab infections due to the unique clone identified in this cluster have been detected.
Conclusions:
Despite adhering to HCD cleaning and disinfection strategies beyond manufacturer instructions for use, HCDs became colonized with and ultimately transmitted M. abscessus to 3 patients. Design modifications to better contain aerosols or filter exhaust during device operation are needed to prevent NTM transmission events from water-based HCDs.
A commonly used confrontation naming task used in the United States is The Boston Naming Test (BNT). Performance differences has been found in Caucasian and ethnic minorities on the BNT. The Cordoba Naming Test (CNT) is a 30-item confrontation naming task developed in Argentina. Past research has shown acculturation levels can influence cognitive performance. Furthermore, one study evaluated geriatric gender differences on CNT performance in Spanish. Researchers reported that older male participants outperformed female participants on the CNT. To our knowledge, researchers have not evaluated ethnic differences on the CNT using a geriatric sample. The purpose of the present study was to examined CNT performance and acculturation in a Latinx and Caucasian geriatric sample. It was predicted the Caucasian group would outperform the Latinx group on the CNT. Moreover, the Caucasian group would report higher acculturation levels on the Abbreviated Multidimensional Acculturation Scale (AMAS) compared to the Latinx group.
Participants and Methods:
The sample consisted of 9 Latinx and 11 Caucasian participants with a mean age of 66.80 (SD =6.10), with an average of 14.30 (SD = 2.00) years of education. All participants were neurologically and psychologically healthy and completed the CNT and the AMAS in English. Acculturation was measured via the AMAS English subscales (i.e., English Language, United States. Identity, United States, Competency). A series of ANCOVAs, controlling for years of education completed and gender, was used to evaluate CNT performance and acculturation.
Results:
The ethnic groups were not well demographically matched (i.e., years of education and gender).We found that the Caucasian group outperformed the Latinx group on CNT performance p = .012, ηp 2 = .34. Furthermore, the Caucasian group reported higher acculturation levels (i.e., English Language, United States, Identity, United States, Competency) compared to the Latinx group p’s < .05, ηps2 = .42-.64.
Conclusions:
To our knowledge, this is the first study to evaluate CNT performance between ethnic groups with a geriatric sample. As expected the Caucasian group outperformed the Latinx group on the CNT. Also, as expected the Caucasian group reported higher English acculturation levels compared to the Latinx group. Our findings are consistent with past studies showing ethnic differences on confrontational naming performance (i.e., The Boston Naming Test), favoring Caucasians. A possible explanation for group differences could have been linguistic factors (e.g., speaking multiple languages) in our Latinx group. Therefore, since our Latinx group reported lower levels of English Language, United States identity, and United States competency the Latinx group assimilation towards United States culture might of influence their CNT performance. Future studies with different ethnic groups (e.g., African-Americans) and a larger sample size should examine if ethnic differences continue to cross-validate in a geriatric sample.
Admission to a Psychiatric inpatient unit can be a stressful time for patients and families. Patient's and carers have advised staff on the ward that there is a lack of information available regarding the policies and procedures in the unit. This includes information on ward rounds, leave arrangements and discharge planning. The aim is to enhance the ward-based experience of patients and their families by attempting to explore areas to improved, particularly about providing information that will help them to understand the process of admission to an inpatient Psychiatric as well as what to expect throughout their admission and on discharge.
Methods
A questionnaire was distributed to all the ‘current’ in-patients and their families. The questionnaire was kept anonymous to encourage everyone to contribute honestly. Data were collected from 20 patients admitted to the ward from 01.02.2022 to 30.04.2022. Data were analysed and shared with the rest of the team to identify gaps in provision of information.
Results
Half of patients reported not receiving an introduction to the ward on admission and being unaware of the roles of different staff members. 70% of the patients and relatives were aware of the facilities of the ward and how to use them. There was a mixed response about satisfaction with running of Multidisciplinary Team Meetings(MDTs), availability of name nurse and medical team and information provision around MDTs, leave arrangement, discharge planning and follow up.
Conclusion
This quality improvement project has highlighted inconsistencies in the quality of and satisfaction with information provision during admission and has helped to recognised areas that needed to be improved. Several steps have been taken to improve quality of care such as copies of care plan and "Welcome to Tissington" booklet have provided. Discharge pathways and name board displayed in reception. Ward round appointments given to patients in advance and named nurse to support patients in writing MDT meeting plan. Invite families to attend care plan reviews, ward rounds and discharge meeting in person/via online. Additional craft items made available for activity, and exercise and walking groups have been introduced. Additional time made available for carers to speak with ward staff. Recruitment of Psychologist and occupational therapists now in post and Carers meeting to commence.
It is important to repeat this quality improvement project regularly to monitor the progress and get more information from families and patients to improve the quality of care given by the ward.
A 2016 study season and 2017 excavation season at the 95-hectare walled site of Kurd Qaburstan on the Erbil plain have generated a variety of new results. Geophysical survey on the lower town revealed details of the Middle Bronze occupation in the southeast part of the site, including the city wall, a large open area, streets, houses, and a monumental temple comparable to examples from Tell al Rimah, Aššur, and Larsa. Excavations confirmed the Middle Bronze date of the temple and explored further Middle Bronze contexts elsewhere on the lower town. On the High Mound North Slope, Middle Bronze occupation included a fortification wall and large-scale architecture inside it. On the High Mound East, Late Bronze architecture of apparent elite character was documented. Archaeobotanical analyses complementing the excavations reveal the existence of naan-style bread in both Middle and Late Bronze contexts. Given radiocarbon and ceramic results, the Middle Bronze occupation at Kurd Qaburstan is datable to c. 1800 B.C., while the Late Bronze phases on the High Mound East belong to an early LB horizon in the 16–15th centuries B.C., perhaps predating the imposition of Mittani political authority in the region.
Despite its potential scalability, little is known about the outcomes of internet-based cognitive behaviour therapy (iCBT) for post-traumatic stress disorder (PTSD) when it is provided with minimal guidance from a clinician.
Aim:
To evaluate the outcomes of minimally guided iCBT for PTSD in a randomised control trial (RCT, Study 1) and in an open trial in routine community care (Study 2).
Method:
A RCT compared the iCBT course (n=21) to a waitlist control (WLC, n=19) among participants diagnosed with PTSD. The iCBT group was followed up 3 months post-treatment. In Study 2, treatment outcomes were evaluated among 117 adults in routine community care. PTSD symptom severity was the primary outcome in both studies, with psychological distress and co-morbid anxiety and depressive symptoms providing secondary outcomes.
Results:
iCBT participants in both studies experienced significant reductions in PTSD symptom severity from pre- to post-treatment treatment (within-group Hedges’ g=.72–1.02), with RCT findings showing maintenance of gains at 3-month follow-up. The WLC group in the RCT also significantly improved, but Study 1 was under-powered and the medium between-group effect favouring iCBT did not reach significance (g=0.64; 95% CI, –0.10–1.38).
Conclusions:
This research provides preliminary support for the utility of iCBT for PTSD when provided with minimal clinician guidance. Future studies are needed to clarify the effect of differing levels of clinician support on PTSD iCBT outcomes, as well as exploring how best to integrate iCBT into large-scale, routine clinical care of PTSD.
The Global Alzheimer’s Platform Foundation® (GAP) is a patient-centric, non-profit organization founded in 2015. GAP is dedicated to speeding the delivery of innovative therapies to persons with Alzheimer’s disease (AD) or Parkinson’s disease (PD) by reducing the duration and cost while improving the effectiveness of AD and PD clinical trials. GAP’s growing network of high-performing AD and PD sites (GAP-Net) allows sponsors to complete clinical trials on a single, optimized trial site platform. GAP-Net sites activate 30% faster than non-GAP sites by leveraging trial services including a central institutional review board. GAP-Net sites experience up to a 24% faster screening rate, higher randomization rates, and fewer low/no randomizations per site compared with sites without the support of GAP Participant Services (GPS). GAP also sponsors the Bio-Hermes trial , designed to evaluate digital and blood-based biomarkers that are projected to accelerate enrollment and lower screen fail costs in clinical trials. Finally, GAP is extending its network globally as part of its mission to accelerate and improve the effectiveness of AD and PD clinical trials.
Ensuring equitable access to health care is a widely agreed-upon goal in medicine, yet access to care is a multidimensional concept that is difficult to measure. Although frameworks exist to evaluate access to care generally, the concept of “access to genomic medicine” is largely unexplored and a clear framework for studying and addressing major dimensions is lacking.
Methods:
Comprised of seven clinical genomic research projects, the Clinical Sequencing Evidence-Generating Research consortium (CSER) presented opportunities to examine access to genomic medicine across diverse contexts. CSER emphasized engaging historically underrepresented and/or underserved populations. We used descriptive analysis of CSER participant survey data and qualitative case studies to explore anticipated and encountered access barriers and interventions to address them.
Results:
CSER’s enrolled population was largely lower income and racially and ethnically diverse, with many Spanish-preferring individuals. In surveys, less than a fifth (18.7%) of participants reported experiencing barriers to care. However, CSER project case studies revealed a more nuanced picture that highlighted the blurred boundary between access to genomic research and clinical care. Drawing on insights from CSER, we build on an existing framework to characterize the concept and dimensions of access to genomic medicine along with associated measures and improvement strategies.
Conclusions:
Our findings support adopting a broad conceptualization of access to care encompassing multiple dimensions, using mixed methods to study access issues, and investing in innovative improvement strategies. This conceptualization may inform clinical translation of other cutting-edge technologies and contribute to the promotion of equitable, effective, and efficient access to genomic medicine.
What is the status of women's writing in German today, in an era when feminism has thoroughly problematized binary conceptions of sex and gender? Drawing on gender and queer theory, including the work of Lauren Berlant, Judith Butler, and Michel Foucault, the essays in this volume rethink conventional ways of conceptualizing female authorship and re-examine the formal, aesthetic, and thematic terms in which "women's literature" has been conceived. With an eye to the literary and feminist legacy of authors such as Christa Wolf and Ingeborg Bachmann, contributors treat the works of many of contemporary Germany's most significant literary voices, including Hatice Akyün, Sibylle Berg, Thea Dorn, Tanja Dückers, Karen Duve, Jenny Erpenbeck, Julia Franck, Katharina Hacker, Charlotte Roche, Julia Schoch, and Antje Rávic Strubel -- authors who, through their writing or their role in the media, engage with questions of what it means to be a woman writer in twenty-first-century Germany. Contributors: Hester Baer, Necia Chronister, Helga Druxes, Valerie Heffernan, Alexandra Merley Hill, Lindsey Lawton, Sheridan Marshall, Beret Norman, Mihaela Petrescu, Jill Suzanne Smith, Carrie Smith-Prei, Maria Stehle, Katherine Stone. Hester Baer is Associate Professor of Germanic Studies at the University of Maryland. Alexandra Merley Hill is Assistant Professor of German at the University of Portland.
ABSTRACT IMPACT: Cholecystokinin-B Receptor -Mediates Growth of Hepatocellular Carcinoma with the use proglumide. Proglumide is a non-selective antagonistic drug therefore, strategies that block signaling at the CCK-BR may provide to be a novel therapeutic option for Hepatocellular Carcinoma treatment OBJECTIVES/GOALS: Cholecystokinin (CCK)and gastrin mediate the growth of Hepatocellular Carcinoma (HCC) through CCK-R and interruption of this signaling pathway could decrease HCC. CCK-Receptors are overexpressed in HCC and proliferation may be mediated through CCK-B. Blockade of the CCK-BR with proglumide decreased both growth in vitro and tumor growth in vivo. METHODS/STUDY POPULATION: RNA was extracted from murine Hepa1-6, RIL-175 and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR and gastrin. CCK-R protein expression was analyzed by flow cytometry. HCC cells were treated in vitro with CCK peptide, the CCK-AR antagonist or the CCK-BR antagonist. Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist proglumide or untreated water for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if proglumide could block autocrine growth by gastrin. RESULTS/ANTICIPATED RESULTS: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with proglumide treatment by 70% (p<0.05) in Hepa1-6 and by 73% (p<0.001) in RIL-75 tumors, respectively. DISCUSSION/SIGNIFICANCE OF FINDINGS: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR maybe a novel therapeutic option for HCC treatment.
OBJECTIVES/GOALS: Non-alcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in the world for which no anti-fibrotic therapies exist. We hypothesized that BMS-22 and maraviroc (MVC), chemokine receptor 2 (CCR2) and 5 (CCR5) antagonists, respectively, would diminish the fibrogenic activity of "fat-exposed" murine pHSCs. METHODS/STUDY POPULATION: pHSCs were isolated from livers of 6 week old male mice following 4 weeks on a NASH-inducing choline-deficient high fat diet (CDAHFD, “fat-exposed”) or standard diet (SD) and passaged in vitro. Early passage (6-12) pHSCs were plate-adhered and TGF-b-treated (10ng/mL) to maximally activate their pro-fibrogenic genes, collagen 1α1 (Col1A1), tissue inhibitor of metalloproteinase 1 (TIMP1), or α-smooth muscle actin (ACTA2). CDAHFD and SD pHSCs were then treated for 48 hours with increasing doses of BMS-22 or MVC (range: 0.3-120ng/mL) to determine (1) the degree of attenuation of the pro-fibrogenic response as measured by qPCR of fibrogenic genes (Col1A1, TIMP1,ACTA2); (2) enhancement of a fibrolytic response as measured by qPCR of matrix metalloproteinases (MMP) 2, 9 and 13 genes; and (3) pHSC migration using the scratch assay. Cell viability and CCR2 and CCR5 gene expression in response to escalating doses of antagonists were also measured. RESULTS/ANTICIPATED RESULTS: Plate- and TGF-b activated CDAHFD pHSCs had a 2-fold greater, dose-dependent attenuation of their pro-fibrogenic activity in response to BMS-CCR2-22 and MVC, when compared with plate- and TGF-b activated SD pHSCs, as measured by reductions in collagen 1α1 (Col1A1) and α-smooth muscle actin (ACTA2) gene expression. TIMP1 gene expression was unaffected by drug treatment for 48 hours. Cell viability was not affected up to doses of 30ng/mL of each drug. pHSCs also demonstrated a dose-dependent increase in CCR2, CCR5 and MMP-9 gene expression in response to surface receptor antagonism. Migration assays comparing CDAHFD and SD pHSCs in response to escalating doses of MVC and BMS-22 are ongoing and expected to demonstrate a significantly decreased migratory capacity of CDAHFD pHSCs than SD pHSCs in response to therapy, reflecting the increased susceptibility of the “fat-exposed” pHSCs to anti-fibrotic therapy than normal pHSCs. DISCUSSION/SIGNIFICANCE OF IMPACT: Anti-fibrotic drugs that dampen pro-fibrogenic activities of “fat-exposed” pHSCs are urgently needed. CCR2 and CCR5 antagonists, BMS-22 and MVC, respectively, can selectively dampen the pro-fibrogenic response of fat-exposed pHSCs, and must be considered for future trials in human NASH. CONFLICT OF INTEREST DESCRIPTION: Dr. Jill Smith has a patent licensing agreement with Immune Therapeutics, Inc.
OBJECTIVES/GOALS: NASH increases the risk of cirrhosis and liver cancer. High-fat diets increase CCK levels and CCK receptors have been identified on fibroblasts and immune cells. We hypothesized that CCK receptor blockade could prevent NASH by altering the hepatic microenvironment and macrophage activation. METHODS/STUDY POPULATION: Female mice were fed a Choline Deficient Ethionine supplemented (CDE) saturated fat diet or control high-fat diet for 18 weeks. Mice in each group were treated with a CCK receptor antagonist, proglumide (0.1 mg/ml) in the drinking water or regular water. Resected livers were stained for H&E for features of NASH and F4/80 for macrophages analysis. Liver RNA was evaluated for the expression of cytokines and chemokines using an 84-gene Profiler array (Qiagen). Oxidative stress was analyzed by qRT-PCR for heat shock proteins (HSPs) 27, 60, 70 and 90 and for glutathione by a fluorometric assay. Differences in CDE fed and CDE/proglumide-treated mouse livers were evaluated. RESULTS/ANTICIPATED RESULTS: Livers from mice on the CDE diet displayed histologic features of NASH that were prevented by proglumide. Cytokines and chemokines expression, especially CCL20 and CCL2, were increased in the CDE fed mice and these levels were reduced greater than 20-fold with proglumide. Infiltration of F4/80+ macrophages was markedly increased in the CDE livers and these were reduced by > 50% (p < 0.0001) with proglumide. RNA expression of HSP70 (p = 0.006) and HSP27 (p = 0.011) were reduced with proglumide. Hepatic glutathione concentration more than doubled in the CDE/proglumide treated mice compared to CDE mice. CCK-B receptor expression increased in the CDE-fed mouse livers compared to controls. DISCUSSION/SIGNIFICANCE OF IMPACT: CCK receptor blockade decreases NASH by reducing hepatic macrophages, oxidative stress, and blocking inflammatory cytokines and chemokines. This data supports our novel hypothesis that CCK receptors play a role in NASH and proglumide may provide an innovative treatment for this condition.
Implementation of genome-scale sequencing in clinical care has significant challenges: the technology is highly dimensional with many kinds of potential results, results interpretation and delivery require expertise and coordination across multiple medical specialties, clinical utility may be uncertain, and there may be broader familial or societal implications beyond the individual participant. Transdisciplinary consortia and collaborative team science are well poised to address these challenges. However, understanding the complex web of organizational, institutional, physical, environmental, technologic, and other political and societal factors that influence the effectiveness of consortia is understudied. We describe our experience working in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, a multi-institutional translational genomics consortium.
Methods:
A key aspect of the CSER consortium was the juxtaposition of site-specific measures with the need to identify consensus measures related to clinical utility and to create a core set of harmonized measures. During this harmonization process, we sought to minimize participant burden, accommodate project-specific choices, and use validated measures that allow data sharing.
Results:
Identifying platforms to ensure swift communication between teams and management of materials and data were essential to our harmonization efforts. Funding agencies can help consortia by clarifying key study design elements across projects during the proposal preparation phase and by providing a framework for data sharing data across participating projects.
Conclusions:
In summary, time and resources must be devoted to developing and implementing collaborative practices as preparatory work at the beginning of project timelines to improve the effectiveness of research consortia.
Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD).
Method
Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009–2016) and hospital admission (1981–2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.
Results
For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04–1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45–2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30–0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.
Conclusions
There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.
Cognitive impairment is strongly linked with persistent disability in people with mood disorders, but the factors that explain cognitive impairment in this population are unclear.
Aims
To estimate the total effect of (a) bipolar disorder and (b) major depression on cognitive function, and the magnitude of the effect that is explained by potentially modifiable intermediate factors.
Method
Cross-sectional study using baseline data from the UK Biobank cohort. Participants were categorised as having bipolar disorder (n = 2709), major depression (n = 50 975) or no mood disorder (n = 102 931 and n = 105 284). The outcomes were computerised tests of reasoning, reaction time and memory. The potential mediators were cardiometabolic disease and psychotropic medication. Analyses were informed by graphical methods and controlled for confounding using regression, propensity score-based methods and G-computation.
Results
Group differences of small magnitude were found on a visuospatial memory test. Z-score differences for the bipolar disorder group were in the range −0.23 to −0.17 (95% CI −0.39 to −0.03) across different estimation methods, and for the major depression group they were approximately −0.07 (95% CI −0.10 to −0.03). One-quarter of the effect was mediated via psychotropic medication in the bipolar disorder group (−0.05; 95% CI −0.09 to −0.01). No evidence was found for mediation via cardiometabolic disease.
Conclusions
In a large community-based sample in middle to early old age, bipolar disorder and depression were associated with lower visuospatial memory performance, in part potentially due to psychotropic medication use. Mood disorders and their treatments will have increasing importance for population cognitive health as the proportion of older adults continues to grow.
Declaration of interest
I.J.D. is a UK Biobank participant. J.P.P. is a member of the UK Biobank Steering Committee.