Publications by authors named "Sarah Fischer"

141 Publications

Experimental validation of the abrasive wear stage of the gross taper failure mechanism in total hip arthroplasty.

Med Eng Phys 2021 Sep 9;95:25-29. Epub 2021 Jul 9.

Endolab Mechanical Engineering GmbH, Rosenheim, Germany.

Background: Gross taper failure (GTF) is a rare but catastrophic failure mode of the head-stem-taper junction of hip prostheses, facilitated by massive material loss. GTF is a two stage process initiated by corrosion leading to head bottoming out, followed by abrasive wear due to the head rotating on the stem. The purpose of this study was to reproduce the clinical failure patterns and to determine the material loss during simulated gait.

Methods: Six cobalt-chromium alloy heads (36 mm, 12/14 taper) with three different head lengths (short / medium / extra long) were combined with stem taper replicas made from titanium alloy sized to achieve bottoming out. A hip simulator was used to simulate gait loading after (ISO 14242-1 for 2 million cycles).

Results: Wear patterns from in-vitro testing match the clinical failure patterns. Stem taper wear increased linearly with time (p< 0.001). After two million cycles the material loss of short / medium / extra long heads was (M+-STD) 1168±242 mg / 400±23 mg / 94±12 mg on the stem side and 46±36 mg / 46±24 mg / 70±8 mg on the head side. Stem taper wear decreased with increasing head length (p=0.01), whereas clinical failures are mostly seen for long and extra long heads.
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http://dx.doi.org/10.1016/j.medengphy.2021.07.003DOI Listing
September 2021

Experimental validation of the abrasive wear stage of the gross taper failure mechanism in total hip arthroplasty.

Med Eng Phys 2021 Sep 9;95:25-29. Epub 2021 Jul 9.

Endolab Mechanical Engineering GmbH, Rosenheim, Germany.

Background: Gross taper failure (GTF) is a rare but catastrophic failure mode of the head-stem-taper junction of hip prostheses, facilitated by massive material loss. GTF is a two stage process initiated by corrosion leading to head bottoming out, followed by abrasive wear due to the head rotating on the stem. The purpose of this study was to reproduce the clinical failure patterns and to determine the material loss during simulated gait.

Methods: Six cobalt-chromium alloy heads (36 mm, 12/14 taper) with three different head lengths (short / medium / extra long) were combined with stem taper replicas made from titanium alloy sized to achieve bottoming out. A hip simulator was used to simulate gait loading after (ISO 14242-1 for 2 million cycles).

Results: Wear patterns from in-vitro testing match the clinical failure patterns. Stem taper wear increased linearly with time (p< 0.001). After two million cycles the material loss of short / medium / extra long heads was (M+-STD) 1168±242 mg / 400±23 mg / 94±12 mg on the stem side and 46±36 mg / 46±24 mg / 70±8 mg on the head side. Stem taper wear decreased with increasing head length (p=0.01), whereas clinical failures are mostly seen for long and extra long heads.
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http://dx.doi.org/10.1016/j.medengphy.2021.07.003DOI Listing
September 2021

Burn Resuscitation Practices in North America: Results of the Acute Burn ResUscitation Multicenter Prospective Trial (ABRUPT).

Ann Surg 2021 Aug 19. Epub 2021 Aug 19.

Department of Surgery, University of California, Davis School of Medicine and Shriners Hospitals for Children Northern California, Sacramento, CA Department of Surgery, Sunnybrook Medical Center, Toronto, Ontario Department of Public Health Sciences, School of Medicine, University of California, Davis, Sacramento, CA Department of Surgery, University of Utah, Salt Lake City, UT Department of Surgery, University of South Florida, Tampa, FL; Department of Surgery Saint Barnabas, Livingston, NJ Department of Surgery, University of Wisconsin, Madison, WI Department of Surgery, University of Iowa, Iowa City, IA Department of Surgery, Wake Forrest University, Winston-Salem, NC Department of Surgery, Institute of Surgical Research, San Antonio, TX Department of Surgery, Arizona Burn Center, Maricopa, AZ Department of Surgery, Metro Health Center, Cleveland, OH; Department of Surgery Ascension Via Christi St. Francis, Wichita, KS Department of Surgery, University of Michigan, Ann Arbor, MI Department of Pharmacy, University of Tennessee Health Science Center, Memphis, TN Department of Surgery, West Penn Medical Center, Pittsburgh, PA Department of Plastic Surgery, University of Alberta, Edmonton, Alberta Department of Surgery, Massachusetts General Hospital, Boston, MA Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, TX Department of Surgery, University of Texas Medical Branch, Galveston, TX Department of Surgery, University of Loyola, Maywood, IL Department of Plastic Surgery, University of Indiana, Indianapolis, IN.

Objectives: ABRUPT was a prospective, non-interventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, in order to design a future prospective randomized trial.

Summary Background Data: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation.

Methods: Patients ≥ 18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols.

Results: Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2± 2.3 versus 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours) but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤ 12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone.

Conclusion: Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate.
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http://dx.doi.org/10.1097/SLA.0000000000005166DOI Listing
August 2021

Flood disturbance affects morphology and reproduction of woody riparian plants.

Sci Rep 2021 Aug 13;11(1):16477. Epub 2021 Aug 13.

Department of Geography, King's College London, 40 Aldwych, London, WC2B 4BG, UK.

Riparian forests are structured and maintained by their hydrology. Woody riparian plants typically adapt to the local flood regime to maximise their likelihood of survival and reproductive success. Understanding how extant trees form and reproduce in response to flood disturbance is crucial for predicting vegetation changes and informing restoration. Working in a temperate evergreen riparian forest, we aimed to determine whether disturbance-based responses of plants found in other ecosystems also typify woody plants in riparian forests where disturbances are often mild or chronic, non-lethal, annual events. Using plant surveys and 20-year modelled hydrological data, we examined whether (1) the morphology (main stem diameter, height, crown width, crown extent, stem leaning) and (2) reproduction type (sexual and asexual reproduction) and extent of three dominant woody species (Eucalyptus camphora, Leptospermum lanigerum and Melaleuca squarrosa) vary with flood regime (flood frequency and flood duration); and (3) whether different morphology is associated with different reproductive strategies. Increased flooding generally resulted in increased stem numbers and greater stem leaning-morphologies associated with asexual reproduction-of our study species. More frequent flooding also reduced plant size and sexual reproduction in E. camphora. Sexual reproduction in the studied species was more common in taller plants with single, more upright stems in good condition. Flexible morphology and plastic reproductive strategy may constitute an adaptation of trees to mild or chronic disturbance in floodplains. Our findings suggest that flood regime (i.e. variable frequency and duration of flooding events) is critical to the structural integrity and self-maintenance of species-diverse riparian forests.
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http://dx.doi.org/10.1038/s41598-021-95543-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363665PMC
August 2021

A 24-generation-old founder mutation impairs splicing of RBBP8 in Pakistani families affected with Jawad syndrome.

Clin Genet 2021 Oct 16;100(4):486-488. Epub 2021 Jul 16.

Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Jawad syndrome is a multiple congenital anomaly and intellectual disability syndrome with mutation in RBBP8 reported only in two families. Here, we report on two new families from Pakistan and identified a previously reported variant in RBBP8, NM_002894.3:c.1808-1809delTA. We could show that this mutation impairs splicing resulting in two different abnormal transcripts. Finally, we could verify a shared haplotype among all four families and estimate the founder event to have occurred some 24 generations ago.
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http://dx.doi.org/10.1111/cge.14028DOI Listing
October 2021

RNA and quantitative proteomic analysis of Dictyostelium knock-out cells lacking the core autophagy proteins ATG9 and/or ATG16.

BMC Genomics 2021 Jun 15;22(1):444. Epub 2021 Jun 15.

Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany.

Background: Autophagy is an evolutionary ancient mechanism that sequesters substrates for degradation within autolysosomes. The process is driven by many autophagy-related (ATG) proteins, including the core members ATG9 and ATG16. However, the functions of these two core ATG proteins still need further elucidation. Here, we applied RNA and tandem mass tag (TMT) proteomic approaches to identify differentially expressed genes (DEGs) and proteins (DEPs) in Dictyostelium discoideum ATG9‾, ATG16‾ and ATG9‾/16‾ strains in comparison to AX2 wild-type cells.

Result: In total, we identified 332 (279 up and 53 down), 639 (487 up and 152 down) and 260 (114 up and 146 down) DEGs and 124 (83 up and 41 down), 431 (238 up and 193 down) and 677 (347 up and 330 down) DEPs in ATG9‾, ATG16‾ and ATG9‾/16‾ strains, respectively. Thus, in the single knock-out strains, the number of DEGs was higher than the number of DEPs while in the double knock-out strain the number of DEPs was higher. Comparison of RNA and proteomic data further revealed, that only a small proportion of the transcriptional changes were reflected on the protein level. Gene ontology (GO) analysis revealed an enrichment of DEPs involved in lipid metabolism and oxidative phosphorylation. Furthermore, we found increased expression of the anti-oxidant enzymes glutathione reductase (gsr) and catalase A (catA) in ATG16‾ and ATG9‾/16‾ cells, respectively, indicating adaptation to excess reactive oxygen species (ROS).

Conclusions: Our study provides the first combined transcriptome and proteome analysis of ATG9‾, ATG16‾ and ATG9‾/16‾ cells. Our results suggest, that most changes in protein abundance were not caused by transcriptional changes, but were rather due to changes in protein homeostasis. In particular, knock-out of atg9 and/or atg16 appears to cause dysregulation of lipid metabolism and oxidative phosphorylation.
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http://dx.doi.org/10.1186/s12864-021-07756-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204557PMC
June 2021

Recent Sexual Assault Predicting Changes in Coping Motives for Alcohol Use in First-Year College Women.

Violence Vict 2021 Jun;36(3):424-435

Department of Psychology, George Mason University, Fairfax, Virginia, USA.

Sexual assault and heavy alcohol consumption are common among college students. There is strong evidence that the two are associated, but more remains to be understood about the nature of the relationship. Drinking motives have been found to mediate the relationship between sexual assault and drinking problems and between depression and alcohol risk (Kenney, Anderson, & Stein, 2018; Lindgren, Neighbors, Blayney, Mullins, & Kasen, 2012), however drinking motives have not been studied as an outcome. The current study investigated the impact of a recent sexual assault on the endorsement of coping motives for drinking in first year college women using hierarchical regression analysis with Time 2 coping motives as the outcome variable. Lifetime experience of sexual assault and Time 1 coping motives were entered in the first step of the model and a dichotomous variable indicating a recent sexual assault was entered in the second step of the model. Sexual assault during the first semester of college was found to be a significant predictor of coping motives at the end of the semester after controlling for lifetime history of sexual assault and endorsement of coping motives at Time 1. These findings suggest that coping motives for drinking may change following a sexual assault and are of concern due to the negative outcomes associated with drinking to cope. Drinking motives may be an important target of interventions provided to survivors of sexual assault to reduce risk of future drinking-related problems.
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http://dx.doi.org/10.1891/VV-D-19-00159DOI Listing
June 2021

Impact of the Microbial Origin and Active Microenvironment on the Shape of Biogenic Elemental Selenium Nanomaterials.

Environ Sci Technol 2021 07 21;55(13):9161-9171. Epub 2021 May 21.

Helmholtz-Zentrum Dresden - Rossendorf, Institute of Resource Ecology, Bautzner Landstrasse 400, 01328 Dresden, Germany.

The shape of nanomaterials affects their colloidal properties, cellular uptake, and fate in the environment. The microbial origin and microenvironment can play a role in altering the shape of the nanomaterial. However, such studies have never been conducted. Here, we demonstrate that the selenium nanomaterials produced by K-12 are stable and remain as BioSe-Nanospheres under thermophilic conditions, while those produced by anaerobic granular sludge transform to BioSe-Nanorods, due to a lower quantity of proteins coating these nanoparticles, which has been verified by proteomics analysis as well as using chemically synthesized selenium nanomaterials. Furthermore, the presence of JG-B5T transform the purified BioSe-Nanospheres produced by K-12 to BioSe-Nanorods, though they are not transformed in the absence of JG-B5T. This is due to the production of peptidases by JG-B5T that cleaves the protein coating the BioSe-Nanospheres produced by K-12, leading to their transformation to trigonal BioSe-Nanorods, which is the thermodynamically more stable state. These findings suggest that the fate of selenium and probably other redox-active elements released from the biological wastewater treatment units needs to be reevaluated and improved by including microbial criteria for better accuracy.
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http://dx.doi.org/10.1021/acs.est.0c07217DOI Listing
July 2021

Protocol for the Mason: Health Starts Here prospective cohort study of young adult college students.

BMC Public Health 2021 05 12;21(1):897. Epub 2021 May 12.

Department of Nutrition and Food Studies, College of Health and Human Services, George Mason University, Peterson Hall 4113, Fairfax, USA.

Background: Young adulthood is a period of increasing independence for the 40% of young adults enrolled in U.S. colleges. Previous research indicates differences in how students' health behaviors develop and vary by gender, race, ethnicity, and socioeconomic status. George Mason University is a state institution that enrolls a highly diverse student population, making it an ideal setting to launch a longitudinal cohort study using multiple research methods to evaluate the effects of health behaviors on physical and psychological functioning, especially during the COVID-19 pandemic.

Results: Mason: Health Starts Here was developed as a longitudinal cohort study of successive waves of first year students that aims to improve understanding of the natural history and determinants of young adults' physical health, mental health, and their role in college completion. The study recruits first year students who are 18 to 24 years old and able to read and understand English. All incoming first year students are recruited through various methods to participate in a longitudinal cohort for 4 years. Data collection occurs in fall and spring semesters, with online surveys conducted in both semesters and in-person clinic visits conducted in the fall. Students receive physical examinations during clinic visits and provide biospecimens (blood and saliva).

Conclusions: The study will produce new knowledge to help understand the development of health-related behaviors during young adulthood. A long-term goal of the cohort study is to support the design of effective, low-cost interventions to encourage young adults' consistent performance of healthful behaviors, improve their mental health, and improve academic performance.
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http://dx.doi.org/10.1186/s12889-021-10969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114021PMC
May 2021

Enabling clinician engagement in safety and quality improvement.

Aust Health Rev 2021 Aug;45(4):455-462

Clinical Excellence Commission, Level 3, 1 Reserve Road, St Leonards, NSW 2065, Australia. Email:

Objective The aim of this study was to determine how individual, group and leadership factors influence clinician engagement in safety and quality improvement work. Methods The study was conducted through an online questionnaire. Participants were alumni of Australian healthcare safety and quality improvement capability development programs. Relationships between five factors influencing clinicians' perception of value for time and effort in safety and quality improvement work were explored. The five factors were psychological empowerment; task cohesion; social cohesion; transformational leadership behaviour of project leads and sponsors; and value for time and effort for self and patients. Correlation and regression analyses were used to explore the aspects of the hypothesised model. Moderation and mediation analysis was then used to explore the relationships further. Structural equation modelling was used to determine the path model. Results All factors showed strong positive correlations, with psychological empowerment and transformational leadership having the strongest relationships with perceived value for effort for self and patient. The factorial structure of measures was examined, and all indicators loaded significantly on their corresponding latent constructs and the model showed a good fit to the data. Conclusions The findings of this study suggest that the most crucial factor to clinician engagement in safety and quality improvement at the point of care is the leader's behaviour and how that influences team dynamics and individual motivation and empowerment. What is known about the topic? Healthcare organisations remain challenged regarding clinician engagement in safety and quality improvement. Although much is known about clinicians' perceptions of safety and quality, there is more to understand about what practically motivates clinicians to engage. Tapping into individual, group and leadership factors' influences on clinician engagement offers a deeper perspective. What does this paper add? This study explored the individual, group and leadership factors that drive clinician engagement. The factors include the clinician's individual motivation and empowerment to participate, the group dynamics that surround the clinician and the leadership behaviours of the team's leader. The research design allowed for greater understanding about how and to what extent these factors drive clinician engagement. The study's findings can be applied in practice in capability development activities or leadership for safety and quality improvement. What are the implications for practitioners? Rather than taking a perspective that the clinician needs to engage, this study suggests a strong onus on leadership behaviours to engage those clinicians. Focusing on the self as leader and a leader's own behaviours, as well as how those behaviours are fostering positive team dynamics and motivating and empowering individual team members, will have a great benefit on clinician engagement in safety and quality improvement. Higher clinical engagement in safety and quality improvement should translate into better value care.
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http://dx.doi.org/10.1071/AH20151DOI Listing
August 2021

Parenting-focused mindfulness intervention reduces stress and improves parenting in highly-stressed mothers of adolescents.

Mindfulness (N Y) 2021 Feb 21;12(2):450-462. Epub 2018 Sep 21.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511.

Parent stress has been associated with negative outcomes for youth and may be particularly high during adolescence. Mindfulness interventions have the potential to reduce parent stress and to improve parenting behavior and parent-child relationship quality. The present randomized controlled study examined effects of a parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, for highly stressed parents of adolescents. Eighty three mothers of 12-17 year olds reporting high stress were randomly assigned to the PM intervention or to a minimal-intervention Parent Education (PE) control group. At pre- and post-intervention, mothers reported on their mindfulness, stress, parenting stress, mindful parenting, and parent-adolescent relationship quality. At pre- and post-intervention, mothers' observed parenting behaviors and reported negative emotional responses to a laboratory parent-adolescent interaction task (PAIT) were also collected. Findings indicated that the PM intervention, compared to PE, increased mothers' mindfulness, reduced parenting stress in two domains, increased mindful parenting related to emotional awareness in parenting, and improved parent-adolescent relationship quality. For mothers of girls (but not mothers of boys), the PM intervention also decreased negative parenting behavior and decreased negative emotional responses in PAIT. Effects sizes were medium to large. In sum, findings support parenting-focused mindfulness training as a viable intervention strategy for highly-stressed parents.
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http://dx.doi.org/10.1007/s12671-018-1026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962755PMC
February 2021

Affective Neural Mechanisms of a Parenting-Focused Mindfulness Intervention.

Mindfulness (N Y) 2021 Feb 16;12(2):392-404. Epub 2019 Feb 16.

Caitlin Turpyn, Department of Psychology, George Mason University, Fairfax, VA 22030, USA; Tara Chaplin, Department of Psychology, George Mason University, Fairfax, VA 22030, USA; Sarah Fischer, Department of Psychology, George Mason University, Fairfax, VA 22030, USA; James Thompson, Department of Psychology, George Mason University, Fairfax, VA 22030, USA; John Fedota, Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, 21224, USA; Ruth Baer, Department of Psychology, University of Kentucky, Lexington, KY, 40506, USA; Alexandra Martelli, Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284, USA.

Objectives: Behavioral evidence suggests that parenting-focused mindfulness interventions can improve parenting practices and enhance family wellbeing, potentially operating through altered emotional processing in parents. However, the mechanisms through which parent mindfulness interventions achieve their positive benefits have not yet been empirically tested, knowledge which is key to refine and maximize intervention effects. Thus, as part of a randomized controlled trial, the present study examined the affective mechanisms of an 8-week parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, versus a minimal-intervention parent education control.

Methods: Twenty highly stressed mothers of adolescents completed pre- and post-intervention behavioral and fMRI sessions, in which mothers completed a parent-adolescent conflict interaction, fMRI emotion task, and fMRI resting state scan. Mothers reported on their mindful parenting, and maternal emotional reactivity to the parent-adolescent conflict task was assessed via observed emotion expression, self-reported negative emotion, and salivary cortisol reactivity.

Results: Results indicated that the PM intervention increased brain responsivity in left posterior insula in response to negative affective stimuli, and altered resting state functional connectivity in regions involved in self-reference, behavioral regulation, and social-emotional processing. Changes in mothers' brain function and connectivity were associated with increased mindful parenting and decreased emotional reactivity to the parent-adolescent conflict task.

Conclusions: Findings suggest that mindfulness-based changes in maternal emotional awareness at the neurobiological level are associated with decreased emotional reactivity in parenting interactions, illuminating potential neurobiological targets for future parent-focused intervention.
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http://dx.doi.org/10.1007/s12671-019-01118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962669PMC
February 2021

Where Do Models for Change Management, Improvement and Implementation Meet? A Systematic Review of the Applications of Change Management Models in Healthcare.

J Healthc Leadersh 2021 12;13:85-108. Epub 2021 Mar 12.

School of Population Health, University of New South Wales, Sydney, NSW, Australia.

Background: The increasing prioritisation of healthcare quality across the six domains of efficiency, safety, patient-centredness, effectiveness, timeliness and accessibility has given rise to accelerated change both in the uptake of initiatives and the realisation of their outcomes to meet external targets. Whilst a multitude of change management methodologies exist, their application in complex healthcare contexts remains unclear. Our review sought to establish the methodologies applied, and the nature and effectiveness of their application in the context of healthcare.

Methods: A systematic review and narrative synthesis was undertaken. Two reviewers independently screened the titles and abstracts followed by the full-text articles that were potentially relevant against the inclusion criteria. An appraisal of methodological and reporting quality of the included studies was also conducted by two further reviewers.

Results: Thirty-eight studies were included that reported the use of 12 change management methodologies in healthcare contexts across 10 countries. The most commonly applied methodologies were Kotter's Model (19 studies) and Lewin's Model (11 studies). Change management methodologies were applied in projects at local ward or unit level (14), institutional level (12) and system or multi-system (6) levels. The remainder of the studies provided commentary on the success of change efforts that had not utilised a change methodology with reference to change management approaches.

Conclusion: Change management methodologies were often used as guiding principle to underpin a change in complex healthcare contexts. The lack of prescription application of the change management methodologies was identified. Change management methodologies were valued for providing guiding principles for change that are well suited to enable methodologies to be applied in the context of complex and unique healthcare contexts, and to be used in synergy with implementation and improvement methodologies.
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http://dx.doi.org/10.2147/JHL.S289176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966357PMC
March 2021

Where Do Models for Change Management, Improvement and Implementation Meet? A Systematic Review of the Applications of Change Management Models in Healthcare.

J Healthc Leadersh 2021 12;13:85-108. Epub 2021 Mar 12.

School of Population Health, University of New South Wales, Sydney, NSW, Australia.

Background: The increasing prioritisation of healthcare quality across the six domains of efficiency, safety, patient-centredness, effectiveness, timeliness and accessibility has given rise to accelerated change both in the uptake of initiatives and the realisation of their outcomes to meet external targets. Whilst a multitude of change management methodologies exist, their application in complex healthcare contexts remains unclear. Our review sought to establish the methodologies applied, and the nature and effectiveness of their application in the context of healthcare.

Methods: A systematic review and narrative synthesis was undertaken. Two reviewers independently screened the titles and abstracts followed by the full-text articles that were potentially relevant against the inclusion criteria. An appraisal of methodological and reporting quality of the included studies was also conducted by two further reviewers.

Results: Thirty-eight studies were included that reported the use of 12 change management methodologies in healthcare contexts across 10 countries. The most commonly applied methodologies were Kotter's Model (19 studies) and Lewin's Model (11 studies). Change management methodologies were applied in projects at local ward or unit level (14), institutional level (12) and system or multi-system (6) levels. The remainder of the studies provided commentary on the success of change efforts that had not utilised a change methodology with reference to change management approaches.

Conclusion: Change management methodologies were often used as guiding principle to underpin a change in complex healthcare contexts. The lack of prescription application of the change management methodologies was identified. Change management methodologies were valued for providing guiding principles for change that are well suited to enable methodologies to be applied in the context of complex and unique healthcare contexts, and to be used in synergy with implementation and improvement methodologies.
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http://dx.doi.org/10.2147/JHL.S289176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966357PMC
March 2021

Effects of A Parenting-Focused Mindfulness Intervention on Adolescent Substance Use and Psychopathology: A Randomized Controlled Trial.

Res Child Adolesc Psychopathol 2021 07 23;49(7):861-875. Epub 2021 Feb 23.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Substance use and psychopathology symptoms increase in adolescence. One key risk factor for these is high parent stress. Mindfulness interventions reduce stress in adults and may be useful to reduce parent stress and prevent substance use (SU) and psychopathology in adolescents. This study tested the feasibility and effects of a mindfulness intervention for parents on adolescent SU and psychopathology symptoms. Ninety-six mothers of 11-17 year olds were randomly assigned to a mindfulness intervention for parents (the Parenting Mindfully [PM] intervention) or a brief parent education [PE] control group. At pre-intervention, post-intervention, 6-month follow-up, and 1-year follow-up, adolescents reported on SU and mothers and adolescents reported on adolescent externalizing and internalizing symptoms. Primary intent to treat analyses found that the PM intervention prevented increases in adolescent SU over time, relative to the PE control group. The PM intervention also prevented increases in mother-reported externalizing symptoms over time relative to the PE control group. However, PM did not have a significant effect on internalizing symptoms. PM had an indirect effect on adolescent-reported externalizing symptoms through greater mother mindfulness levels at post-intervention, suggesting mother mindfulness as a potential intervention mechanism. Notably, while mothers reported high satisfaction with PM, intervention attendance was low (31% of mothers attended zero sessions). Secondary analyses with mothers who attended >  = 50% of the interventions (n = 48) found significant PM effects on externalizing symptoms, but not SU. Overall, findings support mindfulness training for parents as a promising intervention and future studies should work to promote accessibility for stressed parents.Clinical Trials Identifier: NCT02038231; Date of Registration: January 13, 2014.
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http://dx.doi.org/10.1007/s10802-021-00782-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159911PMC
July 2021

Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab.

Therap Adv Gastroenterol 2021 14;14:1756284820982802. Epub 2021 Jan 14.

Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen, 91054, Germany.

Background: Long-term data on inflammatory bowel disease (IBD) patients switched from originator to biosimilar infliximab SB2 are lacking. The aim of the conducted study was to investigate the effectiveness, immunogenicity and safety of a large prospectively followed-up IBD patient cohort that was entirely switched from originator infliximab to biosimilar SB2 treatment.

Methods: This was a prospective, single-center, longitudinal, observational study describing clinical outcomes in IBD patients, over an 80-week period following switch from originator infliximab to SB2. Primary outcome measures were change of disease activity [Harvey-Bradshaw Index for Crohn's disease (CD), partial Mayo Score for ulcerative colitis (UC)], C-reactive protein (CRP), infliximab trough levels (TLs), anti-drug antibodies (ADAs) and adverse events.

Results: One hundred and forty-four IBD patients (94 CD, 50 UC), with median duration of 30.5 months' (range 2-110) treatment with originator infliximab were evaluated. Mean change of disease activity compared with baseline was -0.9 (SD 2.6), -0.4 (2.2) and -0.4 (2.0) in CD; 0.1 (1.1), 0.1 (1.1) and 0.1 (1.3) in UC patients at weeks 24, 48 and 72. Median infliximab TLs were 6.2 µg/ml (interquartile range 2.3-12.2), 5.0 µg/ml (2.7-10.0), 6.6 µg/ml (3.5-12.4) and 5.1 µg/ml (2.7-10.9) at baseline and weeks 24, 48 and 72. Median CRP levels were within normal ranges throughout the study. After the switch, 9.8% of the patients developed new ADAs. Persistence on SB2 was 90% (95% confidence interval 0.85-0.95), 79% (0.72-0.86), 72% (0.64-0.80) at weeks 26, 52 and 78. Serious adverse events occurred in 11 patients.

Conclusion: Over the individual patient follow-up of 80 weeks, switch to biosimilar SB2 from originator infliximab does not result in increased disease activity or changed immunogenicity patterns. The switch to SB2 was well tolerated.
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http://dx.doi.org/10.1177/1756284820982802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812413PMC
January 2021

Lack of guilt, shame, and remorse following weight stigma expression: a real-time assessment pilot study.

PeerJ 2020 22;8:e10294. Epub 2020 Dec 22.

Department of Psychology, George Mason University, Fairfax, VA, United States of America.

Objective: Weight stigma is pervasive and is associated with negative health and psychological outcomes. Few studies have examined weight stigma perpetration or the emotions individuals experience after perpetrating weight stigma. This study used experience sampling to explore the nature and frequency of weight stigma behaviors and cognitions and moral emotions (shame, guilt, remorse, pride) in the perpetrator following weight stigma perpetration.

Methods: Participants were college students ( = 31, 77.1% female). Participants completed baseline measures of anti-fat attitudes and one week of experience sampling phone prompts assessing: (1) weight stigma behaviors and cognitions and (2) moral emotions. Generalized estimating equation analyses were used to model trajectories of moral emotions after weight stigma events.

Results: Thirty-one participants reported 1,008 weight stigma events over 7.5 days. Feelings of guilt, shame, and remorse decreased after weight stigma perpetration. Individuals also reported feeling less proud after engaging in weight stigma.

Conclusions: Weight stigma occurs frequently as reported by perpetrators. A lack of remorse, guilt, and shame is evident in undergraduates after they express weight stigma; however, individuals in this study also reported feeling less pride after perpetration. This study highlights the need for future studies to explore the expression of weight stigma from the perspective of perpetrators instead of targets. Results highlight the pervasiveness and normative nature of weight stigma perpetration in everyday life and the need to better understand the emotional response following weight stigma perpetration as a potential mechanism of its perpetuation.
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http://dx.doi.org/10.7717/peerj.10294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761191PMC
December 2020

Managing Complex Healthcare Change: A Qualitative Exploration of Current Practice in New South Wales, Australia.

J Healthc Leadersh 2020 10;12:143-151. Epub 2020 Dec 10.

School of Population Health, University of New South Wales, Sydney, New South Wales, 2052, Australia.

Purpose: As the cost of healthcare continues to rise, healthcare organizations internationally are seeking long-term solutions to eradicate inefficiency, achieve value-based healthcare, and minimize hospital inpatient services. This requires transformational change in healthcare organizations, and associated change management and leadership capability at multiple levels. Despite the critical need for effective change leadership and management in healthcare, limited evidence exists that this currently occurs in addition to the capability and capacity for managing change in health systems.

Methods: Semi-structured interviews were undertaken with 16 healthcare managers and leaders at a range of levels in nine healthcare organizations across the public health system of one Australian state (New South Wales), including metropolitan, regional and rural geographical areas. Thematic content analysis was undertaken with the emergent data.

Results: Four key themes emerged from the data: 1) lack of adoption of frameworks and methods for change management for any scope or scale of change, 2) inadequate resources for delivering, managing and leading change, 3) insufficient leadership, capacity and capability in managing change, and 4) the need for support and culture that supports change at all levels of the system.

Conclusion: Ensuring dedicated resources for change and sufficient capacity and capability amongst health professionals and managers at every level in a health system are required for effective management of change. An enabling culture for change, supported by adequate education and training in change leadership and management are critical in order for the benefits of health service and system changes to be realised.
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http://dx.doi.org/10.2147/JHL.S274958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735780PMC
December 2020

Would people living with epilepsy benefit from palliative care?

Epilepsy Behav 2021 01 24;114(Pt A):107618. Epub 2020 Nov 24.

Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.
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http://dx.doi.org/10.1016/j.yebeh.2020.107618DOI Listing
January 2021

Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model.

Mol Neurodegener 2020 11 9;15(1):65. Epub 2020 Nov 9.

Department of Medicine, Box 675, University of Rochester Medical Center, Nephrology Division, 601 Elmwood Avenue, Rochester, NY, 14642, USA.

Background: A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear.

Methods: Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation - collectively referred as "PTM-mimetics" - as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age. Genetically-encoded fluorescent biosensors were expressed in touch neurons and used to measure neuronal morphology, mitochondrial morphology, mitophagy, and macro autophagy.

Results: Unlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage neuronal mitophagy in response to mitochondrial stress.

Conclusions: Limiting the expression of tau results in a genetic model where modifications that mimic pathologic tauopathy-associated PTMs contribute to cryptic, stress-inducible phenotypes that evolve with age. These findings and their relationship to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.
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http://dx.doi.org/10.1186/s13024-020-00410-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654055PMC
November 2020

Advancing Critical Applications of High Resolution Mass Spectrometry for DOM Assessments: Re-Engaging with Mass Spectral Principles, Limitations, and Data Analysis.

Environ Sci Technol 2020 10 17;54(19):11654-11656. Epub 2020 Sep 17.

Department of Civil, Environmental and Architectural Engineering, Environmental Engineering Program, University of Colorado Boulder, Boulder, Colorado 80309, United States.

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http://dx.doi.org/10.1021/acs.est.0c04557DOI Listing
October 2020

Implicit and Explicit Anti-Fat Attitude Change Following Brief Cognitive Dissonance Intervention for Weight Stigma.

Obesity (Silver Spring) 2020 10 26;28(10):1853-1859. Epub 2020 Aug 26.

Department of Psychology, George Mason University, Fairfax, Virginia, USA.

Objective: Research has demonstrated that explicit anti-fat attitudes decrease immediately following a brief cognitive dissonance-based intervention targeting weight stigma. The current study explores changes in explicit and implicit anti-fat attitudes immediately following a cognitive dissonance-based weight stigma intervention and 1 week after.

Methods: College students (N = 156) were randomly assigned to a control or dissonance weight stigma intervention. Weight stigma attitudes were assessed at three time points, and participants completed a measure of values at baseline. Participants in the dissonance condition were told that they had anti-fat attitudes that were inconsistent with their values, whereas participants in the control group were told that their attitudes aligned with their values. All participants reviewed feedback at a follow-up visit before completing explicit and implicit weight stigma assessments a final time.

Results: Individuals in the dissonance condition reported statistically significant decreases in explicit attitudes from Visit 1 to Visit 3. In contrast, there was not a significant condition by time interaction on implicit attitudes.

Conclusions: This study provides support for cognitive dissonance-based interventions to reduce explicit, but not implicit, anti-fat attitudes following repeated exposure to dissonance induction.
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http://dx.doi.org/10.1002/oby.22909DOI Listing
October 2020

Hepatitis C Clearance by Direct-Acting Antivirals Impacts Glucose and Lipid Homeostasis.

J Clin Med 2020 Aug 21;9(9). Epub 2020 Aug 21.

Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany.

Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters.

Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment.

Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time ( = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: = 0.45; = 0.003, pSWE: = 0.35; = 0.02, APRI: = 0.44; = 0.003, FIB-4: = 0.41; < 0.001).

Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
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http://dx.doi.org/10.3390/jcm9092702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564474PMC
August 2020

Mechanical Metamaterials on the Way from Laboratory Scale to Industrial Applications: Challenges for Characterization and Scalability.

Materials (Basel) 2020 Aug 14;13(16). Epub 2020 Aug 14.

Fraunhofer IWM Institute for Mechanics of Materials, 79108 Freiburg im Breisgau, Germany.

Mechanical metamaterials promise a paradigm shift in materials design, as the classical processing-microstructure-property relationship is no longer exhaustively describing the material properties. The present review article provides an application-centered view on the research field and aims to highlight challenges and pitfalls for the introduction of mechanical metamaterials into technical applications. The main difference compared to classical materials is the addition of the mesoscopic scale into the materials design space. Geometrically designed unit cells, small enough that the metamaterial acts like a mechanical continuum, enabling the integration of a variety of properties and functionalities. This presents new challenges for the design of functional components, their manufacturing and characterization. This article provides an overview of the design space for metamaterials, with focus on critical factors for scaling of manufacturing in order to fulfill industrial standards. The role of experimental and simulation tools for characterization and scaling of metamaterial concepts are summarized and herewith limitations highlighted. Finally, the authors discuss key aspects in order to enable metamaterials for industrial applications and how the design approach has to change to include reliability and resilience.
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http://dx.doi.org/10.3390/ma13163605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475856PMC
August 2020

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

Epilepsy Curr 2020 Sep 21;20(5):245-264. Epub 2020 Aug 21.

2948Drake University, Des Moines, IA, USA.

Purpose: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE.

Methods: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process.

Results: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study).

Conclusions: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.
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http://dx.doi.org/10.1177/1535759720928269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576920PMC
September 2020

Speech-language pathologists and prosody: Clinical practices and barriers.

J Commun Disord 2020 Sep - Oct;87:106024. Epub 2020 Jul 3.

Communication Sciences and Disorders, University of Mississippi, University, MS 38677, United States; Speech-Language-Hearing: Sciences and Disorders, 1000 Sunnyside Avenue, University of Kansas, Lawrence, KS 66045, United States. Electronic address:

Prosodic impairments occur in many clinical populations, including those with autism and motor speech disorders. These impairments can negatively impact intelligibility, as well as an individual's ability to signal and understand linguistic contrasts and emotions. For this study, we surveyed 245 Speech-Language Pathologists (SLPs) to assess their clinical practices with regards to prosody and to identify potential barriers to addressing prosody in the clinic. While a majority of respondents agreed that prosody was within their scope of practice, they reported that they rarely assessed or treated prosody when they suspected that a client had a prosodic impairment. Overall, respondents felt they were lacking in knowledge of the nature of prosody, experience with clients who have prosodic impairments, and knowledge of assessment and treatment methods for prosody. Recommendations include increasing training opportunities, encouraging collaboration between researchers and SLPs with expertise in prosody, and the development of a clinically feasible prosody assessment.
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http://dx.doi.org/10.1016/j.jcomdis.2020.106024DOI Listing
September 2021

Scoring functions for drug-effect similarity.

Brief Bioinform 2021 May;22(3)

IBIMA, Rostock University Medical Center, Rostock, 18041, Germany.

Motivation: The difficulty to find new drugs and bring them to the market has led to an increased interest to find new applications for known compounds. Biological samples from many disease contexts have been extensively profiled by transcriptomics, and, intuitively, this motivates to search for compounds with a reversing effect on the expression of characteristic disease genes. However, disease effects may be cell line-specific and also depend on other factors, such as genetics and environment. Transcription profile changes between healthy and diseased cells relate in complex ways to profile changes gathered from cell lines upon stimulation with a drug. Despite these differences, we expect that there will be some similarity in the gene regulatory networks at play in both situations. The challenge is to match transcriptomes for both diseases and drugs alike, even though the exact molecular pathology/pharmacogenomics may not be known.

Results: We substitute the challenge to match a drug effect to a disease effect with the challenge to match a drug effect to the effect of the same drug at another concentration or in another cell line. This is welldefined, reproducible in vitro and in silico and extendable with external data. Based on the Connectivity Map (CMap) dataset, we combined 26 different similarity scores with six different heuristics to reduce the number of genes in the model. Such gene filters may also utilize external knowledge e.g. from biological networks. We found that no similarity score always outperforms all others for all drugs, but the Pearson correlation finds the same drug with the highest reliability. Results are improved by filtering for highly expressed genes and to a lesser degree for genes with large fold changes. Also a network-based reduction of contributing transcripts was beneficial, here implemented by the FocusHeuristics. We found no drop in prediction accuracy when reducing the whole transcriptome to the set of 1000 landmark genes of the CMap's successor project Library of Integrated Network-based Cellular Signatures. All source code to re-analyze and extend the CMap data, the source code of heuristics, filters and their evaluation are available to propel the development of new methods for drug repurposing.

Availability: https://bitbucket.org/ibima/moldrugeffectsdb.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Briefings in Bioinformatics online.
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http://dx.doi.org/10.1093/bib/bbaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138836PMC
May 2021

Functional Characterisation of the Autophagy ATG12~5/16 Complex in .

Cells 2020 05 9;9(5). Epub 2020 May 9.

Centre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.

Macroautophagy, a highly conserved and complex intracellular degradative pathway, involves more than 20 core autophagy (ATG) proteins, among them the hexameric ATG12~5/16 complex, which is part of the essential ubiquitin-like conjugation systems in autophagy. single, double, and triple gene knock-out mutant strains displayed similar defects in the conjugation of ATG8 to phosphatidylethanolamine, development, and cell viability upon nitrogen starvation. This implies that ATG5, 12 and 16 act as a functional unit in canonical autophagy. Macropinocytosis of TRITC dextran and phagocytosis of yeast were significantly decreased in ATG5¯ and ATG5¯/12¯ and even further in ATG5¯/12¯/16¯ cells. In contrast, plaque growth on was about twice as fast for ATG5¯ and ATG5¯/12¯/16¯ cells in comparison to AX2, but strongly decreased for ATG5¯/12¯ cells. Along this line, phagocytic uptake of was significantly reduced in ATG5¯/12¯ cells, while no difference in uptake, but a strong increase in membrane association of was seen for ATG5¯ and ATG5¯/12¯/16¯ cells. Proteasomal activity was also disturbed in a complex fashion, consistent with an inhibitory activity of ATG16 in the absence of ATG5 and/or ATG12. Our results confirm the essential function of the ATG12~5/16 complex in canonical autophagy, and furthermore are consistent with autophagy-independent functions of the complex and its individual components. They also strongly support the placement of autophagy upstream of the ubiquitin-proteasome system (UPS), as a fully functional UPS depends on autophagy.
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http://dx.doi.org/10.3390/cells9051179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290328PMC
May 2020
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