Publications by authors named "K C Prager"

104 Publications

Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial.

EBioMedicine 2022 Jun 29;80:104021. Epub 2022 Apr 29.

MODAG GmbH, Wendelsheim, Germany; Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany. Electronic address:

Background: Synucleinopathies such as Parkinson ́s disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) are characterized by deposition of misfolded and aggregated α-synuclein. Small aggregates (oligomers) of α-synuclein have been shown to be the most relevant neurotoxic species and are targeted by anle138b, an orally bioavailable small molecule compound which shows strong disease-modifying effects in animal models of synucleinopathies.

Methods: Anle138b was studied in a single-centre, double-blind, randomised, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects. Eligible participants were randomly assigned (1:1 for sentinel subjects and 1:5 for main group) to placebo or anle138b (dose range 50 mg to 300 mg per day), respectively. In addition, the effect of food on the pharmakokinetics of anle138b in healthy subjects was examined in doses of 150 mg per day. Participants were randomized to treatment sequence (fed→fasted) or (fasted→fed). Treatment was administered orally in hard gelatine capsules containing either 10 mg or 30 mg of anle138b or excipient only. The primary endpoints were safety and tolerability, the secondary endpoint was pharmakokinetics. Data from all randomized individuals were evaluated.

Clinicaltrials: gov-identifier: NCT04208152. EudraCT-number: 2019-004218-33.

Findings: Between December 17, 2019 and June 27, 2020 196 healthy volunteers were screened and 68 participants were enrolled. Of these, all completed the study per protocol. There were no major protocol deviations. Adverse events in this healthy volunteer trial were mostly mild and all fully recovered or resolved prior to discharge. From baseline to completion of the trial no medically significant individual changes were observed in any system organ class. Already at multiple doses of 200 mg, exposure levels above the fully effective exposure in the MI2 mouse Parkinson model were observed.

Interpretation: The favourable safety and PK profile of anle138b in doses resulting in exposures above the fully effective plasma level in a mouse Parkinson model warrant further clinical trials in patients with synucleinopathies.

Funding: This study was funded by MODAG GmbH and by the Michael J. Fox foundation for Parkinson's Research.
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http://dx.doi.org/10.1016/j.ebiom.2022.104021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065877PMC
June 2022

A License to Practice Medicine Cannot Be a License to Harm.

Am J Med 2022 Aug 27;135(8):e229-e230. Epub 2022 Feb 27.

Director of Clinical Ethics, Columbia University Medical Center/New York Presbyterian Hospital, New York, NY.

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http://dx.doi.org/10.1016/j.amjmed.2022.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882365PMC
August 2022

In COVID-19 Patients Who Suffer In-Hospital Cardiac Arrest, Cardiopulmonary Resuscitation Outcomes May Be Impacted by Arrest Etiology and Local Pandemic Conditions.

Crit Care Explor 2022 Feb 8;4(2):e0605. Epub 2022 Feb 8.

Columbia University Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, New York, NY.

Objectives: The utility and risks to providers of performing cardiopulmonary resuscitation after in-hospital cardiac arrest in COVID-19 patients have been questioned. Additionally, there are discrepancies in reported COVID-19 in-hospital cardiac arrest survival rates. We describe outcomes after cardiopulmonary resuscitation for in-hospital cardiac arrest in two COVID-19 patient cohorts.

Design: Retrospective cohort study.

Setting: New York-Presbyterian Hospital/Columbia University Irving Medical Center in New York, NY.

Patients: Those admitted with COVID-19 between March 1, 2020, and May 31, 2020, as well as between March 1, 2021, and May 31, 2021, who received resuscitation after in-hospital cardiac arrest.

Interventions: None.

Measurement And Main Results: Among 103 patients with coronavirus disease 2019 who were resuscitated after in-hospital cardiac arrest in spring 2020, most self-identified as Hispanic/Latino or African American, 35 (34.0%) had return of spontaneous circulation for at least 20 minutes, and 15 (14.6%) survived to 30 days post-arrest. Compared with nonsurvivors, 30-day survivors experienced in-hospital cardiac arrest later (day 22 vs day 7; = 0.008) and were more likely to have had an acute respiratory event preceding in-hospital cardiac arrest (93.3% vs 27.3%; < 0.001). Among 30-day survivors, 11 (73.3%) survived to hospital discharge, at which point 8 (72.7%) had Cerebral Performance Category scores of 1 or 2. Among 26 COVID-19 patients resuscitated after in-hospital cardiac arrest in spring 2021, 15 (57.7%) had return of spontaneous circulation for at least 20 minutes, 3 (11.5%) survived to 30 days post in-hospital cardiac arrest, and 2 (7.7%) survived to hospital discharge, both with Cerebral Performance Category scores of 2 or less. Those who survived to 30 days post in-hospital cardiac arrest were younger (46.3 vs 67.8; = 0.03), but otherwise there were no significant differences between groups.

Conclusions: Patients with COVID-19 who received cardiopulmonary resuscitation after in-hospital cardiac arrest had low survival rates. Our findings additionally show return of spontaneous circulation rates in these patients may be impacted by hospital strain and that patients with in-hospital cardiac arrest preceded by acute respiratory events might be more likely to survive to 30 days, suggesting Advanced Cardiac Life Support efforts may be more successful in this subpopulation.
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http://dx.doi.org/10.1097/CCE.0000000000000605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826953PMC
February 2022

Participatory research in times of COVID-19 and beyond: Adjusting your methodological toolkits.

One Earth 2022 Jan;5(1):62-73

Environmental Social Science Research Group (ESSRG), Budapest, Hungary.

Solving grand environmental societal challenges calls for transdisciplinary and participatory methods in social-ecological research. These methods enable co-designing the research, co-producing the results, and co-creating the impacts together with concerned stakeholders. COVID-19 has had serious impacts on the choice of research methods, but reflections on recent experiences of "moving online" are still rare. In this perspective, we focus on the challenge of adjusting different participatory methods to online formats used in five transdisciplinary social-ecological research projects. The key added value of our research is the lessons learned from a comparison of the pros and cons of adjusting a broader set of methods to online formats. We conclude that combining the adjusted online approaches with well-established face-to-face formats into more inclusive hybrid approaches can enrich and diversify the pool of available methods for postpandemic research. Furthermore, a more diverse group of participants can be engaged in the research process.
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http://dx.doi.org/10.1016/j.oneear.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779601PMC
January 2022

Building community resilience in a context of climate change: The role of social capital.

Ambio 2022 Jun 11;51(6):1371-1387. Epub 2022 Jan 11.

School of Energy, Geoscience Infrastructure and Society, Heriot Watt University, Edinburgh, UK.

Social capital is considered important for resilience across social levels, including communities, yet insights are scattered across disciplines. This meta-synthesis of 187 studies examines conceptual and empirical understandings of how social capital relates to resilience, identifying implications for community resilience and climate change practice. Different conceptualisations are highlighted, yet also limited focus on underlying dimensions of social capital and proactive types of resilience for engaging with the complex climate change challenge. Empirical insights show that structural and socio-cultural aspects of social capital, multiple other factors and formal actors are all important for shaping the role of social capital for guiding resilience outcomes. Thus, finding ways to work with these different elements is important. Greater attention on how and why outcomes emerge, interactions between factors, approaches of formal actors and different socio-cultural dimensions will advance understandings about how to nurture social capital for resilience in the context of climate change.
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http://dx.doi.org/10.1007/s13280-021-01678-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005590PMC
June 2022
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