In the Service of the Electress

This chapter begins by looking at Elizabeth Stuart's use of jewellery to understand the complex networks of honour and obligation she was negotiating. By the middle of 1615, the atmosphere in Heidelberg had changed, and for the better. Elizabeth asserted her authority in Heidelberg by taking responsibility for a small area of the soon-to-be-famous Heidelberger Gardens, the Hortus Palatinus, and with the full approval of her husband. She employed French architect and engineer Salomon de Caus to design the Hortus Palatinus; he stayed with Elizabeth until 1619, collaborating with her on the designs of several masques. Meanwhile, the Schomberg marriage and its celebrations served not only to unite the Anglo-Scottish and German factions at the Heidelberg Court, but also indicate a general improvement in relations between Frederick V and Elizabeth, something which may be put down to the retirement of the Dowager Electress. The chapter then recounts the death of Elizabeth's chief lady-in-waiting, Anne Dudley. It also illustrates the arrival of Elizabeth's first daughter, Palatine princess Elisabeth; it was Elizabeth's children who began the long process of binding her to Germany. By June of 1619, she was pregnant with her fourth child, Rupert, but still Elizabeth wished to return to England.

Mandating the COVID-19 Vaccine for U.S. Service Members: An Exploration of Ethical Arguments

ABSTRACT As the COVID-19 pandemic continues across the globe, the advent of novel vaccines has created a possible path to prepandemic life for many. Still, many individuals, including those in the U.S. military, remain hesitant about getting vaccinated. The U.S. Food and Drug Administration recently granted full approval to the Pfizer-BioNTech mRNA vaccine (Comirnaty). Consistent with messaging from President Biden, the Department of Defense leadership has instructed the military to prepare for mandatory vaccination. While many have praised this declaration, others have raised concerns regarding the suppression of individual service member autonomy. This commentary explains the different ethical principles relevant to individual autonomy and how they are understood in a military context and then explores the ethical arguments both for and against mandating vaccination for all U.S. service members.

Psychoanalysis of the Doctrine of Acute Pneumonia

It is difficult to predict how the founder of psychoanalysis, Sigmund Freud, would react to an attempt to link his theory and the method of treating mental disorders based on it [1] with such a purely physical disease as acute pneumonia (AP). It is unlikely that such an innovation could cause full approval and support. However, in this context, we are not talking about psychoanalysis as a therapeutic method for AP. In this case, only the diagnostic features of this technique are of interest. The essence of psychoanalysis, which is based on the search for the causes of the so-called echoes of the past, as well as the connection between conscious and unconscious phenomena, can be useful in order to understand the causes of errors and paradoxes that exist in solving the problem of AP. In other words, we are not talking about the nuances of the disease itself, but about the peculiarities of its nature, since the interpretation of the essence of AP determines the principles of treatment and the final results.

Pharmacodynamics of Remdesivir: How to Improve for COVID-19 Treatment

Potential clinical benefit in SARS-CoV-2 infection upon remdesivir treatment has been established. Recently, FDA has granted full approval for the clinical use of remdesivir for COVID therapy. However, the efficacy of remdesivir alone or in combination with other antivirals is still open to research, especially in terms of benefits vs. risk ratio. We here review remdesivir therapy based on a search for relevant pharmacological evidences with regards to the Pharmacokinetics (PK) and Pharmacodynamics (PD) of appropriate antiviral compounds against COVID-19 alone or in combination with other potential therapies. Drug–Drug Interactions (DDIs), if any in case of combo treatments have also been taken into consideration. We found promising in vitro evidence for efficacy of remdesivir, in combination with (hydroxy) chloroquine and/or favipiravir against SARS-CoV-2 infection in cell culture studies. However, clinical trial results from these combinations were not in line with the promising in vitro data, and therefore limit the use of such combinations in practice. Remdesivir and antibody therapies have also been used clinically either in combination or in sequential application. However, there are no substantive evaluable clinical data on these uses as of now. Additionally, some other drug combinations with remdesivir have been proposed in this article for future improvement in therapies.

Guidance for researchers wanting to link NHS data using non-consent approaches: a thematic analysis of feedback from the Health Research Authority Confidentiality Advisory Group

IntroductionThe use of linked data and non-consent methodologies is a rapidly growing area of health research due to the increasing detail, availability and scope of routinely collected electronic health records data. However, gaining the necessary legal and governance approvals to undertake data linkage is a complex process in England. ObjectivesWe reflect on our own experience of establishing lawful basis for data linkage through Section 251 approval, with the intention to build a knowledgebase of practical advice for future applicants. MethodsThematic analysis was conducted on a corpus of Section 251 feedback reports from the NHS Health Research Authority Confidentiality Advisory Group. ResultsFour themes emerged from the feedback. These were: (a) Patient and Public Involvement, (b)~Establishing Rationale, (c) Data maintenance and contingency, and the need to gain (d) Further Permissions from external authorities prior to full approval. ConclusionsSecuring Section 251 approval poses ethical, practical and governance challenges. However, through a comprehensive, planned approach Section 251 approval is possible, enabling researchers to unlock the potential of linked data for the purposes of health research.

P0228THE NEFIGARD TRIAL: THE EFFECT OF NEFECON® (BUDESONIDE) IN PATIENTS WITH PRIMARY IGA NEPHROPATHY AT RISK OF DEVELOPING END-STAGE RENAL DISEASE

Background and Aims Since the first description of IgA nephropathy (IgAN) over 50 years ago, it has been recognised that the mucosal immune system plays a crucial role in the pathogenesis of this common global cause of kidney failure. Recently, particular attention has focussed on the importance of the gut-associated lymphoid tissue (GALT) as the potential source of the poorly O-galactosylated IgA1 that triggers the formation of nephritogenic immune complexes in IgAN. Pathway analysis based on a large meta-analysis of genome wide association studies identified the intestinal immune network for IgA production as the most enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway in IgAN. Furthermore, separate studies have shown that the IgA in glomerular IgA deposits is indistinguishable from mucosal IgA. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. After 9 months’ treatment, urine protein–creatinine ratio (UPCR) was reduced by 29.3% in the NEFECON® 16 mg group compared with the placebo group. Estimated glomerular filtration rate (eGFR) dropped 4.7 ml/min/1.73 m2 in the placebo group with no deterioration seen in the NEFECON® 16 mg group. Incidence of patients reporting adverse events was similar in all groups. These data led to the design of the NefIgArd study which aims to assess the efficacy, safety, and tolerability of NEFECON® 16 mg in patients with IgAN at risk of end-stage renal disease. Method The NefIgArd study is a randomised, double-blind, placebo-controlled Phase 3 trial, with two parts – PART A a 15–35-day screening period, 9-month treatment and 3-month follow-up period; and PART B a 12-month no-treatment follow-up period (Figure). The study is recruiting across 146 nephrology clinics in 19 countries. Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria >1 g/24 h and eGFR between 35 and 90 ml/min per 1.73 m2 (CKD-EPI) despite optimised renin–angiotensin system blockade. Patients are randomised on a 1:1 ratio to NEFECON® 16 mg/day or placebo. Consistent with the Kidney Health Initiative White Paper “Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy” published in early 2019, the primary outcome of Part A is to assess the effect of NEFECON® 16 mg on 24 h UPCR at 9 months compared with placebo. The Part B primary outcome is based on data presented at the NKF/FDA/EMA workshop in March 2018 that supported eGFR slope as an endpoint for full approval and will assess the effect of NEFECON® 16 mg on a 2-year eGFR-based endpoint compared with placebo. In comparison with other studies that are recruiting, we believe that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of non-protocol treatments and loss of patients from the study that could dilute the true treatment effect of NEFECON®. Results As of 1 January 2020, 207 patients have been randomised, and Part A is expected to complete in Q4 2020, with Part B completing in 2022. To ensure the NefIgArd study results are fully translatable to the global IgAN population, NefIgArd will also open in China in 2020. Conclusion The NefIgArd study builds on the experience of the NEFIGAN trial, the largest commercially sponsored study ever completed in IgAN. The design of the NefIgArd study has used state-of-the-art data to evaluate kidney outcomes, using proteinuria as a reasonably likely surrogate of the effect of NEFECON® on long-term kidney outcomes and confirming long-term renoprotection using an NKF/FDA/EMA-suggested eGFR-based endpoint as a basis for full approval.

Access to new therapies: FDA accelerated approvals and the corresponding Canadian regulatory and funding decisions.

e19066 Background: Accelerated approval (AA) by the FDA enables earlier access to promising new therapies while evidence generation is ongoing. Health Canada (HC) has a similar process with a Notice of Compliance conditional (NOCc) before full approval (NOC). Canada implemented health technology assessment (HTA) for determination of funding through the pan Canadian Oncology Drug Review (pCODR) in 2011. This study evaluated timelines and decisions from AA approval to HC NOC/c to HTA approval and formulary listing. Methods: FDA AA malignant hematology and oncology approvals from Jan 1 2000-Dec 31 2019 were reviewed. HC decisions were reviewed to determine submission/approval status and dates of NOC/c. pCODR decisions were reviewed to determine submission/approval status and dates of decision. First date of provincial formulary listing was collected. Results: In the 20 year time frame, there were 97 AA by the FDA. Current FDA status: 48 full approval, 44 pending verification and 5 withdrawn. Of the 92 AA that remain approved, HC status: 44 received NOC, 24 NOCc, 24 were not submitted for review, 2 currently under review. Of the 5 AA that were withdrawn; 3 were submitted to HC and received NOC/c and all were subsequently withdrawn. From 2011, 31 of 45 HC approved indications were reviewed at pCODR: 17 received a positive recommendation conditional on cost-effectiveness, 9 not recommended, 3 withdrawn by company, 2 pending final decision. Of the 10 not recommended/withdrawn, 6 were subsequently re-submitted and approved. Time from AA to NOC/c was 9.4 m, time from NOC/c to pCODR decision 15.0 m and time from pCODR decision to first formulary listing 18.4 m. Conclusions: Despite significant timeline differences between AA and HC NOC/c all indications that received AA submitted to Canada were granted regulatory approval. Since 2011, 74% of HC approved therapies submitted to pCODR were recommended and added to formularies. Collaboration between FDA and HC, independent regulatory agencies, through innovative programs such as FDA Project Orbis, may improve time from AA to NOC/c. Stringent criteria for HTA recommendation results in lower approval rates however, provision of additional data at re-submission may enable subsequent approval and adoption of treatment.