Protocol and rationale for a randomized controlled SGLT2 inhibitor trial in pediatric and young adult populations with chronic kidney disease: DOUBLE PRO-TECT Alport.

BACKGROUND AND HYPOTHESIS: Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose-co-transporter-2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKD). Whether benefits extend to children, teenagers, and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2-inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years. METHODS AND RATIONALE: DOUBLE PRO-TECT Alport is a multicenter, randomized, double-blind, placebo-controlled trial (RCT). Participants (aged 10 to 39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (> 3 months) maximum tolerated dose of a renin-angiotensin-system-inhibitor (RASi) and must have a Urinary Albumin to Creatinine Ratio (UACR) of >300 mg/g (pediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day -to- matched placebo. Most participants are expected to be children with a normal glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to Week 48) and key secondary (eGFR change from baseline to Week 52) efficacy outcomes will be analyzed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation. CONCLUSION: DOUBLE PRO-TECT Alport will assess whether SGLT2-inhibitors can safely reduce change from baseline in UACR as a marker for progression of CKD in young patients living with AS.

A syllabus for research ethics committees: training needs and resources in different European countries.

This paper reports a European Forum for Good Clinical Practice workshop held in 2011 to consider a research ethics committee training syllabus, subsequent training needs and resources. The syllabus that was developed was divided into four competencies: committee working; scientific method; ethical analysis and the regulatory framework. Appropriate training needs for each, with possible resources, were discussed. Lack of funding for training was reported as a major problem but affordable alternatives were debated. Strengths and weaknesses of this approach were discussed and the resultant proposal will be disseminated through the European Forum for Good Clinical Practice and the research ethics committees of member states.

[Teaching medical history in the German medical curriculum: prospects and risks]. / Medizinhistorische Lehre im Querschnittsbereich Geschichte, Theorie, Ethik der Medizin: Bedrohung oder Chance?

The paper analyses the special situation of teaching medical history in German medical schools. According to German law (Approbationsordnung für Arzte) medical history is part of an interdisciplinary subject (Querschnittsbereich) which is called "history, theory, ethics of medicine". The paper presents some historical attempts to show the relevance of medical history for medical education, explores the present context of teaching medical history in Germany, and gives some recommendations for teaching medical history under the new circumstances.

[Motivation and barriers to participation in clinical trials]. / Motivation und Barrieren für die Teilnahme an klinischen Studien.

BACKGROUND: Clinical trials are essential in clinically orientated medical research. Enrollment of patients is determined by patient-related barriers, protocol-related barriers, and motivation and behavior of the physician. MAIN THESES: Patients enrollment in clinical trials is determined by disease, possible diagnostic or therapeutic benefit of study procedures, effort of protocol procedures, and trust of the relationship between the physician and patient. Randomized trials, extensive study procedures and the possibility of receiving placebo are barriers to participation. Understanding of the communication process and knowledge of patients' needs are the base education to gain patients' informed consent to enter a clinical trial and a stable compliance in the course of the study. Motivation of physicians to enroll patients in a clinical trial is determined, e. g., by environmental conditions in clinic or doctors' office, the time and effort of study procedures, and individual academic interest. CONCLUSION: Awareness of factors (positive and negative) which influence motivation of participation in a clinical trial is useful to provide strategies for successful enrollment of patients.

[A good start for future reformation in rebus medicis". Georg Ernst Stahl's medical theory and piousness of the 18th century]. / "Ein guter Anfang zu künfftiger Reformation in rebus medicis". Georg Ernst Stahls medizinische Theorie und der Pietismus des 18. Jahrhunderts.

Historical research has generally claimed a close connection between Georg Ernst STAHL'S (1659-1734) medical theory and 18th century Pietism. STAHL himself has been often presented as a religious Pietist and as a follower of August Hermann FRANCKE (1663-1727). The present paper analyses the relationship between STAHL'S theory and the medical concepts of Pietist physicians. It is shown that (1.) the assertion, that STAHL'S theory was essentially influenced by religious Pietism, cannot be proved, and that (2.) Pietist physicians adopted, but also simplified and distorted STAHL'S medical theory. Furthermore it is shown, that STAHL kept himself aloof from the Halle Pietists and their institutions.

[Motivation of patients to participate in clinical trials. An explorative survey]. / Bereitschaft von Patienten zum Einschluss in klinische Studien : Eine explorative Studie.

BACKGROUND: Difficulties in recruiting patients for clinical trials lead to increasing costs, and prolonged implementation of evidences into medical practice. Knowledge about motivation and barriers in potential participants would be helpful to develop successful recruitment strategies. Currently, no systematic research of determining factors affecting the decision to participate in clinical studies is available from German samples. METHODS: After been given details about a potential participation in a clinical or diagnostic study in nine study centers, patients were recruited for an additional structured questionnaire survey concerning motivation and barriers to participation. RESULTS: 62 patients were included into the survey. 95.1% did not have any experience with clinical studies before. 66.1% met the physician explaining the study and asking for informed consent for the first time. Despite this, 96.6% judged the physician to be competent. Family and friends were important for decision-making about the participation in a study. Gender was only of marginal influence. The majority of patients (91.4%) expected advantages of the study for their own. 88% of the patients denominated potential advantages for other patients as an additional motivator. The possibility of adverse events was inferior for patients in decision-making about participation in a clinical trial. CONCLUSION: Physicians recruiting patients for clinical studies should be well prepared about details of the study and should have adequate time for an introductory conversation in a quiet environment. Including relatives into the introductory conversation may enhance the motivation and therefore the success of recruitment. Potential advantages of a participation for the own treatment and additionally for other patients should be highlighted. Possible side effects should be explained in a realistic manner.

Nuchal cystic hygroma in five fetuses from 1819 to 1826 in the Meckel-anatomical collections at the University of Halle, Germany.

The Anatomical collection of the Department of Anatomy and Cell Biology, Medical School of the University of Halle, Germany, comprises more than 8,000 specimens. Around 600 of them show congenital anomalies. The collection of abnormal human and animal fetuses began as the private collection of Johann Friedrich Meckel the Elder (1724-1774), his son Philipp Friedrich Theodor Meckel (1755-1803) and his grandson Johann Friedrich Meckel the Younger (1781-1833). Meckel the Younger founded the systematic science of developmental pathology. Radiographical techniques, computer tomographic (CT) methods, magnetic resonance imaging (MRI), and comparative genomic hybridization (CGH) were used to diagnose abnormal human fetuses in the Meckel-anatomical collections. Cystic hygroma colli was found in five of the human fetuses originally described by JF Meckel the Younger in 1826 and one of his students in 1819 [Hencke, 1819]. CGH analyses were used to test whether the observed cystic hygroma colli could be caused by chromosomal aneuploidies. CGH-ratio profiles of all chromosomes were apparently normal. PCR-based sex determination tests on ancient DNA were used to determine the fetal gonosomal constitution. It is likely that the Meckel specimens are among the oldest fetuses in which Ullrich-Turner "phenotype" has been diagnosed.

[Pietism and medicine in the first half of the 18th century]. / "Dab auch zugleich die Gottseligkeit dadurch gebauet wird"-Pietismus und Medizin in der ersten Hälfte des 18. Jahrhunderts.

In the beginning of the 18th century Halle Pietists tried to establish a specific approach to sickness and healing. They constructed close links between physical illness on the one hand and the religious concept of individual piety, penance and rebirth on the other. This new' pietist medicine largely depended on Georg Ernst Stahl's medical theory, which was not pietist in itself, but was adopted and simplified by pietist physicians. Although conclusive and rhetorically present in programmatic texts, pietist medicine turned out to be less influential on medical practice than expected.