Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. PATIENTS AND METHODS: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Rolling Medical Practice: Ambulant Mobile Medical Care for Rural Areas.

We designed, constructed, and evaluated a mobile medical care vehicle called "Rollende Arztpraxis" (rolling medical practice, RMP) that delivers the full medical care of a general practitioner to increase medical care supply in rural areas. Six communities have been identified, where the RMP has been visited 501 times in 14 months. Two different schedules of stops and treatment times have been tested. We show that the RMP treated mainly elderly and multimorbid patients. An accompanying study showed high acceptance and satisfaction of treated patients and treating doctors. An economic evaluation of three different utilization models with three treatment modes each showed no financial sustainability. We show that ambulatory care in rural areas can be complemented by a mobile care unit, if legal and financial barriers can be overcome.

Fear and Anger in Great Britain: Blame Assignment and Emotional Reactions to the Financial Crisis.

While we know that emotional reactions are important influences on political behavior, we know far less about the sources of these emotions. This paper studies the causes of fear and anger in reaction to a negative stimulus: the financial crisis. Anger should have been experienced among individuals who believed a specific actor was to blame for the crisis. Moreover, individuals should have been particularly angry if they blamed an actor who should be accountable to them, for example the national government. I test these expectations using a panel survey run in Britain between 2005 and 2010. This data shows that British citizens experienced anger if they held an actor responsible for the crisis. Moreover, they felt particularly angry if they held the Labour government (and to a lesser extent the European Union) responsible. These findings underline the importance of studying the causes of emotional reactions and show how these may be linked to common institutional distinctions between political systems.

Representative misconduct, voter perceptions and accountability: Evidence from the 2009 House of Commons expenses scandal.

This paper examines electoral accountability after the 2009-10 UK expenses scandal. Existing research shows that Members of Parliament (MPs) implicated in the scandal fared only marginally worse in the election than non-implicated colleagues. This lack of electoral accountability for misconduct could have arisen either because voters did not know about their representative's wrongdoing or because they chose not to electorally sanction them. We combine panel survey data with new measures of MP implication in the expenses scandal to test where electoral accountability failed. We find that MP implication influenced voter perceptions of wrongdoing more than expected. In contrast, constituents were only marginally less likely to vote for MPs who were implicated in the scandal. Electoral accountability may therefore be constrained even when information about representative misconduct is easily available and clearly influences voter perceptions.

An international survey of physician and patient understanding, perception, and attitudes to atrial fibrillation and its contribution to cardiovascular disease morbidity and mortality.

AIMS: Atrial fibrillation (AF) is not always perceived as a serious health threat, but is the most common sustained arrhythmia, with a major impact on morbidity, mortality, and patient quality of life (QoL). A survey was undertaken to examine the level of understanding, perception, and attitudes of the cardiovascular risks associated with AF. METHODS AND RESULTS: The AF AWARE group (an international coalition of organizations with an interest in AF) conducted an international quantitative survey in 11 countries in 2009, to investigate patients' (n = 825) and cardiologists' (n = 810) perceptions of AF, preferences for communicating information on AF and burden of AF. Both patients and physicians considered AF life-threatening (55 and 43%, respectively). Physicians were more concerned about the risk of stroke and hospitalizations than patients, whereas patients were most concerned about death risk. One in four patients felt unable to explain AF and >33% were worried or fearful about their disease. Many physicians (51%) wanted more patient information with >60% viewing available information as poor/difficult to find. Hospital specialists and GPs were identified as key information sources for patients. Most patients (83%) reported symptoms, yet 75% claimed to be satisfied with AF therapies. Atrial fibrillation patients, often with associated diseases, made an average of nine visits per year to their doctors, who consider AF difficult and time consuming to manage. Patients and physicians rated the QoL impact of AF as moderate to high. CONCLUSIONS: A comprehensive international patient and professional information and support programme on AF is needed to improve management and consequently health outcomes.

Postoperative hypoesthesia and pain: qualitative assessment after open and laparoscopic inguinal hernia repair.

BACKGROUND: Chronic pain is an important outcome variable after inguinal hernia repair that is generally not assessed by objective methods. The aim of this study was to objectively investigate chronic pain and hypoesthesia after inguinal hernia repair using three types of operation: open suture, open mesh, and laparoscopic. METHODS: A total of 96 patients were included in the study with a median follow-up of 4.7 years. Open suture repair was performed in 40 patients (group A), open mesh repair in 20 patients (group B), and laparoscopic repair in 36 patients (group C). Hypoesthesia and pain were assessed using von Frey monofilaments. Quality of life was investigated with Short Form 36. RESULTS: Pain occurring at least once a week was found in 7 (17.5%) patients of group A, in 5 (25%) patients of group B, and in 6 (16.6%) patients of group C. Area and intensity of hyposensibility were increased significantly after open nonmesh and mesh repair compared to those after laparoscopy (p = 0.01). Hyposensibility in patients who had laparoscopic hernia repair was significantly associated with postoperative pain (p = 0.03). Type of postoperative pain was somatic in 19 (61%), neuropathic in 9 (29%), and visceral in 3 (10%) patients without significant differences between the three groups. CONCLUSIONS: The incidence of hypoesthesia in patients who had laparoscopic hernia repair is significantly lower than in those who had open hernia repair. Hypoesthesia after laparoscopic but not after open repair is significantly associated with postoperative pain. Von Frey monofilaments are important tools for the assessment of inguinal hypoesthesia and pain in patients who had inguinal hernia repair allowing quantitative and qualitative comparison between various surgical techniques.

Management patterns and health care use after intracerebral hemorrhage. a cost-of-illness study from a societal perspective in Germany.

BACKGROUND: The German cost-of-illness study of stroke is a multicenter study in 6 departments of internal medicine, 9 departments of general neurology and 15 departments of neurology with an acute stroke unit. The aims of this study are to describe the management patterns, cost of treatment and overall resource utilization after intracerebral hemorrhage (ICH) as well as the major differences to ischemic stroke (IS). METHODS: During a 12-month period, 30 participating centers with a special interest in stroke prospectively included 586 patients with ICH which were collected in a joint data bank. About 75% of all patients could be centrally followed up via structured telephone interviews after 3 and 12 months to assess further acute hospital and rehabilitation stays, outpatient resource utilization, functional outcome and quality of life. RESULTS: Mortality after 3 months (33.5%) was markedly higher than in patients with IS from the same hospitals. Accordingly, only 30.9% of patients had regained independent functional status after 3 months. Cumulative cost of treatment amounted to 5301 EUR for inpatient stay in the documenting hospital and 8920 EUR for the overall hospital stay including rehabilitation. Mean direct cost after discharge during the first year amounted to 4598 EUR and the loss of work force was equivalent to 5537 EUR in all surviving patients. CONCLUSION: This study provides a comprehensive overview of patient characteristics, treatment strategies and health care cost of ICH from a societal perspective in Germany.

Assessment of functioning and disability after ischemic stroke.

BACKGROUND AND PURPOSE: Functioning and disability after ischemic stroke are clinically meaningful and of major relevance to patients. Despite many instruments available to assess these outcomes, little is known about their interrelation and predictive factors. METHODS: We prospectively identified 4264 patients with acute ischemic stroke from 30 hospitals in Germany during a 1-year period between 1998 and 1999 and registered them in a common data bank. The patients were centrally followed up via telephone interview after 100 days and 1 year to assess various scales such as the Barthel Index (BI), modified Rankin Scale (MRS), extended Barthel Index (EBI), Short Form-36 Physical Functioning (SF-36 PF), and Center for Epidemiologic Studies-Depression short form (CES-D). RESULTS: Outcome status could be assessed in 67.2% of patients 100 days after hospital admission. Of these, 13.9% had died, 53.7% had regained functional independence (BI <95), 46.3% had no or mild residual symptoms (MRS < or =1), and 44.6% had no higher cognitive deficits on the EBI. Of the patients who personally answered the follow-up questions, 67% had no major physical disability (SF-36 PF <60), and 32.9% reported symptoms classified as depression (CES-D > or =10). The high percentage of patients reaching the maximum score (ceiling effect) in the BI was less pronounced in the MRS and SF-36 PF. The predictive factors for dichotomized outcomes on each scale were similar for adverse functioning and disability but varied considerably for depression. CONCLUSIONS: To avoid ceiling effects in outcome distribution of patients treated in specialized stroke centers, the MRS and SF-36 PF instruments are preferable to the BI. Parametric use of the SF-36 PF could further improve outcome measurement by considering individual treatment effects.