First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

The perils of aiming too high: Discrepancy between goals and performance in individuals with depressive symptoms.

BACKGROUND AND OBJECTIVES: Negative evaluation processes play a pivotal role in the development and maintenance of depressive symptoms. However, it remains to be understood, whether evaluation processes in depression are impaired by maladaptive goal setting. METHOD: In a non-clinical sample (N = 50) of individuals with high (BDI-II-Score: 13-29) and low (BDI-II-Score: 0-3) levels of depressive symptoms goal setting prior to working on a cognitive task was measured. Goal feasibility was experimentally manipulated using an easy and a difficult version of the task. RESULTS: When goal feasibility was low, a high level of depressive symptoms was associated with setting unattainable goals. Whereas individuals with low level of depressive symptoms adjusted their goals to a lower (more realistic) level when task difficulty increased, individuals with high level of depressive symptoms initially adhered to significantly higher goals, so that their performance failed to meet their self-set standards. After depressed individual revised their goals downwards, their subsequent performance on the task also worsened. LIMITATIONS: The use of a non-clinical sample with self-reported depressive symptoms limits the generalizability of our findings to a clinical population. Future research would benefit from the use of a larger sample with patients suffering from clinical depression. CONCLUSIONS: The findings support the notion that negative evaluation processes in depressed individuals might be linked with their tendency to generate intractable conflicts between self-set inappropriate high goals and their own capacities to perform. However, the findings need to be confirmed in clinical samples to draw conclusions about the role of goal setting in negative evaluation processes in depression.

Chamber bioaerosol study: human emissions of size-resolved fluorescent biological aerosol particles.

Humans are a prominent source of airborne biological particles in occupied indoor spaces, but few studies have quantified human bioaerosol emissions. The chamber investigation reported here employs a fluorescence-based technique to evaluate bioaerosols with high temporal and particle size resolution. In a 75-m(3) chamber, occupant emission rates of coarse (2.5-10 µm) fluorescent biological aerosol particles (FBAPs) under seated, simulated office-work conditions averaged 0.9 ± 0.3 million particles per person-h. Walking was associated with a 5-6× increase in the emission rate. During both walking and sitting, 60-70% or more of emissions originated from the floor. The increase in emissions during walking (vs. while sitting) was mainly attributable to release of particles from the floor; the associated increased vigor of upper body movements also contributed. Clothing, or its frictional interaction with human skin, was demonstrated to be a source of coarse particles, and especially of the highly fluorescent fraction. Emission rates of FBAPs previously reported for lecture classes were well bounded by the experimental results obtained in this chamber study. In both settings, the size distribution of occupant FBAP emissions had a dominant mode in the 3-5 µm diameter range.

Progress in thermal comfort research over the last twenty years.

Climate change and the urgency of decarbonizing the built environment are driving technological innovation in the way we deliver thermal comfort to occupants. These changes, in turn, seem to be setting the directions for contemporary thermal comfort research. This article presents a literature review of major changes, developments, and trends in the field of thermal comfort research over the last 20 years. One of the main paradigm shift was the fundamental conceptual reorientation that has taken place in thermal comfort thinking over the last 20 years; a shift away from the physically based determinism of Fanger's comfort model toward the mainstream and acceptance of the adaptive comfort model. Another noticeable shift has been from the undesirable toward the desirable qualities of air movement. Additionally, sophisticated models covering the physics and physiology of the human body were developed, driven by the continuous challenge to model thermal comfort at the same anatomical resolution and to combine these localized signals into a coherent, global thermal perception. Finally, the demand for ever increasing building energy efficiency is pushing technological innovation in the way we deliver comfortable indoor environments. These trends, in turn, continue setting the directions for contemporary thermal comfort research for the next decades.

Quantitative relationships between occupant satisfaction and satisfaction aspects of indoor environmental quality and building design.

UNLABELLED: The article examines which subjectively evaluated indoor environmental parameters and building features mostly affect occupants' satisfaction in mainly US office buildings. The study analyzed data from a web-based survey administered to 52,980 occupants in 351 office buildings over 10 years by the Center for the Built Environment. The survey uses 7-point ordered scale questions pertaining to satisfaction with indoor environmental parameters, workspace, and building features. The average building occupant was satisfied with his/her workspace and building. Proportional odds ordinal logistic regression shows that satisfaction with all 15 parameters listed in the survey contributed significantly to overall workspace satisfaction. The most important parameters were satisfaction with amount of space (odds ratio OR 1.57, 95% CI: 1.55-1.59), noise level (OR 1.27, 95% CI: 1.25-1.29), and visual privacy (OR 1.26, 95% CI: 1.24-1.28). Satisfaction with amount of space was ranked to be most important for workspace satisfaction, regardless of age group (below 30, 31-50 or over 50 years old), gender, type of office (single or shared offices, or cubicles), distance of workspace from a window (within 4.6 m or further), or satisfaction level with workspace (satisfied or dissatisfied). Satisfaction with amount of space was not related to the gross amount of space available per person. PRACTICAL IMPLICATIONS: To maximize workspace satisfaction, designer should invest in aspects that increase satisfaction with amount of space and storage, noise level, and visual privacy. Office workers will be most satisfied with their workspace and building when located close to a window in a private office. This may affect job satisfaction, work performance, and personal and company productivity.

[Stigmatization of patients with schizophrenia: the influence of university courses on the attitudes of prospective psychologists and doctors]. / Stigmatisierung von Patienten mit Schizophrenie: Prägt das Studium die Einstellungen angehender Psychologen und Mediziner?

BACKGROUND: Some studies revealed that psychiatrists have more negative attitudes than psychologists towards patients with schizophrenia. This raises the question of whether different models of the aetiology of schizophrenia and the amount of personal contact influence the attitudes of mental health professionals. SAMPLE AND METHODS: Explicit and implicit attitudes towards schizophrenia were assessed in medical and psychology students (n=60 and n=61, respectively) as well as their familiarity with the disorder and their subjective models of its aetiology. RESULTS: Medical and psychology students showed a substantial level of negative attitudes. Personal contact was negatively associated with stereotypes among medical students and positively associated among psychology students. Positive attitudes were related to biogenetic causal beliefs among medical students and to psychosocial causal beliefs among psychology students. CONCLUSIONS: The results emphasise the need to adapt antistigma campaigns to target groups. They also indicate the superiority of a multidimensional aetiology over monocausal aetiological models in reducing stigma.

Correlation between temperature satisfaction and unsolicited complaint rates in commercial buildings.

UNLABELLED: This paper analyzes the relation between temperature satisfaction ratings expressed on a questionnaire and unsolicited complaint rates recorded in a maintenance database. The key findings are as follows: (i) the satisfaction ratings and complaint rates are negatively correlated with a moderate magnitude (r(s) = -0.31 to -0.36), and the correlation is statistically significant (P = 0.01-0.005), and (ii) the percent dissatisfied with temperature and the complaint rate are positively correlated with moderate magnitude (r(s) = 0.31-0.36), and the correlation is statistically significant (P = 0.01-0.004). Both data sets contain 'real-world' measures of temperature satisfaction, with the complaints contributing directly to the cost of operations and maintenance. The relationship between two validates a new method of assessing the economic cost of thermal discomfort in commercial buildings. PRACTICAL IMPLICATIONS: Complaints in commercial buildings indicate occupants' dissatisfaction to their environments. It not only deteriorates occupants' performance and organization productivity, but also increases building maintenance and operating cost. Nailing economic consequences of complaints will enable monetary comparison of discomfort cost with building and operating costs. This comparison may be desirable for building owners and tenants to make well-informed decisions on construction, rental, and retrofit. It may also be used to evaluate complaint diagnostic and eliminating techniques.

Thermal sensation and comfort in transient non-uniform thermal environments.

Most existing thermal comfort models are applicable only to steady-state, uniform thermal environments. This paper presents summary results from 109 human tests that were performed under non-uniform and transient conditions. In these tests, local body areas were independently heated or cooled while the rest of the body was exposed to a warm, neutral or cool environment. Skin temperatures, core temperature, thermal sensation and comfort responses were collected at 1- to 3-min intervals. Based on these tests, we have developed predictive models of local and overall thermal sensation and comfort.

[Cancer pain management in Germany - results and analysis of a questionnaire]. / Tumorschmerztherapie in Deutschland - Ergebnisse und Analysen einer Befragung von Arzten.

The German regulations for opioid prescriptions have been changed in February 1998. The regulations have been made much more easier and should therefore have improved the pain management in Germany. We investigated the knowledge of the WHO analgesic ladder and how they have been followed in a nation-wide survey among physicians not specialised in pain management. Only 9% of the questionnaires were returned. Although the majority of the physicians (93%) reported knowledge about the WHO recommendations for the treatment of cancer pain, more than 15% of the participating physicians rated transdermal fentanyl as a weak opioid or even as a non-opioid. A negative pain management index in 15% of the patients gave evidence of poor quality in pain management. The majority of patients (84%) did not receive immediate release analgesics for the treatment of breakthrough pain. Continuous medical education is still necessary before a further alleviation of regulations will help to reduce the undertreatment of patients suffering from cancer pain in Germany.

Convective and radiative heat transfer coefficients for individual human body segments.

Human thermal physiological and comfort models will soon be able to simulate both transient and spatial inhomogeneities in the thermal environment. With this increasing detail comes the need for anatomically specific convective and radiative heat transfer coefficients for the human body. The present study used an articulated thermal manikin with 16 body segments (head, chest, back, upper arms, forearms, hands, pelvis, upper legs, lower legs, feet) to generate radiative heat transfer coefficients as well as natural- and forced-mode convective coefficients. The tests were conducted across a range of wind speeds from still air to 5.0 m/s, representing atmospheric conditions typical of both indoors and outdoors. Both standing and seated postures were investigated, as were eight different wind azimuth angles. The radiative heat transfer coefficient measured for the whole-body was 4.5 W/m2 per K for both the seated and standing cases, closely matching the generally accepted whole-body value of 4.7 W/m2 per K. Similarly, the whole-body natural convection coefficient for the manikin fell within the mid-range of previously published values at 3.4 and 3.3 W/m2 per K when standing and seated respectively. In the forced convective regime, heat transfer coefficients were higher for hands, feet and peripheral limbs compared to the central torso region. Wind direction had little effect on convective heat transfers from individual body segments. A general-purpose forced convection equation suitable for application to both seated and standing postures indoors was hc = 10.3v0.6 for the whole-body. Similar equations were generated for individual body segments in both seated and standing postures.

[Oral vaccines against poliomyelitis and vaccination-related paralytic poliomyelitis in Germany. Do we need a new immunization strategy?]. / Schluckimpfung gegen Poliomyelitis und impfassoziierte paralytische Poliomyelitis in Deutschland. Brauchen wir eine neue Impfstrategie?

Oral vaccination against poliomyelitis, which was carried out worldwide, lead to eradication of poliomyelitis in the United States, in South America and parts of Europe; in other parts of the world, paralytic poliomyelitis is still a severe risk of health. In those countries where poliomyelitis has been eradicated, it is presently discussed whether the vaccination schedules should be changed to an inactivated polio vaccine (IPV), as in polio-free countries only cases of paralytic poliomyelitis after vaccinations have been reported. Behringwerke's data from a 30-year period of analysing adverse drug reaction reveal the following: using the trivalent oral polio vaccine (OPV), based on WHO case definition, the risk for vaccine-associated paralytic poliomyelitis with permanent damage is approximately 1 case for 4.5 million vaccinations (0.22 per million) in vaccinees, and approximately 1 case for 11 million (0.09 per million) in contact persons. This low risk is in line with the data ascertained worldwide.

Symptom reporting in cancer patients: the role of negative affect and experienced social stigma.

BACKGROUND: Recent research suggests that patients' appraisal of somatic symptoms is more closely related to emotional variables (particularly negative affect) than to their actual health as determined by external criteria. METHODS: Sixty surgical cancer patients who at the time of a routine follow-up examination filled out the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire-C30, which included a positive/negative affect scale and a scale tapping into experienced social stigma. Patients' health status was determined in two ways: the examining physician gave a global judgement on a standardized scale at the end of the examination, and an additional two external physicians later rated the patients based on the findings listed in the medical record. RESULTS: Patients' reports of somatic symptoms were strongly correlated with two measures of negative affect (r = 0.75 and r = 0.65, respectively) and with experienced social stigma (r = 0.51). In contrast, the correlations between reported symptoms and the examining or external physicians' ratings were considerably weaker (r = 0.31 and r = 0.19). According to a multiple linear regression with 6 predictors, negative affect was the best single predictor of symptom reporting (beta = 0.68; P < 0.001) and global quality of life (beta = 0.48; P < 0.001). Factor analysis yielded a dimension of somatopsychosocial distress that accounted for 44.1% of the variance and is comprised of reported symptoms (factor loading = 0.86), negative affect (0.90 and 0.82), experienced social stigma (0.74), and global quality of life (0.70). Physicians' ratings and positive affect constituted two additional separate factors. CONCLUSIONS: Cancer patients' reporting of somatic symptoms by means of a standardized quality of life questionnaire is closely related to emotional and social distress and is not equivalent to health status as determined from a clinical perspective. Researchers and practitioners have to be aware of this fact when interpreting quality of life data. Furthermore, negative affect deserves attention as an important signal for intervention in tumor follow-up programs.

Determination of pseudofacility in man.

Based on a new method of measuring episcleral venous pressure (EVP), i.e., using the 'air-jet principle' of Krakau et al. (1973), pseudofacility was determined in 20 human eyes. According to Bárány's formula, a mean value of 23.3% of the total facility was found, and a mean value of 16.9% according to Goldmann's formula.