Use of person-centred music to manage wound dressing-related pain: a mixed method case study.

OBJECTIVE: To determine whether person-centred music (PCMusic) contributes to reducing pain during painful leg ulcer dressing change procedures indicated by: decreased levels of indicators related to stress; decreased pain scores; and a more favourable treatment climate during the dressing change procedure. METHOD: A case study of a 51-year-old female patient with chronic inherited disease weakening her connective tissues. Quantitative data entailed temporal measurements of stress indicators including: heart pulse rate; oxygen saturation (SpO2); saliva cortisol; and a visual analogue scale (VAS). Qualitative data comprised phenomenological treatment descriptions and patient/licensed practical nurse (LPN) questionnaires. RESULTS: The patient's body temperature remained steady throughout all treatments. Blood pressure was excluded due to missing data. No significant pulse rate differences in relation to music/no music could be observed during treatment. Comparing PCMusic to the patient's own other music (POOM), the pulse rate was greater in both magnitude and variation when the patient listened to POOM. Oxygen saturation showed no significant difference between PCMusic and music/no music. No significant difference was observed pre-/post-debridement with music. Similarly, no significant difference was observed pre-/post-debridement with no music. Treatment with no music showed the highest VAS score; PCMusic treatments had the lowest scores. Qualitative data showed that both patient and LPNs found that PCMusic decreased pain during dressing change. CONCLUSION: The results of this case study indicate that PCMusic is a suitable complementary treatment to decrease patient pain. Patients' general health status is important when using quantitative stress/pain marker measurements. For cohort selection in future studies, we suggest healthy patients undergoing slightly painful or unpleasant treatments, patients in postoperative care and obstetric care.

Diagnosis and treatment impacts on wound care efficiency drivers: real-world analysis.

Objective: The prevalence and economic burden of wounds are growing. Any wound has the potential to become hard-to-heal and require frequent care. Clinicians need to find ways to absorb demand on services without compromising outcomes. Drivers of wound care efficiency-time-to-heal, frequency of dressing change and the incidence of complications-can be evaluated to shape future wound management. A survey of wound care was conducted by clinicians from five centres in Sweden over a one-week period, during which clinicians documented every wound once. At the time of surveying, 49% of wounds were considered to be improving, infection incidence was 11.7% and dressings were changed a mean of 2.2 times per week, with highly exuding wounds changed 6.9 times per week. The data highlighted the importance of diagnosing patient and wound characteristics in selecting treatments and organising care. Recognised gaps in diagnoses potentially identify opportunities to influence healing, complication incidence and intensity of nursing, thus reducing demand on resources. In conclusion, this survey highlights opportunities to reduce the burdens these drivers present. Through improved diagnosis and alignment to recognised care pathways, there is potential to improve patient outcomes and alleviate the strains placed upon wound care providers.

Fighting Off Wound Pathogens in Horses with Honeybee Lactic Acid Bacteria.

In the global perspective of antibiotic resistance, it is urgent to find potent topical antibiotics for the use in human and animal infection. Healing of equine wounds, particularly in the limbs, is difficult due to hydrostatic factors and exposure to environmental contaminants, which can lead to heavy bio-burden/biofilm formation and sometimes to infection. Therefore, antibiotics are often prescribed. Recent studies have shown that honeybee-specific lactic acid bacteria (LAB), involved in honey production, and inhibit human wound pathogens. The aim of this pilot study was to investigate the effects on the healing of hard-to-heal equine wounds after treatment with these LAB symbionts viable in a heather honey formulation. For this, we included ten horses with wound duration of >1 year, investigated the wound microbiota, and treated wounds with the novel honeybee LAB formulation. We identified the microbiota using MALDI-TOF mass spectrometry and DNA sequencing. In addition, the antimicrobial properties of the honeybee LAB formulation were tested against all wound isolates in vitro. Our results indicate a diverse wound microbiota including fifty-three bacterial species that showed 90 % colonization by at least one species of Staphylococcus. Treatment with the formulation promoted wound healing in all cases already after the first application and the wounds were either completely healed (n = 3) in less than 20 days or healing was in progress. Furthermore, the honeybee LAB formulation inhibited all pathogens when tested in vitro. Consequently, this new treatment option presents as a powerful candidate for the topical treatment of hard-to-heal wounds in horses.

Wound management for the 21st century: combining effectiveness and efficiency.

Treatment of wounds of different aetiologies constitutes a major part of the total health care budget. It is estimated that 1·5-2 million people in Europe suffer from acute or chronic wounds. These wounds are managed both in hospitals and in community care. The patients suffering from these wounds report physical, mental and social consequences of their wounds and the care of them. It is often believed that the use of wound dressings per se is the major cost driver in wound management, whereas in fact, nursing time and hospital costs are together responsible for around 80-85% of the total cost. Healing time, frequency of dressing change and complications are three important cost drivers. However, with the use of modern, advanced technology for more rapid wound healing, all these cost drivers can be substantially reduced. A basic understanding of the terminology and principles of Health Economics in relation to wound management might therefore be of interest.

Lactic acid bacterial symbionts in honeybees - an unknown key to honey's antimicrobial and therapeutic activities.

Could honeybees' most valuable contribution to mankind besides pollination services be alternative tools against infections? Today, due to the emerging antibiotic-resistant pathogens, we are facing a new era of searching for alternative tools against infections. Natural products such as honey have been applied against human's infections for millennia without sufficient scientific evidence. A unique lactic acid bacterial (LAB) microbiota was discovered by us, which is in symbiosis with honeybees and present in large amounts in fresh honey across the world. This work investigates if the LAB symbionts are the source to the unknown factors contributing to honey's properties. Hence, we tested the LAB against severe wound pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and vancomycin-resistant Enterococcus (VRE) among others. We demonstrate a strong antimicrobial activity from each symbiont and a synergistic effect, which counteracted all the tested pathogens. The mechanisms of action are partly shown by elucidating the production of active compounds such as proteins, fatty acids, anaesthetics, organic acids, volatiles and hydrogen peroxide. We show that the symbionts produce a myriad of active compounds that remain in variable amounts in mature honey. Further studies are now required to investigate if these symbionts have a potential in clinical applications as alternative tools against topical human and animal infections.

A pilot study investigating lactic acid bacterial symbionts from the honeybee in inhibiting human chronic wound pathogens.

Treatment and management of chronic wounds is a large burden on the health sector and causes substantial suffering for the patients. We believe that 13 lactic acid bacteria (LAB) symbionts isolated from the honey crop of the honeybee are important players in the antimicrobial action of honey, by producing antimicrobial substances and can be used in combination with heather honey as an effective treatment in wound management. A total of 22 patients with chronic ulcers were included; culture-dependent and molecular-based (MALDI-MS and 16S rRNA gene sequencing) techniques were used to identify bacteria from chronic wounds. These clinical isolates were used for in vitro antimicrobial testing with standardised viable LAB and sterilised heather honey mixture. Twenty of the patients' wounds were polymicrobial and 42 different species were isolated. Patient isolates that were tested in vitro were inhibited by the LAB and honey combination with inhibitory zones comparable with different antibiotics. LAB and heather honey in combination presents a new topical option in chronic wound management because of the healing properties of honey, antimicrobial metabolite production from the LAB and their bactericidal effect on common chronic wound pathogens. This new treatment may be a stepping stone towards an alternative solution to antibiotics.

Diagnosis-specific disability pension and risk of all-cause and cause-specific mortality--a cohort study of 4.9 million inhabitants in Sweden.

BACKGROUND: The incidence of disability pension (DP) is high in several European countries. However, knowledge on associations of cause-specific DP and premature death is limited. The aims were to: 1) investigate the association between cause-specific DP and all-cause and cause-specific mortality among women and men and 2) examine period effects of this association. METHODS: Three prospective population-based cohort studies were conducted, the first including all individuals aged 16-64 years who lived in Sweden all of 1995 and who were not on DP before 1995 (N = 5,006,523, 48.8% women). Those granted DP in 1995 were compared to those not granted DP regarding mortality during 1996-2009. Two other cohorts were created in a similar fashion, for 2000 and 2005, respectively, and in comparisons each of the three cohorts were followed up for four years with regard to all-cause mortality as well as death due to cancer, circulatory disorders, or suicide. All analyses were stratified by sex and we controlled for a number of socio-demographic factors and inpatient care. RESULTS: Individuals with granted DP had a higher mortality risk, women (HR 1.75; 95% CI 1.68-1.82) and men (HR 1.66; 95% CI 1.61-1.71) and highest for cancer. People on DP with some diagnoses had higher risk of premature death in other causes of death than their DP diagnoses. All-cause mortality risk varied with DP-diagnosis and was lowest for musculoskeletal diagnoses. The mortality HR decreased among women with DP between the cohort 1995, HR 2.07 (1.92-2.24) and the cohort 2005, 1.84 (1.71-1.99). Here, temporal decreases in mortality risk occurred particularly in DP due to mental diagnoses and cancer. CONCLUSIONS: All DP diagnoses were associated with a higher mortality risk. Even individuals granted DP due to diagnoses with low mortality risk displayed a higher risk for premature death. This warrants close monitoring of disability pensioners and further studies on consequences of being on disability pension.

Associations between number of sick-leave days and future all-cause and cause-specific mortality: a population-based cohort study.

BACKGROUND: As the number of studies on the future situation of sickness absentees still is very limited, we aimed to investigate the association between number of sick-leave days and future all-cause and cause-specific mortality among women and men. METHODS: A cohort of 2 275 987 women and 2 393 248 men, aged 20-64 years in 1995 was followed 1996-2006 with regard to mortality. Data were obtained from linked authority-administered registers. The relative risks (RR) and 95% confidence intervals (CI) of mortality with and without a 2-year wash-out period were estimated by multivariate Poisson regression analyses. All analyses were stratified by sex, adjusting for socio demographics and inpatient care. RESULTS: A gradually higher all-cause mortality risk occurred with increasing number of sick-leave days in 1995, among both women (RR 1.11; CI 1.07-1.15 for those with 1-15 sick-leave days to RR 2.45; CI 2.36-2.53 among those with 166-365 days) and men (RR 1.20; CI 1.17-1.24 to RR 1.91; CI 1.85-1.97). Multivariate risk estimates were comparable for the different causes of death (circulatory disease, cancer, and suicide). The two-year washout period had only a minor effect on the risk estimates. CONCLUSION: Even a low number of sick-leave days was associated with a higher risk for premature death in the following 11 years, also when adjusting for morbidity. This was the case for both women and men and also for cause-specific mortality. More knowledge is warranted on the mechanisms leading to higher mortality risks among sickness absentees, as sickness certification is a common measure in health care, and most sick leave is due to diagnoses you do not die from.

Objective evaluation by reflectance spectrophotometry can be of clinical value for the verification of blanching/non blanching erythema in the sacral area.

Early detection of non blanching erythema (pressure ulcer category I) is necessary to prevent any further skin damage. An objective method to discriminate between blanching/non blanching erythema is presently not available. The purpose of this investigation was to explore if a non invasive objective method could differentiate between blanching/non blanching erythema in the sacral area of patients undergoing hip fracture surgery. Seventy-eight patients were included. The sacral area of all patients was assessed using (i) conventional finger-press test and (ii) digital reading of the erythema index assessed with reflectance spectrophotometry. The patients were examined at admission and during 5 days postsurgery. Reflectance spectrophotometry measurements proved able to discriminate between blanching/non blanching erythema. The reliability, quantified by the intra-class correlation coefficient, was excellent between repeated measurements over the measurement period, varying between 0·82 and 0·96, and a significant change was recorded in the areas from day 1 to day 5 (P < 0·0001). The value from the reference point did not show any significant changes over the same period (P = 0·32). An objective method proven to identify early pressure damage to tissue can be a valuable tool in clinical practice.

Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death.

The p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38α, p38ß, p38γ and p38δ, forms one of the key MAPK pathways. The p38 MAPKs are implicated in many cellular processes including inflammation, differentiation, cell growth, cell cycle and cell death. The function of p38 MAPKs in mitotic entry has been well established, but their role in mitotic progression has remained controversial. We identify p38γ MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38γ results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38γ-depleted cells die at mitotic arrest or soon after abnormal exit from M-phase. We show that p38 MAPKs are activated at the kinetochores and spindle poles throughout mitosis by kinase(s) that are stably bound to these structures. Finally, p38γ is required for the normal kinetochore localization of polo-like kinase 1 (Plk1), and this contributes to the activity of the p38 MAPK pathway. Our data suggest a link between mitotic regulation and the p38 MAPK pathway, in which p38γ prevents chromosomal instability and supports mitotic cell viability.

Problems experienced by gynecologists/obstetricians in sickness certification consultations.

OBJECTIVE: To explore frequencies and experiences with problems in sickness certification consultations among gynecologists and obstetricians in two different years. DESIGN: Cross-sectional surveys on two occasions; in 2004 and 2008. SETTING: Gynecological, obstetric and maternal health care. SAMPLE: Physicians working in gynecology, obstetrics or maternal health care in two Swedish counties from two samples: in 2004 (n = 315), and in 2008 (n = 327). METHODS: Data regarding sickness certification consultations were obtained from comprehensive questionnaires that had been mailed to the physicians in two Swedish counties in 2004 and in 2008, respectively. OUTCOME MEASURES: Frequencies and types of problems in sickness certification consultations, organizational support, and need to acquire more competence. RESULTS: The majority experienced that patients requested to be on sick leave for a reason other than work incapacity due to disease or injury, at least a few times per year (85% in 2004 and 88% in 2008). The most problematic situation to handle was when the physician and the patient had different opinions about the need for sick leave (2004: 66% and 2008: 58%). The physicians expressed a need for more competence about the options and responsibilities of employers, social insurance officers and physicians in sickness certification cases. CONCLUSIONS: Most gynecologists/obstetricians find sickness certification consultations problematic and especially when encountering patients requesting to be on sick leave for reasons other than disease. The physicians expressed a need for more competence in insurance medicine, especially about their own and other stakeholders' options and responsibilities.

Prevalence of antibiotic-resistant bacteria in residents of nursing homes in a Swedish municipality: healthcare staff knowledge of and adherence to principles of basic infection prevention.

BACKGROUND: The aims of this study were to investigate the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae in residents living in Swedish nursing homes, and if carriage of resistant bacteria was related to antibiotic treatment, other risk factors, and/or staff's adherence to guidelines for infection control. METHODS: Five hundred and sixty residents from 9 nursing homes on a total of 67 wards participated in the study and had microbiological cultures taken. Faecal samples were obtained from 495 residents (88.3%). ESBL-positive residents were followed for 2 y with repeated sampling. Two hundred and ninety-six [corrected] staff members were interviewed and observed regarding familiarity with and adherence to infection control guidelines. RESULTS: No resident was positive for MRSA or VRE. Fifteen of the residents were found to be ESBL-positive. Residents living on wards where ESBL-positive residents were identified had been treated more frequently with antibiotics (42%), compared to those on wards where no residents with ESBL were found (28%; p = 0.02). ESBL-positive Escherichia coli isolates from residents living in adjacent rooms were found to be closely genetically related when analysed by pulsed-field gel electrophoresis, indicating transmission between residents. Staff adherence to infection control guidelines sometimes revealed shortcomings, but no significant differences regarding compliance to the guidelines could be found. CONCLUSION: Carriage of resistant bacteria was uncommon and only ESBL-producing Enterobacteriaceae were identified in Swedish nursing homes. Usage of antibiotics was higher on wards where ESBL-positive residents were detected and there was an indication of transmission of ESBL between residents.

Specialist prescribing of psychotropic drugs to older persons in Sweden--a register-based study of 188,024 older persons.

BACKGROUND: The situation for older persons with mental disorders other than dementia disorders has scarcely been studied. The older population is increasing worldwide and along with this increase the prevalence of mental disorders will also rise. The treatment of older persons with mental disorders entails complex challenges, with drugs constituting the major medical treatment. Knowledge of geriatric psychiatry is essential for providing older persons with appropriate treatment and care. This study aimed to evaluate the prescription of drugs for mental disorders to older persons (≥ 65) in Sweden, focused on the medical specialties of the prescribing physicians. METHODS: Data concerning drug treatment for older persons from 2006 to 2008 was gathered from the Swedish Prescribed Drug Register. Mental disorders, defined as affective, psychotic and anxiety disorders (ICD-10 F20-42) were evaluated in order to identify associated drugs. Included was a total of 188,024 older individuals, who collectively filled 2,013,079 prescriptions for the treatment of mental disorders. Descriptive analyses were performed, including frequency distribution and 95% CI. The competence of the prescribers was analyzed by subdividing them into five groups: geriatricians, psychiatrists, general practitioners (GPs), other specialists, and physicians without specialist education. RESULTS: GPs represented the main prescribers, whereas geriatricians and psychiatrists rarely prescribed drugs to older persons. Benzodiazepines and tricyclic antidepressants were the most commonly prescribed drugs. Women were prescribed drugs from geriatricians and psychiatrists to a greater extent than men. CONCLUSIONS: This study examined the prescription of psychotropic drugs to older persons. Physicians specialized in older persons' disorders and mental health were rarely the prescribers of these drugs. Contrary to clinical guidelines, benzodiazepines and tricyclic antidepressants were commonly prescribed to older persons, emphasizing the need for continuous examination of pharmaceutical treatment for older persons. The results indicate a future need of more specialists in geriatrics and psychiatry.

Short-term sick leave and future risk of sickness absence and unemployment - the impact of health status.

BACKGROUND: In previous studies the authors have found sick leave to be a predictor of future sick leave, unemployment and disability pension. Although sick leave reflects underlying health problems, some studies have suggested that sick leave may have consequences beyond the consequences of the underlying illness. However, few studies have aimed at studying consequences of sick leave while adjusting for ill health. This study aims to explore whether short-term sick leave increases the risk of future long-term sick leave, disability pension, and unemployment. Furthermore, we aim to control for the potentially confounding effects of physical and mental health status. METHODS: Data were gathered from the Stockholm Public Health Cohort (SPHC), restricted to 11,156 employed individuals (48.6% men) aged 18-59, without long-term sick leave, disability pension or in-patient care the year before inclusion (2002). These were followed-up with regard to unemployment, long-term sick leave, and disability pension in 2006 and 2007.Odds ratios (OR) with corresponding 95% confidence intervals (CI) were estimated by logistic regression, controlling for six different measures of health status (limiting long-standing illness, self-rated health, mental health, somatic disease, musculoskeletal pain and in-patient care) and socio-demographic factors. RESULTS: Results from the unadjusted analyses indicated increased risks of long-term sick leave (OR 2.00; CI 1.62-2.46) and short-term unemployment (OR 1.76; CI 1.35-2.29) for individuals exposed to more than one short-term sick-leave spell. There were no increased odds of long-term unemployment (OR 0.54; CI 0.28-1.04) or disability pension (OR 0.72; CI 0.42-1.24). After adjusting for the different measures of health status the odds ratio for short-term unemployment was not statistically significant (OR 1.29; CI 0.97-1.74). The odds ratios for the other outcomes slightly increased after adjustment for the used measures of health status. CONCLUSIONS: The results support the assumption that short-term sick leave may have consequences for future sick leave beyond the effect of ill health. The results point to the importance of paying attention to short-term sick leave in order to prevent subsequent sickness absence.

Psychiatrists' work with sickness certification: frequency, experiences and severity of the certification tasks in a national survey in Sweden.

BACKGROUND: Many psychiatrists are involved in sickness certification of their patients; however, there is very limited knowledge about this aspect of their work. The objective of this study was to explore frequencies of problematic issues in the sickness certification tasks and experiences of severity regarding these problematic issues among psychiatrists. METHODS: A cross-sectional nationwide questionnaire study to all physicians in Sweden. The 579 specialists in psychiatry who answered the questionnaire, were under 65 years of age, worked mainly in psychiatric care, and had consultations involving sickness certification at least once a week were included. RESULTS: The frequency of problematic sickness certification consultations a few times per year or more often was considered by 87.3% of the psychiatrists; 11.7% handle such cases at least once a week. A majority (60.9%) reported 'not having enough time with the patient' at least once a week. The psychiatrists had access to several categories of professionals in their daily work. More than one third certified unnecessarily long sick-leave periods at least once a month due to waiting times for Social Insurance Office investigations or for treatments or investigations within health care. CONCLUSION: The majority found it problematic to assess the level and duration of work incapacity, but also other types of problems like unnecessarily long sick-leave periods due to different types of waiting times. The findings have implications for different kinds of organisational and managerial support and training in sickness certification issues, like guidance to assess the level and duration of work incapacity.

Mental disorders affect older persons in Sweden--a register-based study.

OBJECTIVE: The study aimed to estimate the prevalence of mental disorders based on pharmaceutical use among the old (age ≥65) in Sweden for the years 2006-2008. METHODS: Data on the mental health of older persons were approximated on the basis of recommended prescriptions for pharmaceuticals, gathered from the Swedish Register on Prescribed Pharmaceuticals (SRPP). Each disorder (ICD-10, F20-F42, and F60-F61) was analyzed to identify associated recommended pharmaceuticals. Anatomical Therapeutic Chemical Classification codes were applied. The data covered 188,024 individuals who received 2,013,079 prescriptions for pharmaceuticals for mental disorders during a 3-year period. Persons with pharmaceuticals for dementia disorders were excluded from the calculations of the prevalence of mental disorders. RESULTS: The prevalence of mental disorders among the old in Sweden, measured on the basis of pharmaceutical use, was 6.6% in 2006, 2007, and 2008, respectively. Men constituted one-third of cases and women two-thirds. Prevalence was lowest in the age group 65-69 and increased subsequently with age. CONCLUSIONS: This fundamental register-based study included a great number of older persons and shows that mental disorders affect every fifteenth older person in Sweden. The prevalence of mental disorders increases with increasing age. The results highlight the extent of mental disorders among older persons, which is important to know when planning care for these patients. This study, by investigating a large population, provides a solid basis for general planning as well as for future mental disorder research.

Work-related psychosocial events as triggers of sick leave--results from a Swedish case-crossover study.

BACKGROUND: Although illness is an important cause of sick leave, it has also been suggested that non-medical risk factors may influence this association. If such factors impact on the period of decision making, they should be considered as triggers. Yet, there is no empirical support available.The aim was to investigate whether recent exposure to work-related psychosocial events can trigger the decision to report sick when ill. METHODS: A case-crossover design was applied to 546 sick-leave spells, extracted from a Swedish cohort of 1430 employees with a 3-12 month follow-up of new sick-leave spells. Exposure in a case period corresponding to an induction period of one or two days was compared with exposure during control periods sampled from workdays during a two-week period prior to sick leave for the same individual. This was done according to the matched-pair interval and the usual frequency approaches. Results are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Most sick-leave spells happened in relation to acute, minor illnesses that substantially reduced work ability. The risk of taking sick leave was increased when individuals had recently been exposed to problems in their relationship with a superior (OR 3.63; CI 1.44-9.14) or colleagues (OR 4.68; CI 1.43-15.29). Individuals were also more inclined to report sick on days when they expected a very stressful work situation than on a day when they were not under such stress (OR 2.27; CI 1.40-3.70). CONCLUSIONS: Exposure to problems in workplace relationships or a stressful work situation seems to be able to trigger reporting sick. Psychosocial work-environmental factors appear to have a short-term effect on individuals when deciding to report sick.

Frequency and severity of problems that general practitioners experience regarding sickness certification.

OBJECTIVE: Tasks involved in sickness certification constitute potential problems for physicians. The objective in this study was to obtain more detailed knowledge about the problems that general practitioners (GPs) experience in sickness certification cases, specifically regarding reasons for issuing unnecessarily long sick-leave periods. DESIGN: A cross-sectional national questionnaire study. SETTING: Primary health care in Sweden. SUBJECTS: The 2516 general practitioners (GPs), below 65 years of age, who had consultations involving sickness certification every week. This makes it the by far largest such study worldwide. The response rate among GPs was 59.9%. RESULTS: Once a week, half of the GPs (54.5%) found it problematic to handle sickness certification, and one-fourth (25.9%) had a patient who wanted to be sickness absent for some reason other than medical work incapacity. Issues rated as problematic by many GPs concerned assessing work capacity, prognosticating the duration of incapacity, handling situations in which the GP and the patient had different opinions on the need for sick leave, and managing the two roles as physician for the patient and medical expert in writing certificates for other authorities. Main reasons for certifying unnecessarily long sick-leave periods were long waiting times in health care and in other organizations, and younger and male GPs more often reported doing this to avoid conflicts with the patient. CONCLUSION: A majority of the GPs found sickness certification problematic. Most problems were related to professional competence in insurance medicine. Better possibilities to develop, maintain, and practise such professionalism are warranted.

FLIM-FRET Analysis of Ras Nanoclustering and Membrane-Anchorage.

On the plasma membrane, Ras is organized into laterally segregated proteo-lipid complexes called nanoclusters. The extent of Ras nanoclustering correlates with its signaling output, positioning nanocluster as dynamic signaling gain modulators. Recent evidence suggests that stacked dimers of Ras and Raf are elemental units at least of one type of Ras nanocluster. However, it is still incompletely understood, in which physiological contexts nanoclustering is regulated and which constituents are parts of nanocluster. Nonetheless, disruption of nanoclustering faithfully diminishes Ras activity in cells, suggesting Ras nanocluster as potential drug targets.While there are several methods available to study Ras nanocluster , fluorescence or Förster resonance energy transfer (FRET ) between fluorescently labeled, nanoclustered Ras proteins is a relatively simple readout. FRET measurements using fluorescence lifetime imaging microscopy (FLIM ) have proven to be robust and sensitive to determine Ras nanoclustering changes. Loss of FRET that emerges due to nanoclustering reports on all processes upstream of Ras nanoclustering, i.e., also on proper trafficking or lipid modification of Ras. Here we report our standard FLIM-FRET protocol to measure nanoclustering-dependent FRET of Ras in mammalian cells. Importantly, nanoclustering-dependent FRET is one of the few methods that can detect differences between the Ras isoforms.

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling.

The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 µM-44 µM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.