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1.  The ‘Dark Side’ and ‘Bright Side’ of Personality: When Too Much Conscientiousness and Too Little Anxiety Are Detrimental with Respect to the Acquisition of Medical Knowledge and Skill 
PLoS ONE  2014;9(2):e88606.
Theory suggests that personality traits evolved to have costs and benefits, with the effectiveness of a trait dependent on how these costs and benefits relate to the present circumstances. This suggests that traits that are generally viewed as positive can have a ‘dark side’ and those generally viewed as negative can have a ‘bright side’ depending on changes in context. We test this in a sample of 220 UK medical students with respect to associations between the Big 5 personality traits and learning outcomes across the 5 years of a medical degree. The medical degree offers a changing learning context from pre-clinical years (where a more methodical approach to learning is needed) to the clinical years (where more flexible learning is needed, in a more stressful context). We argue that while trait conscientiousness should enhance pre-clinical learning, it has a ‘dark side’ reducing the acquisition of knowledge in the clinical years. We also suggest that anxiety has a ‘bright side’ enhancing the acquisition of skills in the clinical years. We also explore if intelligence enhances learning across the medical degree. Using confirmatory factor analysis and structural equation modelling we show that medical skills and knowledge assessed in the pre-clinical and clinical years are psychometrically distinguishable, forming a learning ‘backbone’, whereby subsequent learning outcomes are predicted by previous ones. Consistent with our predictions conscientiousness enhanced preclinical knowledge acquisition but reduced the acquisition of clinical knowledge and anxiety enhanced the acquisition of clinical skills. We also identified a curvilinear U shaped association between Surgency (extraversion) and pre-clinical knowledge acquisition. Intelligence predicted initial clinical knowledge, and had a positive total indirect effect on clinical knowledge and clinical skill acquisition. For medical selection, this suggests that selecting students high on conscientiousness may be problematic, as it may be excluding those with some degree of moderate anxiety.
doi:10.1371/journal.pone.0088606
PMCID: PMC3937323  PMID: 24586353
2.  Graduate entry to medicine: widening psychological diversity 
Background
At Nottingham University more than 95% of entrants to the traditional 5-year medical course are school leavers. Since 2003 we have admitted graduate entrants (GEM) to a shortened (4-year) course to 'widen access to students from more disadvantaged backgrounds'. We have recently shown that the GEM course widens academic and socio-demographic diversity of the medical student population. This study explored whether GEM students also bring psychological diversity and whether this could be beneficial.
Methods
We studied: a) 217 and 96 applicants to the Nottingham 5- and 4-year courses respectively, applying in the 2002-3 UCAS cycle, and, b) 246 school leavers starting the 5-year course and 39 graduate entrants to the 4-year course in October 2003. The psychological profiles of the two groups of applicants and two groups of entrants were compared using their performance in the Goldberg 'Big 5' Personality test, the Personal Qualities Assessment (PQA; measuring interpersonal traits and interpersonal values), and the Lovibond and Lovibond measure of depression, anxiety and stress. For the comparison of the Entrants we excluded the 33 school leavers and seven graduates who took the tests as Applicants.
Statistical analyses were undertaken using SPSS software (version 16.0).
Results
Graduate applicants compared to school leaver applicants were significantly more conscientious, more confident, more self controlled, more communitarian in moral orientation and less anxious. Only one of these differences was preserved in the entrants with graduates being less anxious. However, the graduate entrants were significantly less empathetic and conscientious than the school leavers.
Conclusion
This study has shown that school leaver and graduate entrants to medical school differ in some psychological characteristics. However, if confirmed in other studies and if they were manifest in the extreme, not all the traits brought by graduates would be desirable for someone aiming for a medical career.
doi:10.1186/1472-6920-9-67
PMCID: PMC2784445  PMID: 19912642
3.  Prospective survey of performance of medical students during preclinical years. 
The performance during the preclinical course of 517 students who had applied to this medical school for admission in 1981 and who had been accepted by the school or by another British medical school was analysed in relation to variables measured at the time of application to find factors that predicted success in the preclinical course, whether students chose to take an intercalated degree, and the class achieved in the intercalated degree. Thirty one of the 507 students who entered medical school withdrew from the course or failed their examinations; these students were particularly likely not to have an A level in a biological science. O level grades were of minimal predictive value for performance during the preclinical course. A level grades discriminated between successful and unsuccessful students but had too low a specificity or sensitivity to be of use in individual prediction. Mature entrants performed better overall than school leavers. Background variables accounted for only 14.2% of the variance in performance, implying that motivation and personality may be more important in determining performance. The 80 students who chose to take an intercalated degree were more likely to be men and not to be mature entrants; for a further 50 students intercalated degrees were obligatory. Performance in the intercalated degree related to performance during the preclinical course and to assessments made at the selection interview but not to achievement at O or A level.
PMCID: PMC1340851  PMID: 3089415
4.  Association of personality with the development and persistence of obesity: a meta-analysis based on individual–participant data 
Obesity Reviews  2012;14(4):315-323.
Personality is thought to affect obesity risk but before such information can be incorporated into prevention and intervention plans, robust and converging evidence concerning the most relevant personality traits is needed. We performed a meta-analysis based on individual–participant data from nine cohort studies to examine whether broad-level personality traits predict the development and persistence of obesity (n = 78,931 men and women; mean age 50 years). Personality was assessed using inventories of the Five-Factor Model (extraversion, neuroticism, agreeableness, conscientiousness and openness to experience). High conscientiousness – reflecting high self-control, orderliness and adherence to social norms – was associated with lower obesity risk across studies (pooled odds ratio [OR] = 0.84; 95% confidence interval [CI] = 0.80–0.88 per 1 standard deviation increment in conscientiousness). Over a mean follow-up of 5.4 years, conscientiousness predicted lower obesity risk in initially non-obese individuals (OR = 0.88, 95% CI = 0.85–0.92; n = 33,981) and was associated with greater likelihood of reversion to non-obese among initially obese individuals (OR = 1.08, 95% CI = 1.01–1.14; n = 9,657). Other personality traits were not associated with obesity in the pooled analysis, and there was substantial heterogeneity in the associations between studies. The findings indicate that conscientiousness may be the only broad-level personality trait of the Five-Factor Model that is consistently associated with obesity across populations.
doi:10.1111/obr.12007
PMCID: PMC3717171  PMID: 23176713
Longitudinal analysis; meta-analysis; obesity; personality
5.  Predicting the “strugglers”: a case-control study of students at Nottingham University Medical School 
BMJ : British Medical Journal  2006;332(7548):1009-1013.
Objective To identify potential predictors of undergraduate students who struggle during their medical training.
Design Case-control study. Cases were students who had experienced academic or personal difficulties that affected their progression on the course (“strugglers”). Controls were selected at random from the corresponding year cohorts, using a ratio of four controls for each struggler.
Setting University of Nottingham Medical School.
Participants Students who entered the course over five consecutive years.
Main outcome measures Likelihood ratios for independent risk factors for struggling on the course
Results 10-15% of each year's student intake were identified as strugglers. Significant independent predictors of students being in this category were negative comments in the academic reference (likelihood ratio 2.25, 95% confidence intervals 1.44 to 3.50), lower mean examination grade at A level (2.19, 1.37 to 3.51), and the late offer of a place (1.98, 1.19 to 3.30). Male sex was a less significant risk factor (1.70, 1.09 to 2.65) as was a lower grade at GCSE science (2.13, 1.12 to 4.05). In UK students whose ethnicity was known, not being white was a significant predictor of struggling (2.77, 1.52 to 5.05) but the presence of negative comments was not. Age at entry to the course and the possession of a previous degree were not predictive.
Conclusions Our results support retention of existing selection practices relating to academic achievement and critical review of students' references. We plan to undertake further investigation of the reasons why some students, including men, those with late offers and those from ethnic minority backgrounds, may do less well on the Nottingham course.
doi:10.1136/bmj.38730.678310.63
PMCID: PMC1450046  PMID: 16543299
6.  Childhood Conscientiousness Relates to Objectively Measured Adult Physical Health Four Decades Later 
Objective
Many lifespan personality-and-health models assume that childhood personality traits result in life-course pathways leading through morbidity to mortality. Although childhood conscientiousness in particular predicts mortality, there are few prospective studies that have investigated the associations between childhood personality and objective health status in adulthood. The present study tested this crucial assumption of lifespan models of personality and health using a comprehensive assessment of the Big Five traits in childhood (M age = 10 years) and biomarkers of health over 40 years later (M age = 51 years).
Methods
Members of the Hawaii Personality and Health Cohort (N = 753, 368 men, 385 women) underwent a medical examination at mean age 51. Their global health status was evaluated by well-established clinical indicators that were objectively measured using standard protocols, including blood pressure, lipid profile, fasting blood glucose, and body mass index. These indicators were combined to evaluate overall physiological dysregulation, and grouped into five more homogeneous subcomponents (glucose intolerance, blood pressure, lipids, obesity, and medications).
Results
Lower levels of childhood conscientiousness predicted more physiological dysregulation (β = −.11, p < .05), greater obesity (β = − .10, p < .05), and worse lipid profiles (β = −.10, p < .05), after controlling for the other Big Five childhood personality traits, gender, ethnicity, parental home ownership, and adult conscientiousness.
Conclusions
These findings are consistent with a key assumption in lifespan models that childhood conscientiousness is associated with objective health status in older adults. They open the way for testing mechanisms by which childhood personality may influence mortality through morbidity; mechanisms that could then be targeted for intervention.
doi:10.1037/a0031655
PMCID: PMC3754851  PMID: 23527514
Big Five traits; global health status; physiological dysregulation; lifespan models
7.  A holistic review of the medical school admission process: examining correlates of academic underperformance 
Medical Education Online  2014;19:10.3402/meo.v19.22919.
Background
Despite medical school admission committees’ best efforts, a handful of seemingly capable students invariably struggle during their first year of study. Yet, even as entrance criteria continue to broaden beyond cognitive qualifications, attention inevitably reverts back to such factors when seeking to understand these phenomena. Using a host of applicant, admission, and post-admission variables, the purpose of this inductive study, then, was to identify a constellation of student characteristics that, taken collectively, would be predictive of students at-risk of underperforming during the first year of medical school. In it, we hypothesize that a wider range of factors than previously recognized could conceivably play roles in understanding why students experience academic problems early in the medical educational continuum.
Methods
The study sample consisted of the five most recent matriculant cohorts from a large, southeastern medical school (n=537). Independent variables reflected: 1) the personal demographics of applicants (e.g., age, gender); 2) academic criteria (e.g., undergraduate grade point averages [GPA], medical college admission test); 3) selection processes (e.g., entrance track, interview scores, committee votes); and 4) other indicators of personality and professionalism (e.g., Mayer-Salovey-Caruso Emotional Intelligence Test™ emotional intelligence scores, NEO PI-R™ personality profiles, and appearances before the Professional Code Committee [PCC]). The dependent variable, first-year underperformance, was defined as ANY action (repeat, conditionally advance, or dismiss) by the college's Student Progress and Promotions Committee (SPPC) in response to predefined academic criteria. This study protocol was approved by the local medical institutional review board (IRB).
Results
Of the 537 students comprising the study sample, 61 (11.4%) met the specified criterion for academic underperformance. Significantly increased academic risks were identified among students who 1) had lower mean undergraduate science GPAs (OR=0.24, p=0.001); 2) entered medical school via an accelerated BS/MD track (OR=16.15, p=0.002); 3) were 31 years of age or older (OR=14.76, p=0.005); and 4) were non-unanimous admission committee admits (OR=0.53, p=0.042). Two dimensions of the NEO PI-R™ personality inventory, openness (+) and conscientiousness (−), were modestly but significantly correlated with academic underperformance. Only for the latter, however, were mean scores found to differ significantly between academic performers and underperformers. Finally, appearing before the college's PCC (OR=4.21, p=0.056) fell just short of statistical significance.
Conclusions
Our review of various correlates across the matriculation process highlights the heterogeneity of factors underlying students’ underperformance during the first year of medical school and challenges medical educators to understand the complexity of predicting who, among admitted matriculants, may be at future academic risk.
doi:10.3402/meo.v19.22919
PMCID: PMC3974177  PMID: 24695362
admissions; underperformance; selection; at-risk students
8.  Can Medical School Performance Predict Residency Performance? Resident Selection and Predictors of Successful Performance in Obstetrics and Gynecology 
Background
During the evaluation process, Residency Admissions Committees typically gather data on objective and subjective measures of a medical student's performance through the Electronic Residency Application Service, including medical school grades, standardized test scores, research achievements, nonacademic accomplishments, letters of recommendation, the dean's letter, and personal statements. Using these data to identify which medical students are likely to become successful residents in an academic residency program in obstetrics and gynecology is difficult and to date, not well studied.
Objective
To determine whether objective information in medical students' applications can help predict resident success.
Method
We performed a retrospective cohort study of all residents who matched into the Johns Hopkins University residency program in obstetrics and gynecology between 1994 and 2004 and entered the program through the National Resident Matching Program as a postgraduate year-1 resident. Residents were independently evaluated by faculty and ranked in 4 groups according to perceived level of success. Applications from residents in the highest and lowest group were abstracted. Groups were compared using the Fisher exact test and the Student t test.
Results
Seventy-five residents met inclusion criteria and 29 residents were ranked in the highest and lowest quartiles (15 in highest, 14 in lowest). Univariate analysis identified no variables as consistent predictors of resident success.
Conclusion
In a program designed to train academic obstetrician-gynecologists, objective data from medical students' applications did not correlate with successful resident performance in our obstetrics-gynecology residency program. We need to continue our search for evaluation criteria that can accurately and reliably select the medical students that are best fit for our specialty.
doi:10.4300/JGME-D-09-00101.1
PMCID: PMC2951767  PMID: 21976076
9.  Admissions processes for five year medical courses at English schools: review 
BMJ : British Medical Journal  2006;332(7548):1005-1009.
Objective To describe the current methods used by English medical schools to identify prospective medical students for admission to the five year degree course.
Design Review study including documentary analysis and interviews with admissions tutors.
Setting All schools (n = 22) participating in the national expansion of medical schools programme in England.
Results Though there is some commonality across schools with regard to the criteria used to select future students (academic ability coupled with a “well rounded” personality demonstrated by motivation for medicine, extracurricular interests, and experience of team working and leadership skills) the processes used vary substantially. Some schools do not interview; some shortlist for interview only on predicted academic performance while those that shortlist on a wider range of non-academic criteria use various techniques and tools to do so. Some schools use information presented in the candidate's personal statement and referee's report while others ignore this because of concerns over bias. A few schools seek additional information from supplementary questionnaires filled in by the candidates. Once students are shortlisted, interviews vary in terms of length, panel composition, structure, content, and scoring methods.
Conclusion The stated criteria for admission to medical school show commonality. Universities differ greatly, however, in how they apply these criteria and in the methods used to select students. Different approaches to admissions should be developed and tested.
doi:10.1136/bmj.38768.590174.55
PMCID: PMC1450044  PMID: 16543300
10.  A qualitative analysis of statements on motivation of applicants for medical school 
BMC Medical Education  2014;14(1):200.
Background
Selection committees try to ascertain that motivated students are selected for medical school. Self-determination theory stresses that the type of motivation is more important than the quantity of motivation. Autonomous motivation, compared to controlled motivation, in students leads to better learning outcomes. Applicants can express their motivation in written statements, a selection tool which has been found to elicit heterogeneous responses, hampering the comparison of applicants. This study investigates the content of applicants’ statements on motivation for medical school in particular, the possibility to distinguish the type of motivation and the differences between selected and non-selected applicants.
Methods
A thematic analysis was conducted on written statements on motivation (n = 96), collected as a part of the selection procedure for the graduate entry program for medicine and research at our institution. Themes were identified as motivation-related and motivation-unrelated (additional). The motivation-related themes were further classified as autonomous and controlled types of motivation. Group percentages for each theme were compared between selected and non-selected applicants using Chi-square test and Fisher exact test.
Results
Applicants mainly described reasons belonging to autonomous type of motivation and fewer reasons belonging to controlled type of motivation. Additional themes in the statements included previous work experience and academic qualifications, ambitions, expectations and descriptions of the program and profession, personal qualities, and personal history. Applicants used strong words to support their stories. The selected and non-selected applicants did not differ in their types of motivation. Non-selected applicants provided more descriptions of personal history than selected applicants (p < 0.05).
Conclusions
The statement on motivation does not appear to distinguish between applicants in selection for medical school. Both selected and non-selected applicants reported mainly autonomous motivation for applying, and included a lot of additional information, which was beyond the scope of what was asked from them. The findings raise a question mark on the validity and reliability of the statement on motivation as a tool for selection. It could however be of added value to enable applicants to tell their story, which they appreciate, and to create awareness of the program, resulting in an informed decision to apply.
doi:10.1186/1472-6920-14-200
PMCID: PMC4180534  PMID: 25248374
Admissions; Medical school selection; Motivation; Self-determination theory; Qualitative methods
11.  Ability of prospective assessment of personality profiles to predict the practice specialty of medical students 
Medical practice encompasses a diverse spectrum of specialties. Factors that impact selection of clinical disciplines by young physicians may have recently evolved associated with changes in medical school demographics. We assessed whether physicians gravitate to certain practice specialties due to preexisting personality traits. The Neuroticism-Extraversion-Openness Personality Inventory Revised Test was administered prospectively to 130 first-year students the week before they began medical school. Scores for five traits (neuroticism, extraversion, openness, agreeableness, conscientiousness) were compared with the selection among nine medical residencies at the conclusion of medical school. Personality scores for medical students selecting psychiatry residencies showed greater degrees of neuroticism (P < 0.01) and openness (P < 0.03). Students electing family practice also deviated from other specialties, showing a lower degree of neuroticism (P < 0.03). Unexpectedly, personality traits in prospective surgical residents did not differ from those of students choosing nonsurgical residencies. Personality profiles present before medical school appear to predict the selection of some residencies and clinical specialties but not others.
PMCID: PMC1769529  PMID: 17256038
12.  Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin 
PLoS Medicine  2013;10(1):e1001378.
Using documents obtained through litigation, S. Swaroop Vedula and colleagues compared internal company documents regarding industry-sponsored trials of off-label uses of gabapentin with the published trial reports and find discrepancies in reporting of analyses.
Background
Details about the type of analysis (e.g., intent to treat [ITT]) and definitions (i.e., criteria for including participants in the analysis) are necessary for interpreting a clinical trial's findings. Our objective was to compare the description of types of analyses and criteria for including participants in the publication (i.e., what was reported) with descriptions in the corresponding internal company documents (i.e., what was planned and what was done). Trials were for off-label uses of gabapentin sponsored by Pfizer and Parke-Davis, and documents were obtained through litigation.
Methods and Findings
For each trial, we compared internal company documents (protocols, statistical analysis plans, and research reports, all unpublished), with publications. One author extracted data and another verified, with a third person verifying discordant items and a sample of the rest. Extracted data included the number of participants randomized and analyzed for efficacy, and types of analyses for efficacy and safety and their definitions (i.e., criteria for including participants in each type of analysis). We identified 21 trials, 11 of which were published randomized controlled trials, and that provided the documents needed for planned comparisons. For three trials, there was disagreement on the number of randomized participants between the research report and publication. Seven types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including ITT and six others. The protocol or publication described ITT using six different definitions, resulting in frequent disagreements between the two documents (i.e., different numbers of participants were included in the analyses).
Conclusions
Descriptions of analyses conducted did not agree between internal company documents and what was publicly reported. Internal company documents provide extensive documentation of methods planned and used, and trial findings, and should be publicly accessible. Reporting standards for randomized controlled trials should recommend transparent descriptions and definitions of analyses performed and which study participants are excluded.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
To be credible, published research must present an unbiased, transparent, and accurate description of the study methods and findings so that readers can assess all relevant information to make informed decisions about the impact of any conclusions. Therefore, research publications should conform to universally adopted guidelines and checklists. Studies to establish whether a treatment is effective, termed randomized controlled trials (RCTs), are checked against a comprehensive set of guidelines: The robustness of trial protocols are measured through the Standard Protocol Items for Randomized Trials (SPIRIT), and the Consolidated Standards of Reporting Trials (CONSORT) statement (which was constructed and agreed by a meeting of journal editors in 1996, and has been updated over the years) includes a 25-point checklist that covers all of the key points in reporting RCTs.
Why Was This Study Done?
Although the CONSORT statement has helped improve transparency in the reporting of the methods and findings from RCTs, the statement does not define how certain types of analyses should be conducted and which patients should be included in the analyses, for example, in an intention-to-treat analysis (in which all participants are included in the data analysis of the group to which they were assigned, whether or not they completed the intervention given to the group). So in this study, the researchers used internal company documents released in the course of litigation against the pharmaceutical company Pfizer regarding the drug gabapentin, to compare between the internal and published reports the reporting of the numbers of participants, the description of the types of analyses, and the definitions of each type of analysis. The reports involved studies of gabapentin used for medical reasons not approved for marketing by the US Food and Drug Administration, known as “off-label” uses.
What Did the Researchers Do and Find?
The researchers identified trials sponsored by Pfizer relating to four off-label uses of gabapentin and examined the internal company protocols, statistical analysis plans, research reports, and the main publications related to each trial. The researchers then compared the numbers of participants randomized and analyzed for the main (primary) outcome and the type of analysis for efficacy and safety in both the internal research report and the trial publication. The researchers identified 21 trials, 11 of which were published RCTs that had the associated documents necessary for comparison.
The researchers found that in three out of ten trials there were differences in the internal research report and the main publication regarding the number of randomized participants. Furthermore, in six out of ten trials, the researchers were unable to compare the internal research report with the main publication for the number of participants analyzed for efficacy, because the research report either did not describe the primary outcome or did not describe the type of analysis. Overall, the researchers found that seven different types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including intention-to-treat analysis. However, the protocol or publication used six different descriptions for the intention-to-treat analysis, resulting in several important differences between the internal and published documents about the number of patients included in the analysis.
What Do These Findings Mean?
These findings from a sample of industry-sponsored trials on the off-label use of gabapentin suggest that when compared to the internal research reports, the trial publications did not always accurately reflect what was actually done in the trial. Therefore, the trial publication could not be considered to be an accurate and transparent record of the numbers of participants randomized and analyzed for efficacy. These findings support the need for further revisions of the CONSORT statement, such as including explicit statements about the criteria used to define each type of analysis and the numbers of participants excluded from each type of analysis. Further guidance is also needed to ensure consistent terminology for types of analysis. Of course, these revisions will improve reporting only if authors and journals adhere to them. These findings also highlight the need for all individual patient data to be made accessible to readers of the published article.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001378.
For more information, see the CONSORT statement website
The EQUATOR Network website is a resource center for the good reporting of health research studies and has more information about the SPIRIT initiative and the CONSORT statement
doi:10.1371/journal.pmed.1001378
PMCID: PMC3558476  PMID: 23382656
13.  Complexity in Non-Pharmacological Caregiving Activities at the End of Life: An International Qualitative Study 
PLoS Medicine  2012;9(2):e1001173.
In a qualitative study reported by Olav Lindqvist and colleagues, the range of nonpharmacological caregiving activities used in the last days of a patient's life are described.
Background
In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient's life.
Methods and Findings
Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings.
Conclusions
Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
End-of-life care is a major public health issue, yet despite the inevitability of death, issues related to death and dying are often taboo, and, if mentioned, are often referred to as “palliative care.” There are detailed definitions of palliative care, but in essence, the purpose of palliative care is to relieve any suffering in patients who are dying from progressive illness and to provide the best possible quality of life for both the patient and his or her family. In order to achieve this aim, both pharmacological and non-pharmacological management is necessary, with the latter taking a central role. Recently, a European Commission Seventh Framework Programme project, OPCARE9, aimed to improve the care of dying patients in Europe and beyond by optimizing research and clinical care for patients with cancer in the last days of their life, especially regarding well-being and comfort as death becomes imminent.
Why Was This Study Done?
There is now a growing literature base in non-pharmacological management at the end of an individual's life, particularly in relation to psychological, ethical, and communication issues as well as family-focused and culturally appropriate care. Despite this progress, there is currently little systematic knowledge in how health workers use such non-pharmacological approaches in their efforts to maximize well-being and comfort in patients experiencing their very last days of life. Therefore, in order to advance knowledge in this important clinical area, in this study the researchers reviewed and identified the variety of non-pharmacological caregiving activities performed by different professionals in the last days and hours of life for patients with cancer (and their families) in palliative care settings in the countries that participated in OPCARE9.
What Did the Researchers Do and Find?
The researchers modified an anthropological approach to collect relevant information in participating European countries—Germany, Italy, the Netherlands, Slovenia, Sweden, Switzerland, and the UK—and Argentina and New Zealand. Staff in palliative care settings generated a list of non-pharmacological caregiving activities after discussion about which interventions and activities they carried out with patients and families during the last days of life. This preliminary list of statements was added to if staff performed a new activity when in contact with patients or the patients' family during the last days of life. The researchers then used computer-assisted qualitative data analysis to code the statements.
Using this methodology, the researchers analyzed 914 statements of caregiving activities from 16 different facilities in nine countries. The greatest number of activities described some type of caregiving for an individual carried out through contact with his or her body, such as attending to diverse bodily needs (such as cleaning and moisturizing) while maintaining comfort and dignity. Listening, talking with, and understanding (particularly between professionals and the family) was the next most frequent activity, followed by creating an esthetical, safe, and pleasing environment for the dying person and his or her family, and necessary “backstage” activities, such as organizing paperwork or care plans. Other common activities included observing and assessing, which were often described as being carried out simultaneously with other interventions; just being present (described as increasingly important close to death); performing rituals surrounding death and dying (usually directed to families); guiding and facilitating (encompassing support in a compassionate manner); and finally, giving oral and written information and advice (usually to families).
What Do These Findings Mean?
These findings show that providing for fundamental human needs close to death is complex and sophisticated but ultimately integrated into a common theme of caregiving. This study also identifies a number of areas needing further investigation, such as enhancing the sensory and general environment for the patient and family. Finally, this study suggests that developing a greater level of detail, such as improved terminology for end-of-life care, would enhance appreciation of the nuances and complexity present in non-pharmacological care provision during the last days of life, with potential benefit for clinical practice, teaching, and research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001173.
The OPCARE9 website details more information about this end-of-life care initiative
The World Health Organization website defines palliative care, and Wikipedia gives more information (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
NHS Choices also provides information about end-of-life care
doi:10.1371/journal.pmed.1001173
PMCID: PMC3279347  PMID: 22347815
14.  Caregiver- and Patient-Directed Interventions for Dementia 
Executive Summary
In early August 2007, the Medical Advisory Secretariat began work on the Aging in the Community project, an evidence-based review of the literature surrounding healthy aging in the community. The Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the ministry’s newly released Aging at Home Strategy.
After a broad literature review and consultation with experts, the secretariat identified 4 key areas that strongly predict an elderly person’s transition from independent community living to a long-term care home. Evidence-based analyses have been prepared for each of these 4 areas: falls and fall-related injuries, urinary incontinence, dementia, and social isolation. For the first area, falls and fall-related injuries, an economic model is described in a separate report.
Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html, to review these titles within the Aging in the Community series.
Aging in the Community: Summary of Evidence-Based Analyses
Prevention of Falls and Fall-Related Injuries in Community-Dwelling Seniors: An Evidence-Based Analysis
Behavioural Interventions for Urinary Incontinence in Community-Dwelling Seniors: An Evidence-Based Analysis
Caregiver- and Patient-Directed Interventions for Dementia: An Evidence-Based Analysis
Social Isolation in Community-Dwelling Seniors: An Evidence-Based Analysis
The Falls/Fractures Economic Model in Ontario Residents Aged 65 Years and Over (FEMOR)
This report features the evidence-based analysis on caregiver- and patient-directed interventions for dementia and is broken down into 4 sections:
Introduction
Caregiver-Directed Interventions for Dementia
Patient-Directed Interventions for Dementia
Economic Analysis of Caregiver- and Patient-Directed Interventions for Dementia
Caregiver-Directed Interventions for Dementia
Objective
To identify interventions that may be effective in supporting the well-being of unpaid caregivers of seniors with dementia living in the community.
Clinical Need: Target Population and Condition
Dementia is a progressive and largely irreversible syndrome that is characterized by a loss of cognitive function severe enough to impact social or occupational functioning. The components of cognitive function affected include memory and learning, attention, concentration and orientation, problem-solving, calculation, language, and geographic orientation. Dementia was identified as one of the key predictors in a senior’s transition from independent community living to admission to a long-term care (LTC) home, in that approximately 90% of individuals diagnosed with dementia will be institutionalized before death. In addition, cognitive decline linked to dementia is one of the most commonly cited reasons for institutionalization.
Prevalence estimates of dementia in the Ontario population have largely been extrapolated from the Canadian Study of Health and Aging conducted in 1991. Based on these estimates, it is projected that there will be approximately 165,000 dementia cases in Ontario in the year 2008, and by 2010 the number of cases will increase by nearly 17% over 2005 levels. By 2020 the number of cases is expected to increase by nearly 55%, due to a rise in the number of people in the age categories with the highest prevalence (85+). With the increase in the aging population, dementia will continue to have a significant economic impact on the Canadian health care system. In 1991, the total costs associated with dementia in Canada were $3.9 billion (Cdn) with $2.18 billion coming from LTC.
Caregivers play a crucial role in the management of individuals with dementia because of the high level of dependency and morbidity associated with the condition. It has been documented that a greater demand is faced by dementia caregivers compared with caregivers of persons with other chronic diseases. The increased burden of caregiving contributes to a host of chronic health problems seen among many informal caregivers of persons with dementia. Much of this burden results from managing the behavioural and psychological symptoms of dementia (BPSD), which have been established as a predictor of institutionalization for elderly patients with dementia.
It is recognized that for some patients with dementia, an LTC facility can provide the most appropriate care; however, many patients move into LTC unnecessarily. For individuals with dementia to remain in the community longer, caregivers require many types of formal and informal support services to alleviate the stress of caregiving. These include both respite care and psychosocial interventions. Psychosocial interventions encompass a broad range of interventions such as psychoeducational interventions, counseling, supportive therapy, and behavioural interventions.
Assuming that 50% of persons with dementia live in the community, a conservative estimate of the number of informal caregivers in Ontario is 82,500. Accounting for the fact that 29% of people with dementia live alone, this leaves a remaining estimate of 58,575 Ontarians providing care for a person with dementia with whom they reside.
Description of Interventions
The 2 main categories of caregiver-directed interventions examined in this review are respite care and psychosocial interventions. Respite care is defined as a break or relief for the caregiver. In most cases, respite is provided in the home, through day programs, or at institutions (usually 30 days or less). Depending on a caregiver’s needs, respite services will vary in delivery and duration. Respite care is carried out by a variety of individuals, including paid staff, volunteers, family, or friends.
Psychosocial interventions encompass a broad range of interventions and have been classified in various ways in the literature. This review will examine educational, behavioural, dementia-specific, supportive, and coping interventions. The analysis focuses on behavioural interventions, that is, those designed to help the caregiver manage BPSD. As described earlier, BPSD are one of the most challenging aspects of caring for a senior with dementia, causing an increase in caregiver burden. The analysis also examines multicomponent interventions, which include at least 2 of the above-mentioned interventions.
Methods of Evidence-Based Analysis
A comprehensive search strategy was used to identify systematic reviews and randomized controlled trials (RCTs) that examined the effectiveness of interventions for caregivers of dementia patients.
Questions
Section 2.1
Are respite care services effective in supporting the well-being of unpaid caregivers of seniors with dementia in the community?
Do respite care services impact on rates of institutionalization of these seniors?
Section 2.2
Which psychosocial interventions are effective in supporting the well-being of unpaid caregivers of seniors with dementia in the community?
Which interventions reduce the risk for institutionalization of seniors with dementia?
Outcomes of Interest
any quantitative measure of caregiver psychological health, including caregiver burden, depression, quality of life, well-being, strain, mastery (taking control of one’s situation), reactivity to behaviour problems, etc.;
rate of institutionalization; and
cost-effectiveness.
Assessment of Quality of Evidence
The quality of the evidence was assessed as High, Moderate, Low, or Very low according to the GRADE methodology and GRADE Working Group. As per GRADE the following definitions apply:
Summary of Findings
Conclusions in Table 1 are drawn from Sections 2.1 and 2.2 of the report.
Summary of Conclusions on Caregiver-Directed Interventions
There is limited evidence from RCTs that respite care is effective in improving outcomes for those caring for seniors with dementia.
There is considerable qualitative evidence of the perceived benefits of respite care.
Respite care is known as one of the key formal support services for alleviating caregiver burden in those caring for dementia patients.
Respite care services need to be tailored to individual caregiver needs as there are vast differences among caregivers and patients with dementia (severity, type of dementia, amount of informal/formal support available, housing situation, etc.)
There is moderate- to high-quality evidence that individual behavioural interventions (≥ 6 sessions), directed towards the caregiver (or combined with the patient) are effective in improving psychological health in dementia caregivers.
There is moderate- to high-quality evidence that multicomponent interventions improve caregiver psychosocial health and may affect rates of institutionalization of dementia patients.
RCT indicates randomized controlled trial.
Patient-Directed Interventions for Dementia
Objective
The section on patient-directed interventions for dementia is broken down into 4 subsections with the following questions:
3.1 Physical Exercise for Seniors with Dementia – Secondary Prevention
What is the effectiveness of physical exercise for the improvement or maintenance of basic activities of daily living (ADLs), such as eating, bathing, toileting, and functional ability, in seniors with mild to moderate dementia?
3.2 Nonpharmacologic and Nonexercise Interventions to Improve Cognitive Functioning in Seniors With Dementia – Secondary Prevention
What is the effectiveness of nonpharmacologic interventions to improve cognitive functioning in seniors with mild to moderate dementia?
3.3 Physical Exercise for Delaying the Onset of Dementia – Primary Prevention
Can exercise decrease the risk of subsequent cognitive decline/dementia?
3.4 Cognitive Interventions for Delaying the Onset of Dementia – Primary Prevention
Does cognitive training decrease the risk of cognitive impairment, deterioration in the performance of basic ADLs or instrumental activities of daily living (IADLs),1 or incidence of dementia in seniors with good cognitive and physical functioning?
Clinical Need: Target Population and Condition
Secondary Prevention2
Exercise
Physical deterioration is linked to dementia. This is thought to be due to reduced muscle mass leading to decreased activity levels and muscle atrophy, increasing the potential for unsafe mobility while performing basic ADLs such as eating, bathing, toileting, and functional ability.
Improved physical conditioning for seniors with dementia may extend their independent mobility and maintain performance of ADL.
Nonpharmacologic and Nonexercise Interventions
Cognitive impairments, including memory problems, are a defining feature of dementia. These impairments can lead to anxiety, depression, and withdrawal from activities. The impact of these cognitive problems on daily activities increases pressure on caregivers.
Cognitive interventions aim to improve these impairments in people with mild to moderate dementia.
Primary Prevention3
Exercise
Various vascular risk factors have been found to contribute to the development of dementia (e.g., hypertension, hypercholesterolemia, diabetes, overweight).
Physical exercise is important in promoting overall and vascular health. However, it is unclear whether physical exercise can decrease the risk of cognitive decline/dementia.
Nonpharmacologic and Nonexercise Interventions
Having more years of education (i.e., a higher cognitive reserve) is associated with a lower prevalence of dementia in crossectional population-based studies and a lower incidence of dementia in cohorts followed longitudinally. However, it is unclear whether cognitive training can increase cognitive reserve or decrease the risk of cognitive impairment, prevent or delay deterioration in the performance of ADLs or IADLs or reduce the incidence of dementia.
Description of Interventions
Physical exercise and nonpharmacologic/nonexercise interventions (e.g., cognitive training) for the primary and secondary prevention of dementia are assessed in this review.
Evidence-Based Analysis Methods
A comprehensive search strategy was used to identify systematic reviews and RCTs that examined the effectiveness, safety and cost effectiveness of exercise and cognitive interventions for the primary and secondary prevention of dementia.
Questions
Section 3.1: What is the effectiveness of physical exercise for the improvement or maintenance of ADLs in seniors with mild to moderate dementia?
Section 3.2: What is the effectiveness of nonpharmacologic/nonexercise interventions to improve cognitive functioning in seniors with mild to moderate dementia?
Section 3.3: Can exercise decrease the risk of subsequent cognitive decline/dementia?
Section 3.4: Does cognitive training decrease the risk of cognitive impairment, prevent or delay deterioration in the performance of ADLs or IADLs, or reduce the incidence of dementia in seniors with good cognitive and physical functioning?
Assessment of Quality of Evidence
The quality of the evidence was assessed as High, Moderate, Low, or Very low according to the GRADE methodology. As per GRADE the following definitions apply:
Summary of Findings
Table 2 summarizes the conclusions from Sections 3.1 through 3.4.
Summary of Conclusions on Patient-Directed Interventions*
Previous systematic review indicated that “cognitive training” is not effective in patients with dementia.
A recent RCT suggests that CST (up to 7 weeks) is effective for improving cognitive function and quality of life in patients with dementia.
Regular leisure time physical activity in midlife is associated with a reduced risk of dementia in later life (mean follow-up 21 years).
Regular physical activity in seniors is associated with a reduced risk of cognitive decline (mean follow-up 2 years).
Regular physical activity in seniors is associated with a reduced risk of dementia (mean follow-up 6–7 years).
Evidence that cognitive training for specific functions (memory, reasoning, and speed of processing) produces improvements in these specific domains.
Limited inconclusive evidence that cognitive training can offset deterioration in the performance of self-reported IADL scores and performance assessments.
1° indicates primary; 2°, secondary; CST, cognitive stimulation therapy; IADL, instrumental activities of daily living; RCT, randomized controlled trial.
Benefit/Risk Analysis
As per the GRADE Working Group, the overall recommendations consider 4 main factors:
the trade-offs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome;
the quality of the evidence;
translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise; and
uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 reflects the overall trade-off between benefits and harms (adverse events) and incorporates any risk/uncertainty (cost-effectiveness).
Overall Summary Statement of the Benefit and Risk for Patient-Directed Interventions*
Economic Analysis
Budget Impact Analysis of Effective Interventions for Dementia
Caregiver-directed behavioural techniques and patient-directed exercise programs were found to be effective when assessing mild to moderate dementia outcomes in seniors living in the community. Therefore, an annual budget impact was calculated based on eligible seniors in the community with mild and moderate dementia and their respective caregivers who were willing to participate in interventional home sessions. Table 4 describes the annual budget impact for these interventions.
Annual Budget Impact (2008 Canadian Dollars)
Assumed 7% prevalence of dementia aged 65+ in Ontario.
Assumed 8 weekly sessions plus 4 monthly phone calls.
Assumed 12 weekly sessions plus biweekly sessions thereafter (total of 20).
Assumed 2 sessions per week for first 5 weeks. Assumed 90% of seniors in the community with dementia have mild to moderate disease. Assumed 4.5% of seniors 65+ are in long-term care, and the remainder are in the community. Assumed a rate of participation of 60% for both patients and caregivers and of 41% for patient-directed exercise. Assumed 100% compliance since intervention administered at the home. Cost for trained staff from Ministry of Health and Long-Term Care data source. Assumed cost of personal support worker to be equivalent to in-home support. Cost for recreation therapist from Alberta government Website.
Note: This budget impact analysis was calculated for the first year after introducing the interventions from the Ministry of Health and Long-Term Care perspective using prevalence data only. Prevalence estimates are for seniors in the community with mild to moderate dementia and their respective caregivers who are willing to participate in an interventional session administered at the home setting. Incidence and mortality rates were not factored in. Current expenditures in the province are unknown and therefore were not included in the analysis. Numbers may change based on population trends, rate of intervention uptake, trends in current programs in place in the province, and assumptions on costs. The number of patients was based on patients likely to access these interventions in Ontario based on assumptions stated below from the literature. An expert panel confirmed resource consumption.
PMCID: PMC3377513  PMID: 23074509
15.  Guidelines, Editors, Pharma And The Biological Paradigm Shift 
Mens Sana Monographs  2007;5(1):27-30.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.
There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.
Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.
A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.
Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.
Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials
The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.
Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.
There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left.
Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.
An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.
We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.
The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.
Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.
Why does pharma adopt questionable tactics? The reasons are essentially two:
What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.
Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.
The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.
What is necessary for industry captains and long-term players is to realise:
Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.
In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.
doi:10.4103/0973-1229.32176
PMCID: PMC3192391  PMID: 22058616
Academia; Pharmaceutical Industry; Clinical Practice Guidelines; Best Practice Guidelines; Academic Medical Centers; Medical Associations; Research Journals; Clinical Research; Public Welfare; Pharma Image; Corporate Welfare; Biological Psychiatry; Law Suits Against Industry
16.  Therapy of unspecific tinnitus without organic cause 
Introduction
There is a variety of medical and non-medical therapies in practice, which were not evaluated regarding its effectiveness by any systematic evidence oriented investigation.
A number of therapies of medical and non-medical type try to treat the different types of tinnitus. The evidence in the scientific literature also had to be cleared in the field of diagnosis and classification as well as medical/psychiatric/psychological procedures of existing medical therapy.
Question
The HTA report had to investigate the following questions:
Which evidence do diagnostic methods in recognition of tinnitus have? Which types of therapy show medical effectiveness at the acute or chronic tinnitus without an organic cause? Which consequences (need for further research, future procedures) can be drawn?
Methodology
In the following databases "tinnitus" was searched according to the search string:
HTA97; INAHTA; CDAR94; CDSR93; CCTR93; ME66; ME0A; HT83; SM78; CA66; CB85; BA70; BA93; EM74; IS74; ET80; EB94; IA70; AZ72; CV72; GE79; EU93; HN69; ED93; EA08
Result: 1932 studies, unsorted after assessment in accordance with EBM criterions, selection: 409 studies.
Due to the completely heterogeneous representation modes of the therapeutic approaches at the treatment of the chronic tinnitus no quantitative synthesis method could be performed. Therefore the methodology of a qualitative overview has been carried out.
Results
The diagnostic confirmation of the non-specific tinnitus without organic cause meets with the problem of the assurance of the diagnosis tinnitus. According to the current opinion the stepwise diagnostics is carried out also in the case of the so called subjective tinnitus. Nothing can be said about the evidence of these procedures since no publication was found about that. A study concerning the evidence of the diagnostic questionnaires from Goebel and Hiller [1] comes to the end that the tinnitus questionnaire frequently used (TF) [2] is the best evaluated procedure.
The number of therapies which treat tinnitus is exceptionally high and makes clear, that the search for "the" tinnitus therapy is still going on. According to the current knowledge tinnitus genesis is multifactorial and therefore there can’t be any standard therapy for tinnitus. The following seven categories can be distinguished:
Ad 1: Machine-aided acoustic therapies
From many studies regarding machine-aided acoustic therapy of tinnitus only two showed an evidence degree that allows scientifically correct statements about the effectiveness of these procedures. Selectively significant improvements could be shown in the comparison with a placebo (apparatus switched off) a superiority of tinnitus-maskers.
Ad 2: Electrostimulation
In an application study of electro-stimulation the results were not evaluated statistically, but it was described descriptively that a successful medical treatment can be expected in about 50% of the cases.
Ad 3: Psychological therapy procedures
Hypnosis did not show positive effectiveness. With regard to biofeedback it can be concluded that this method can be effective in individual cases, however regarded as unreliable from missing reproducibility. Neurobiofeedback could prove that it had a positive therapeutic effect.
From eight controlled studies to relaxation techniques and cognitive behaviour therapy four studies showed a therapeutic effectiveness and four failed. Combined therapies proved generally to be more effective than individual types.
The behaviour medical psychotherapy could show a positive therapy effect. In a study with cognitive therapy and relaxation (three groups, a passive relaxation, an active relaxation and a cognitive therapy) short-term successes could be stated (for one month), however, the parameters of success returned on the initial value after four months.
Also only coincidental and short-term successes could be achieved with cognitive behaviour therapy training, autogenic training and structured group psychotherapy.
Ad 4: Tinnitus Retraining Therapy (TRT)
Unfortunately, the published results of the TRT are methodically frequently bad and scientific of a poor value. Many of the studies presented until now regarding tinnitus retraining therapy are not informative in their scientific context.
In a study with 95 patients with a chronic tinnitus TRT could show a significant, more than six months lasting stable success by comparison to a combination of TET with group behaviour therapy (improvement be achieved around at least ten points in the tinnitus questionnaire (TF)).
Ad 5: Pharmacological therapies
Rheological drugs (medicines for hemodilution) could not show any statistically significant effect in the treatment of tinnitus.
Studies to the medical treatment with tocainides (lidocaine) showed repeatable positive effects on tinnitus in higher dosages (as of 1.2 mg/day). Lamotrigine as a medicine had an effect positively only at with a small fraction of patients. Two studies with GABA receptor agonists could not prove therapeutic effects for tinnitus. Undesired side-effects were observed. Injections with Carvoverine (a glutamate antagonist) achieved significantly successes with a special form of tinnitus, the “Cochlear-synaptic tinnitus (CST)".
A tricyclic antidepressant (Amitriptilin) could prove superiority against placebo. This effect could be confirmed in another study. However Clonazepame (a benzodiazepine), could not achieve any improvement. Short-term improvements were achieved with other benzodiazepines (Clonazepame, Diazepam, Flurazepame, Oxacepame and Alprazolame).
A German retrospective study suggests a graded pharmacological therapy by means of rheological infusion therapy, applications of neurotransmitters, and injections of lidocaine. This method achieved a disappearance or a recovery of the complaints at 95.3% of the acute and 26.7% of the chronic cases.
Ad 6: Surgical procedures
The effects of the operative excision of the stapes (stapedectomy) showed significant effects concerning tinnitus. This method is a routine operation to recover hearing, effects on tinnitus were observed only coincidently.
There are generally high frequencies of improvements of tinnitus after cochlea implantations; however the risk of deterioration is present with this method.
Ad 7: Other and alternative therapy procedures
The hyperbaric oxygen therapy can be considered successful after acute events with tinnitus. The therapy should be started in the first month after appearance of the tinnitus.
The methods transcranial-, electromagnetic and transcutaneous nerve stimulations did not show any significant effects on tinnitus. Also low laser medical treatment showed disappointing effects.
The “pneumatic external contra-pulsation” is described as an unproblematic usable procedure by the authors of the examination, but 10% of the patients had to stop the medical treatment because of complications associated with the medical treatment.
Acupuncture showed significant improvements in comparison to medical treatment. The effectiveness of this therapy could not be reproduced in another study. Five other studies between 1993 and 1999 also did not show any therapeutic effect of this method. Gingko-Biloba preparations did not show any positive effects in large-scale studies on tinnitus.
Discussion
Neither the diagnostic procedures nor the therapeutic methods or the individual therapies reach a usual scientific level in medicine. Unsolved problems concerning insurance, economic as well as legal problems have resulted for the patients and for caring stuff from this unsatisfactory situation.
Numerous competitive tinnitus emergence models led to an incredible creativity in trying out different therapy approaches. No convergence of the therapy procedures can be seen within the last decades of tinnitus research, contrariwise there is always more and more “creativity” of new approaches.
Priority has to be given to find the cause of tinnitus since therapies are a consequence of a better understanding of these symptoms that evidence oriented investigations on an usual scientific level can be started.
Conclusion
The innumerable therapeutic approaches, seeming completely incoherent to their effects should be coordinated on the meaningfulness, on the success parameters and with patient safety in light of the most plausible explanation models for non-specific chronic Tinnitus. To this the facilities of competence centres or related science- directing facilities are recommendable.
Examinations which are carried out also with small numbers show often methodical insufficiencies. It is necessary that minimal requirements on a scientifically clinical experiment, such as design, case number calculation, analytic statistics, control group, are fulfilled.
It is recommendable, that further research has to be promoted regarding tinnitus causes that a coordinated evidence-orientated treatment will be developed.
PMCID: PMC3011356  PMID: 21289968
17.  High Neuroticism and Low Conscientiousness Are Associated with Interleukin-6 
Psychological medicine  2009;40(9):1485-1493.
Background
High Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty.
Methods
A population-based sample (N=4,923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6: age, sex, smoking, weight, aspirin use, and disease burden.
Results
High Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of Conscientiousness had an approximately 40% greater risk of exceeding clinically-relevant thresholds of IL-6.
Conclusions
Consistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health.
doi:10.1017/S0033291709992029
PMCID: PMC2933046  PMID: 19995479
Personality; Interleukin-6; Inflammation; Health; Impulsivity; C-reactive protein
18.  Five teacher profiles in student-centred curricula based on their conceptions of learning and teaching 
BMC Medical Education  2014;14(1):220.
Background
Teachers’ conceptions of learning and teaching are partly unconscious. However, they are critical for the delivery of education and affect students’ learning outcomes. Lasting changes in teaching behaviour can only be realized if conceptions of teachers have been changed accordingly. Previously we constructed a questionnaire named COLT to measure conceptions. In the present study, we investigated if different teacher profiles could be assessed which are based on the teachers’ conceptions. These teacher profiles might have implications for individual teachers, for faculty development activities and for institutes. Our research questions were: (1) Can we identify teacher profiles based on the COLT? (2) If so, how are these teacher profiles associated with other teacher characteristics?
Methods
The COLT questionnaire was sent electronically to all teachers in the first three years of the undergraduate curriculum of Medicine in two medical schools in the Netherlands with student-centred education. The COLT (18 items, 5 point Likert scales) comprises three scales: ‘teacher centredness’, ‘appreciation of active learning’ and ‘orientation to professional practice’. We also collected personal information about the participants and their occupational characteristics. Teacher profiles were studied using a K-means cluster analysis and calculating Chi squares.
Results
The response rate was 49.4% (N = 319/646). A five-cluster solution fitted the data best, resulting in five teacher profiles based on their conceptions as measured by the COLT. We named the teacher profiles: Transmitters (most traditional), Organizers, Intermediates, Facilitators and Conceptual Change Agents (most modern). The teacher profiles differed from each other in personal and occupational characteristics.
Conclusions
Based on teachers’ conceptions of learning and teaching, five teacher profiles were found in student-centred education. We offered suggestions how insight into these teacher profiles might be useful for individual teachers, for faculty development activities and for institutes and departments, especially if involved in a curriculum reform towards student-centred education.
doi:10.1186/1472-6920-14-220
PMCID: PMC4287471  PMID: 25324193
Conceptions of learning and teaching; Teachers; Reflection; Faculty development
19.  The Role of Adherence in the Relationship between Conscientiousness and Perceived Health 
Objective
Conscientious individuals experience better physical health, in part because of their greater propensity to behave in ways that maintain wellness. The current study examined whether and how adherence mediates the relation between conscientiousness and physical health. Moreover, it was examined whether these effects differed for adhering to doctor’s orders (doctor adherence) versus adhering to medication regimens (medication adherence), as the latter is likely more relevant for older adults’ health.
Methods
A nationwide sample of adults (N = 2136, Mage = 51 years) completed personality and adherence measures, in addition to a self-report measure of perceived general health, in an online survey. Correlational analyses were performed to examine the basic relations between the constructs of interest. A bootstrapping approach was employed for examining whether the indirect effect through adherence was conditional on age.
Results
Doctor adherence partially mediated the relation between conscientiousness and perceived health across adulthood. However, the indirect effect of medication adherence was conditional on age, insofar that medication adherence mediated the link between conscientiousness and perceived health only for older adults in the sample (i.e., those around age 51 and over).
Conclusion
These results suggest that while conscientious individuals report higher levels of both doctor and medication adherence, the role of adherence in explaining the link between conscientiousness and health may differ across adulthood.
doi:10.1037/a0023860
PMCID: PMC3196269  PMID: 21604876
conscientiousness; adherence; health behaviors; conditional indirect effects models
20.  Medical Students' Exposure to and Attitudes about the Pharmaceutical Industry: A Systematic Review 
PLoS Medicine  2011;8(5):e1001037.
A systematic review of published studies reveals that undergraduate medical students may experience substantial exposure to pharmaceutical marketing, and that this contact may be associated with positive attitudes about marketing.
Background
The relationship between health professionals and the pharmaceutical industry has become a source of controversy. Physicians' attitudes towards the industry can form early in their careers, but little is known about this key stage of development.
Methods and Findings
We performed a systematic review reported according to PRISMA guidelines to determine the frequency and nature of medical students' exposure to the drug industry, as well as students' attitudes concerning pharmaceutical policy issues. We searched MEDLINE, EMBASE, Web of Science, and ERIC from the earliest available dates through May 2010, as well as bibliographies of selected studies. We sought original studies that reported quantitative or qualitative data about medical students' exposure to pharmaceutical marketing, their attitudes about marketing practices, relationships with industry, and related pharmaceutical policy issues. Studies were separated, where possible, into those that addressed preclinical versus clinical training, and were quality rated using a standard methodology. Thirty-two studies met inclusion criteria. We found that 40%–100% of medical students reported interacting with the pharmaceutical industry. A substantial proportion of students (13%–69%) were reported as believing that gifts from industry influence prescribing. Eight studies reported a correlation between frequency of contact and favorable attitudes toward industry interactions. Students were more approving of gifts to physicians or medical students than to government officials. Certain attitudes appeared to change during medical school, though a time trend was not performed; for example, clinical students (53%–71%) were more likely than preclinical students (29%–62%) to report that promotional information helps educate about new drugs.
Conclusions
Undergraduate medical education provides substantial contact with pharmaceutical marketing, and the extent of such contact is associated with positive attitudes about marketing and skepticism about negative implications of these interactions. These results support future research into the association between exposure and attitudes, as well as any modifiable factors that contribute to attitudinal changes during medical education.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The complex relationship between health professionals and the pharmaceutical industry has long been a subject of discussion among physicians and policymakers. There is a growing body of evidence that suggests that physicians' interactions with pharmaceutical sales representatives may influence clinical decision making in a way that is not always in the best interests of individual patients, for example, encouraging the use of expensive treatments that have no therapeutic advantage over less costly alternatives. The pharmaceutical industry often uses physician education as a marketing tool, as in the case of Continuing Medical Education courses that are designed to drive prescribing practices.
One reason that physicians may be particularly susceptible to pharmaceutical industry marketing messages is that doctors' attitudes towards the pharmaceutical industry may form early in their careers. The socialization effect of professional schooling is strong, and plays a lasting role in shaping views and behaviors.
Why Was This Study Done?
Recently, particularly in the US, some medical schools have limited students' and faculties' contact with industry, but some have argued that these restrictions are detrimental to students' education. Given the controversy over the pharmaceutical industry's role in undergraduate medical training, consolidating current knowledge in this area may be useful for setting priorities for changes to educational practices. In this study, the researchers systematically examined studies of pharmaceutical industry interactions with medical students and whether such interactions influenced students' views on related topics.
What Did the Researchers Do and Find?
The researchers did a comprehensive literature search using appropriate search terms for all relevant quantitative and qualitative studies published before June 2010. Using strict inclusion criteria, the researchers then selected 48 articles (from 1,603 abstracts) for full review and identified 32 eligible for analysis—giving a total of approximately 9,850 medical students studying at 76 medical schools or hospitals.
Most students had some form of interaction with the pharmaceutical industry but contact increased in the clinical years, with up to 90% of all clinical students receiving some form of educational material. The highest level of exposure occurred in the US. In most studies, the majority of students in their clinical training years found it ethically permissible for medical students to accept gifts from drug manufacturers, while a smaller percentage of preclinical students reported such attitudes. Students justified their entitlement to gifts by citing financial hardship or by asserting that most other students accepted gifts. In addition, although most students believed that education from industry sources is biased, students variably reported that information obtained from industry sources was useful and a valuable part of their education.
Almost two-thirds of students reported that they were immune to bias induced by promotion, gifts, or interactions with sales representatives but also reported that fellow medical students or doctors are influenced by such encounters. Eight studies reported a relationship between exposure to the pharmaceutical industry and positive attitudes about industry interactions and marketing strategies (although not all included supportive statistical data). Finally, student opinions were split on whether physician–industry interactions should be regulated by medical schools or the government.
What Do These Findings Mean?
This analysis shows that students are frequently exposed to pharmaceutical marketing, even in the preclinical years, and that the extent of students' contact with industry is generally associated with positive attitudes about marketing and skepticism towards any negative implications of interactions with industry. Therefore, strategies to educate students about interactions with the pharmaceutical industry should directly address widely held misconceptions about the effects of marketing and other biases that can emerge from industry interactions. But education alone may be insufficient. Institutional policies, such as rules regulating industry interactions, can play an important role in shaping students' attitudes, and interventions that decrease students' contact with industry and eliminate gifts may have a positive effect on building the skills that evidence-based medical practice requires. These changes can help cultivate strong professional values and instill in students a respect for scientific principles and critical evidence review that will later inform clinical decision-making and prescribing practices.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001037.
Further information about the influence of the pharmaceutical industry on doctors and medical students can be found at the American Medical Students Association PharmFree campaign and PharmFree Scorecard, Medsin-UKs PharmAware campaign, the nonprofit organization Healthy Skepticism, and the Web site of No Free Lunch.
doi:10.1371/journal.pmed.1001037
PMCID: PMC3101205  PMID: 21629685
21.  Personality and Physician-Assessed Illness Burden in Older Primary Care Patients Over Four Years 
Background
Personality traits have been associated with physician-rated illness burden cross-sectionally, but longitudinal associations between personality and objective medical morbidity remain unclear.
Purpose
To examine associations between personality and physician-rated illness burden 4 years prospectively in older primary care patients.
Method
At baseline, patients (average age = 75, SD = 6.6, 62% female) completed the NEO-Five Factor Inventory. At baseline and 4 yearly follow-ups, a physician completed the Cumulative Illness Rating Scale based on medical records.
Results
Linear mixed effects models revealed that higher neuroticism and lower conscientiousness predicted worse average illness burden longitudinally. Relatively disagreeable persons (25th percentile) accumulated morbidity at a 33% faster rate than agreeable (75th percentile) peers. At the final follow-up, a person at the 75th percentile of neuroticism and the 25th percentile of conscientiousness and agreeableness showed morbidity comparable to a peer of average personality but 10 years older. An individual at the 25th percentile of neuroticism and 75th percentile of conscientiousness and agreeableness showed end-point illness burden comparable to a peer of average personality but 10 years younger. 21% of the morbidity associated with neuroticism was explained by total cholesterol. History of hypertension, smoking, alcohol/drug abuse, and affective symptoms of depression each explained 10% or less of the other observed personality effects.
Conclusion
Personality plays a non-trivial role in healthy aging among older persons. Brief personality assessment may identify at-risk older persons for closer monitoring, enhance the accuracy of medical prognosis, and provide clues for clinical interventions to promote better health.
doi:10.1016/j.jagp.2012.11.013
PMCID: PMC3674148  PMID: 23567416
Personality Traits; Medical Illness; Older persons; Primary Care; Cohort Study
22.  Unhappiness and dissatisfaction in doctors cannot be predicted by selectors from medical school application forms: A prospective, longitudinal study 
Background
Personal statements and referees' reports are widely used on medical school application forms, particularly in the UK, to assess the suitability of candidates for a career in medicine. However there are few studies which assess the validity of such information for predicting unhappiness or dissatisfaction with a career in medicine. Here we combine data from a long-term prospective study of medical student selection and training, with an experimental approach in which a large number of assessors used a paired comparison technique to predict outcome.
Methods
Data from a large-scale prospective study of students applying to UK medical schools in 1990 were used to identify 40 pairs of doctors, matched by sex, for whom personal statements and referees' reports were available, and who in a 2002/3 follow-up study, one pair member was very satisfied and the other very dissatisfied with medicine as a career. In 2005, 96 assessors, who were experienced medical school selectors, doctors, medical students or psychology students, used information from the doctors' original applications to judge which member of each pair of doctors was the happier, more satisfied doctor.
Results
None of the groups of assessors were significantly different from chance expectations in using applicants' personal statements and the referees' reports to predict actual future satisfaction or dissatisfaction, the distribution being similar to binomial expectations. However judgements of pairs of application forms from pairs of doctors showed a non-binomial distribution, indicating consensus among assessors as to which doctor would be the happy doctor (although the consensus was wrong in half the cases). Assessors taking longer to do the task concurred more. Consensus judgements seem mainly to be based on referees' predictions of academic achievement (even though academic achievement is not actually a valid predictor of happiness or satisfaction).
Conclusion
Although widely used in medical student selection to assess motivation, interest and commitment to a medical career, the personal statement and the referee's report cannot validly be used by assessors, including experienced medical school selectors, to identify doctors who will subsequently be dissatisfied with a medical career.
doi:10.1186/1472-6920-5-38
PMCID: PMC1325230  PMID: 16351718
23.  Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing 
PLoS Medicine  2014;11(4):e1001628.
Gary Peltz, Jeffrey Glenn, and colleagues report that a pre-clinical mouse toxicology model can detect liver toxicity of a drug that caused liver failure in several early clinical trial participants in 1993.
Please see later in the article for the Editors' Summary
Background
Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.
Methods and Findings
Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.
Conclusions
FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before new drugs are approved for clinical use, they undergo extensive preclinical (laboratory-based) and clinical testing. In the preclinical studies, scientists investigate the causes of diseases, identify potential new drugs, and test promising drug candidates in animals. Animal testing is performed to determine whether the new drug is likely to work, and to screen for drug-induced toxicity. In preclinical toxicology studies, new drugs are given to two or more animal species to find out whether the drug has any short- or long-term toxic effects such as damage to the liver (hepatotoxicity). Drugs that pass these animal tests enter clinical trials. Phase I clinical trials test new drugs in a handful of healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives the new drug to evaluate its safety further and to get an initial idea of its effectiveness. Finally, in phase III trials, very large groups of patients are randomly assigned to receive the new drug or an established treatment for their disease. These randomized controlled trials provide detailed information about the effectiveness and safety of a candidate drug, and must be completed before a drug can be approved for clinical use.
Why Was This Study Done?
Since animals are not perfect models for people, candidate drugs can cause toxicities in clinical trials that were not predicted by preclinical toxicology testing performed using animal species. For example, in 1993, 15 participants in a phase II trial were given a nucleoside analogue called fialuridine to treat hepatitis B virus infection (nucleoside analogues often have antiviral activity). Seven participants developed liver failure and lactic acidosis (buildup of lactic acid in the blood). Analysis of liver tissue from the affected participants revealed steatosis (fatty degeneration), intracellular fat droplets, and swollen mitochondria (these organelles are the powerhouses of the cell). Five participants subsequently died, and two had to have a liver transplant. In preclinical toxicology testing in mice, rats, dogs, and primates, there had been no indications that fialuridine would be hepatotoxic in people. It now seems that the expression of a nucleoside transporter in the mitochondria of humans but not of other animals may underlie the human-specific mitochondrial toxicity and hepatotoxicity of fialuridine. With several other nucleoside analogues in development, a better screening tool for human-specific mitochondrial toxicity is needed. In this study, the researchers investigate whether fialuridine toxicity can be detected in TK-NOG mice with chimeric (humanized) livers. TK-NOG mice are immunodeficient mice that have been genetically engineered so that human liver cells (hepatocytes) transplanted into these animals establish a long-lived mature “human organ.”
What Did the Researchers Do and Find?
The researchers treated chimeric (with transplanted human liver cells) and control (without transplanted human liver cells) TK-NOG mice with several doses of fialuridine. After treatment with the highest dose (1,600-fold above the dose used in the phase II trial) for four days, the chimeric mice developed liver failure and lactic acidosis. Moreover, steatosis and lipid and mitochondrial abnormalities developed in the regions of their livers that contained human hepatocytes but not in regions that contained mouse hepatocytes. Notably, the control mice had not developed liver toxicity after 14 days of treatment with the highest dose of drug. Liver toxicity was also easily detectable in chimeric mice that had been treated for 14 days with a fialuridine dose only 10-fold above that used in the human trial. Treatment with another nucleoside analogue that does not cause liver toxicity in people did not cause liver toxicity in the chimeric mice.
What Do These Findings Mean?
These findings show that fialuridine-induced liver toxicity can be readily detected using TK-NOG mice that have humanized livers at drug doses only 10-fold higher than those that caused liver failure in the phase II trial. Although the liver toxicity developed much more quickly in these mice than in the human trial participants, the clinical features, laboratory abnormalities, and structural changes seen in the fialuridine-treated chimeric TK-NOG mice closely mirrored those seen in fialuridine-treated people. The use of TK-NOG mice containing humanized livers in toxicology testing will not reveal whether drugs have human-specific toxicities outside the liver. Since they are highly immunocompromised, chimeric TK-NOG mice cannot be used to detect immune-mediated drug toxicities. Nevertheless, these findings suggest that the use of chimeric mice in toxicology studies could help improve the safety of candidate drugs that are tested in humans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001628.
The US Food and Drug Administration, the body that approves drugs for clinical use in the US, provides an overview for patients about the drug development process from the laboratory to the clinic
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides more detailed information for patients and the public about the drug development process, including a section on preclinical research, which includes information on animal testing
The US National Institutes of Health provides information about clinical trials, including personal stories from people who have taken part in clinical trials
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participation in clinical trials
Understanding Animal Research is a UK advocacy group that provides information about the importance of animal research to the public, teachers, scientists, journalists, and policy makers
Wikipedia has a page on animal testing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001628
PMCID: PMC3988005  PMID: 24736310
24.  Big 5 Personality Traits and Interleukin-6: Evidence for “Healthy Neuroticism” in a U.S. Population Sample 
The current study investigated if the Big 5 personality traits predicted interleukin-6 (IL-6) levels in a national sample over the course of 5 years. In addition, interactions among the Big 5 were tested to provide a more accurate understanding of how personality traits may influence an inflammatory biomarker. Data included 1,054 participants in the Midlife Development in the U.S. (MIDUS) biomarkers subproject. The Big 5 personality traits were assessed in 2005-06 as part of the main MIDUS survey. Medication use, comorbid conditions, smoking behavior, alcohol use, body mass index, and serum levels of IL-6 were assessed in 2005-2009 as part of the biomarkers subproject. Linear regression analyses examined personality associations with IL-6. A significant Conscientiousness*Neuroticism interaction revealed that those high in both Conscientiousness and Neuroticism had lower circulating IL-6 levels than people with all other configurations of Conscientiousness and Neuroticism. Adjustment for health behaviors diminished the magnitude of this association but did not eliminate it, suggesting that lower comorbid conditions and obesity may partly explain the lower inflammation of those high in both Conscientiousness and Neuroticism. Our findings suggest, consistent with prior speculation, that average to higher levels of Neuroticism can in some cases be associated with health benefits—in this case when it is accompanied by high Conscientiousness. Using personality to identify those at risk may lead to greater personalization in the prevention and remediation of chronic inflammation.
doi:10.1016/j.bbi.2012.10.020
PMCID: PMC3545072  PMID: 23123863
Personality; interactions; inflammation; interleukin 6; IL-6; health behaviors
25.  Personality Traits Affect Teaching Performance of Attending Physicians: Results of a Multi-Center Observational Study 
PLoS ONE  2014;9(5):e98107.
Background
Worldwide, attending physicians train residents to become competent providers of patient care. To assess adequate training, attending physicians are increasingly evaluated on their teaching performance. Research suggests that personality traits affect teaching performance, consistent with studied effects of personality traits on job performance and academic performance in medicine. However, up till date, research in clinical teaching practice did not use quantitative methods and did not account for specialty differences. We empirically studied the relationship of attending physicians' personality traits with their teaching performance across surgical and non-surgical specialties.
Method
We conducted a survey across surgical and non-surgical specialties in eighteen medical centers in the Netherlands. Residents evaluated attending physicians' overall teaching performance, as well as the specific domains learning climate, professional attitude, communication, evaluation, and feedback, using the validated 21-item System for Evaluation of Teaching Qualities (SETQ). Attending physicians self-evaluated their personality traits on a 5-point scale using the validated 10-item Big Five Inventory (BFI), yielding the Five Factor model: extraversion, conscientiousness, neuroticism, agreeableness and openness.
Results
Overall, 622 (77%) attending physicians and 549 (68%) residents participated. Extraversion positively related to overall teaching performance (regression coefficient, B: 0.05, 95% CI: 0.01 to 0.10, P = 0.02). Openness was negatively associated with scores on feedback for surgical specialties only (B: −0.10, 95% CI: −0.15 to −0.05, P<0.001) and conscientiousness was positively related to evaluation of residents for non-surgical specialties only (B: 0.13, 95% CI: 0.03 to 0.22, p = 0.01).
Conclusions
Extraverted attending physicians were consistently evaluated as better supervisors. Surgical attending physicians who display high levels of openness were evaluated as less adequate feedback-givers. Non-surgical attending physicians who were conscientious seem to be good at evaluating residents. These insights could contribute to future work on development paths of attending physicians in medical education.
doi:10.1371/journal.pone.0098107
PMCID: PMC4028262  PMID: 24844725

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