Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use?

A randomized controlled trial of mindfulness-based cognitive therapy for bipolar disorder.

OBJECTIVE: To compare the efficacy of mindfulness-based cognitive therapy (MBCT) plus treatment as usual (TAU) to TAU alone for patients with bipolar disorder over a 12-month follow-up period. METHOD: Participants with a DSM-IV diagnosis of bipolar disorder were randomly allocated to either MBCT plus TAU or TAU alone. Primary outcome measures were time to recurrence of a DSM-IV major depressive, hypomanic or manic episode; the Montgomery-Åsberg Depression Rating Scale (MADRS); and Young Mania Rating Scale (YMRS). Secondary outcome measures were number of recurrences, the Depression Anxiety Stress Scales (DASS), and the State Trait Anxiety Inventory (STAI). RESULTS: Ninety-five participants with bipolar disorder were recruited to the study (MBCT = 48; TAU = 47). Intention-to-treat (ITT) analysis found no significant differences between the groups on either time to first recurrence of a mood episode or total number of recurrences over the 12-month period. Furthermore, there were no significant between-group differences on the MADRS or YMRS scales. A significant between-group difference was found in STAI - state anxiety scores. There was a significant treatment by time interaction for the DAS - achievement subscale. CONCLUSION: While MBCT did not lead to significant reductions in time to depressive or hypo/manic relapse, total number of episodes, or mood symptom severity at 12-month follow-up, there was some evidence for an effect on anxiety symptoms. This finding suggests a potential role of MBCT in reducing anxiety comorbid with bipolar disorder.

Timing of decompression and fixation after spinal cord injury--when is surgery optimal?

Spinal cord injury affects a large number of young individuals with a significant cost to affected persons, families and societies both in terms of economic and non-economic costs. To date, our interventions have been limited to prevention, good initial resuscitation, modest pharmacotherapy and nursing care. This review examines the role of surgery in spinal cord injury. The pathophysiology of spinal cord injury is reviewed. The compelling animal data for early decompression is discussed as well as evidence for improved neurological outcome with early decompression in humans. Finally, the impact of early surgery on non-neurological outcome and overall complication rates is examined with the concept of "damage control" discussed with relevance to spinal cord injury. It appears that favourable outcomes are achieved with early surgery, with reduced morbidity/mortality, but definitive data is still pending.

Artificial cervical disc replacement: principles, types and techniques.

Cervical arthroplasty after anterior decompression with insertion of a prosthetic total disc replacement has been suggested as an alternate to anterior cervical fusion. Currently there are four cervical arthroplasty devices available on the market whose results in clinical use have been reported. Each device varies in terms of materials, range of motion, insertion technique and constraint. It is not known which device is ideal. Early studies suggest that in the short term, the complication rate and efficacy is no worse than fusion surgery. Long-term results have not yet been reported. This review examines the current prostheses available on the market as well as discussing issues regarding indications and technique. Pitfalls are discussed and early experiences reviewed. In time, it is hoped that a refinement of cervical arthroplasty occurs in terms of both materials and design as well as in terms of indications and clinical outcomes as spinal surgeons enter a new era of the management of cervical spine disease.

RNA association defines a functionally conserved domain in the nuclear pore protein Nup153.

Traffic between the nucleus and cytoplasm takes place through a macromolecular structure termed the nuclear pore complex. To understand how the vital process of nucleocytoplasmic transport occurs, the contribution of individual pore proteins must be elucidated. One such protein, the nucleoporin Nup153, is localized to the nuclear basket of the pore complex and has been shown to be a central component of the nuclear transport machinery. Perturbation of Nup153 function was demonstrated previously to block the export of several classes of RNA cargo. Moreover, these studies also showed that Nup153 can stably associate with RNA in vitro. In this study, we have mapped a domain within Nup153, encompassing amino acids 250-400 in human Nup153, that is responsible for RNA association. After cloning this region of Xenopus Nup153, we performed a cross-species analysis. Despite variation in sequence conservation between Drosophila, Xenopus, and human, this domain of Nup153 displayed robust RNA binding activity in each case, indicating that this property is a hallmark feature of Nup153 and pointing toward a subset of amino acid residues that are key to conferring this ability. We have further determined that a recombinant fragment of Nup153 can bind directly to RNA and that this fragment can interact with endogenous RNA targets. Our findings identify a functionally conserved domain in Nup153 and suggest a role for RNA binding in Nup153 function at the nuclear pore.

The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer.

To identify potential prognostic indicators of ovarian cancer and identify targets for therapeutic strategies, mRNA differential display was used to analyze gene expression differences in normal, benign, and cancerous ovarian tissue. One cDNA isolated by this technique, Op18/stathmin, is a highly conserved gene that is reported to have many different functions within a cell, including signal transduction, control of the cell cycle, and the regulation of microtubules. Quantitative Northern blot analysis of 12 malignant ovarian samples, 8 benign ovarian tumors, and 10 normal ovarian tissue samples demonstrated overexpression of Op18/stathmin mRNA in the malignant cancers. Immunohistochemistry showed an apparent overexpression of Op18/stathmin protein level and an association with proliferating cells.

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival.

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.

An organization-wide approach for an effective communication system, Part 2.

This is the second article in a two-part series that describes an organization's approach to designing, implementing, and evaluating a communication system. Part 1 of this series, published in the March 1998 issue, focused on the design and implementation of this system. This article addresses the evaluation of outcomes related to identified goals to improve communication flow and decision making on multiple levels and to promote accountability for clinical and operational performance. Implementation strategies involving change management, emergence of issues with related implications, and planned evolution of this system also are discussed for ongoing organizational performance improvement.

An organization-wide approach for an effective communication system, Part 1.

This two-part series provides a cogent discussion of designing and implementing an effective communication system, with a committee structure based on the Joint Commission on Accreditation of Health Care Organizations (JCAHO) functions. Part one includes the development and design using a systems approach. Part two, which will be published in the April 1998 issue of JONA, will address the evaluation of outcomes and implications of this communication system. The experiential learning gained from this process is illustrated by the analysis of themes that surfaced during the implementation.

Authoritarianism among medicine and law students.

This study assessed the effects of gender, faculty, and year (level) on "authoritarianism" among university students within the faculties of law and medicine. A questionnaire, using the Ray Adapted F Scale to measure authoritarianism, was administered to 454 students at the University of Western Australia. The first, third and sixth year medical students were compared with first, third and final year law students. Gender alone was responsible for a significant source of variance, with males more authoritarian than females. Faculty alone showed a strong trend towards significance with medicine more authoritarian than law. Although no other 2- or 3- way interactions were significant a trend was apparent in which females became more and males less authoritarian with increasing level.

Substance abuse among medical practitioners.

This paper reviews the literature relating to the prevalence, causes and treatment of substance abuse and psychiatric illness among doctors. Possible aetiological and pathogenic factors influencing drug-dependent doctors are discussed and some problems which arise in the management of these doctors are raised. Local studies in relation to certain personality factors in medical students, to cause of death in a medical cohort, and preliminary impressions from a study of substance-abusing doctors are reported.

Suicide and related deaths in Victorian doctors.

A cohort of University of Melbourne medical graduates (1950-1959 graduates inclusive) was followed up until December 31, 1986. Vital status at the end of the study period was ascertained and, for those who had died, cause of death was determined. The cohort consisted of 1453 members (1279 men and 174 women). One hundred and twenty-six of the group had died (115 men and 11 women) and 68 (4.7%; 57 men and 11 women) were lost to follow-up. The major causes of death were cardiovascular disease and malignant neoplasms. The standardised mortality ratios (SMRs) for all-cause mortality were low (59 for the male doctors and 84 for the female doctors) indicating that male doctors experience a "force of mortality" 59% that of the general population and female doctors 84%. For the male doctors, the SMR for suicide was 113 (95% confidence interval [CI], 54-207) (10 of 115 deaths in male doctors) about double the SMR for mortality from all causes. For the female doctors, the SMR for suicide was 501 (95% CI, 103-1500) (3 of 11 deaths in female doctors). For deaths resulting from all accidents the SMR was low for the males (29) and higher for the females (126). The SMR for mental disorders for the male doctors was marginally raised (132). This study reveals some indication of a problem in doctors in regard to deaths by suicide, other violent deaths and mental disorders. A larger study involving a control group of equivalent social class is required to confirm the findings of this study.

Integrating practice guidelines with financial incentives.

Practice guidelines, in whatever form, hold significant implications for the delivery and the financing of health care. Hence, great care must be taken in developing them. They must be scientifically sound and thus defensible. They must incorporate clinical perspectives and consider patients' preferences. They must cover appropriate as well as inappropriate services. They must foster creation and adoption of a rational payment system. What guidelines, in their best form, can do is enable physicians, faced with an overwhelming array of often conflicting information, to reduce some of the uncertainty they must cope with and to practice the most clinically effective medicine. For physicians to do so requires valid information from a credible source, most often in conjunction with appropriate financial incentives.

Practice guidelines and their role in quality assurance and cost effectiveness.

In a political and economic context, a basic goal of health care is: appropriate outcomes from appropriate services for appropriate costs in the context of a societal agreement on resources available. One way that the issue of appropriate medical services may be approached is through guidelines established by professional societies. The work of the American College of Physicians (ACP) in its Clinical Efficacy Assessment Project (CEAP) and its development of guidelines is described. In order that guidelines be effective and that practice behavior be modified to conform more to data on effectiveness and less to habit, four components are necessary: valid information from a credible source backed by an incentive within a receptive environment. Each of these components is described.