Continuous safety screens for randomized controlled clinical trials with blinded treatment information

Standard methods for testing safety data are needed to ensure the safe conduct of clinical trials. In particular, objective rules for reliably identifying unsafe treatments need to be put into place to help protect patients from unnecessary harm. DMCs are uniquely qualified to evaluate accumulating unblinded data and make recommendations about the continuing safe conduct of a trial. However, it is the trial leadership who must make the tough ethical decision about stopping a trial, and they could benefit from objective statistical rules that help them judge the strength of evidence contained in the blinded data. We design early stopping rules for harm that act as continuous safety screens for randomized controlled clinical trials with blinded treatment information, which could be used by anyone, including trial investigators (and trial leadership). A Bayesian framework, with emphasis on the likelihood function, is used to allow for continuous monitoring without adjusting for multiple comparisons. Close collaboration between the statistician and the clinical investigators will be needed in order to design safety screens with good operating characteristics. Though the math underlying this procedure may be computationally intensive, implementation of the statistical rules will be easy and the continuous screening provided will give suitably early warning when real problems were to emerge. Trial investigators and trial leadership need these safety screens to help them to effectively monitor the ongoing safe conduct of clinical trials with blinded data.^

A Pre-Clinical Assessment of Minocycline for Treatment of Chronic Neuropathic Pain after Spinal Cord Injury

Patients living with a spinal cord injury (SCI) often develop chronic neuropathic pain (CNP). Unfortunately, the clinically approved, current standard of treatment, gabapentin, only provides temporary pain relief. This treatment can cause numerous adverse side effects that negatively affect the daily lives of SCI patients. There is a great need for alternative, effective treatments for SCI-dependent CNP. Minocycline, an FDA-approved antibiotic, has been widely prescribed for the treatment of acne for several decades. However, recent studies demonstrate that minocycline has neuroprotective properties in several pre-clinical rodent models of CNS trauma and disease. Pre-clinical studies also show that short-term minocycline treatment can prevent the onset of CNP when delivered during the acute stage of SCI and can also transiently attenuate established CNP when delivered briefly during the chronic stage of SCI. However, the potential to abolish or attenuate CNP via long-term administration of minocycline after SCI is unknown. The purpose of this study was to investigate the potential efficacy and safety of long-term administration of minocycline to abolish or attenuate CNP following SCI. A severe spinal contusion injury was administered on adult, male, Sprague-Dawley rats. At day 29 post-injury, I initiated a three-week treatment regimen of daily administration with minocycline (50 mg/kg), gabapentin (50 mg/kg) or saline. The minocycline treatment group demonstrated a significant reduction in below-level mechanical allodynia and above- level hyperalgesia while on their treatment regimen. After a ten-day washout period of minocycline, the animals continued to demonstrate a significant reduction in below-level mechanical allodynia and above-level hyperalgesia. However, minocycline-treated animals exhibited abnormal weight gain and hepatotoxicity compared to gapabentin-treated or vehicle-treated subjects.The results support previous findings that minocycline can attenuate CNP after SCI and suggested that minocycline can also attenuate CNP via long-term delivery of minocycline after SCI (36). The data also suggested that minocycline had a lasting effect at reducing pain symptoms. However, the adverse side effects of long-term use of minocycline should not be ignored in the rodent model. Gabapentin treatment caused a significant decrease in below-level mechanical allodynia and below-level hyperalgesia during the treatment regimen. Because gabapentin treatment has an analgesic effect at the concentration I administered, the results were expected. However, I also found that gabapentin-treated animals demonstrated a sustained reduction in pain ten days after treatment withdrawal. This result was unexpected because gabapentin has a short half-life of 1.7 hours in rodents and previous studies have demonstrated that pre-drug pain levels return shortly after withdrawal of treatment. Additionally, the gabapentin-treated animals demonstrated a significant and sustained increase in rearing events compared with all other treatment groups which suggested that gabapentin treatment was not only capable of reducing pain long-term but may also significantly improve trunk stability or improve motor function recovery.

A comparison of adherence with minocycline treatment in Parkinson's disease and rheumatoid arthritis clinical trials

Background: Little is known about the effects on patient adherence when the same study drug is administered in the same dose in two populations with two different diseases in two different clinical trials. The Minocycline in Rheumatoid Arthritis (MIRA) trial and the NIH Exploratory Trials in Parkinson's disease (NET-PD) Futility Study I provide a unique opportunity to do the above and to compare methods measuring adherence. This study may increase understanding of the influence of disease and adverse events on patient adherence and will provide insights to investigators selecting adherence assessment methods in clinical trials of minocycline and other drugs in future.^ Methods: Minocycline adherence by pill count and the effect of adverse events was compared in the MIRA and NET-PD FS1 trials using multivariable linear regression. Within the MIRA trial, agreement between assay and pill count was compared. The association of adverse events with assay adherence was examined using multivariable logistic regression.^ Results: Adherence derived from pill count in the MIRA and NET-PD FS1 trials did not differ significantly. Adverse events potentially related to minocycline did not appear useful to predict minocycline adherence. In the MIRA trial, adherence measured by pill count appears higher than adherence measured by assay. Agreement between pill count and assay was poor (kappa statistic = 0.25).^ Limitations: Trial and disease are completely confounded and hence the independent effect of disease on adherence to minocycline treatment cannot be studied.^ Conclusion: Simple pill count may be preferred over assay in the minocycline clinical trials to measure adherence. Assays may be less sensitive in a clinical setting where appointments are not scheduled in relation to medication administration time, given assays depend on many pharmacokinetic and instrument-related factors. However, pill count can be manipulated by the patient. Another study suggested that self-report method is more sensitive than pill count method in differentiating adherence from non-adherence. An effect of medication-related adverse events on adherence could not be detected.^

Eccentric Exercise in Treatment of Patellar Tendinopathy in High Level Basketball Players. A Randomized Clinical Trial.

Chronic patellar tendinopathy is a common pathology in sporting population. To date, there is no agreed upon protocol as election treatment. Eccentric exercises have been used with satisfactory outcomes (3). The purpose of this trial was to compare the effects of two eccentric exercise protocols.

Eccentric exercise in treatment of patellar tendinopathy in high level basketball players. A randomized clinical trial

Chronic patellar tendinopathy is a common pathology in sporting population. To date, there is no agreed upon protocol as election treatment. Eccentric exercises have been used with satisfactory outcomes.

Trauma Treatment in Forensic Settings: Clinicians' Perspectives, Barriers to Effective Treatment, and Suggestions for Clinical Practice

Between 30% and 90% of the prison population is estimated to have survived traumatic experiences such as sexual, emotional, and physical abuse prior to incarceration (Anonymous, 1999; Fondacaro, Holt, & Powell, 1999; Messina & Grella, 2006; Pollard & Baker, 2000; Veysey, De Cou, & Prescott, 1998). Similarly, information from the Bureau of Justice Statistics (as reported in Warren, 2001) estimated that more than half of the women in state prisons have experienced past physical and sexual abuse. Thus, given the astonishing number of inmates who appear to be victims of some kind of trauma, it seems likely that those who work with these inmates (e.g., prison staff, guards, and treatment providers) will in some way encounter challenges related to the inmates' trauma history. These difficulties may appear in any number of forms including inmates' behavioral outbursts, increased emotionality, sensitivity to triggering situations, and chronic physical or mental health needs (Veysey, et al., 1998). It is also likely that these individuals with trauma histories would benefit greatly from treatment while incarcerated. This treatment could be utilized to minimize symptoms of posttraumatic stress, decrease behavioral problems, and help the inmate function more effectively in society when released from incarceration (Kokorowski & Freng, 2001; Tucker, Cosio, Meshreki, 2003). Few studies have explored the types of trauma treatment that are effective with inmate populations or made specific suggestions for clinicians working in forensic settings (Kokorowski & Freng, 2001). Essentially, there appears to be a large gap in terms of the need for trauma treatment for inmates and the lack of literature addressing what to do about it. However, clinicians across the country seem to be quietly attempting to fulfill this need for trauma treatment with incarcerated populations. They are providing this greatly needed treatment every day. in the face of enormous challenges and often without recognition or the opportunity to share their valuable work with the larger community.

Clinical Implications for Working with Gay Men A Self Psychological Treatment Approach.

Specific training for conducting psychotherapy with gay men is limited for psychologists, particularly when using a Self Psychology theoretical orientation (Robertson, 1996). In fact, psychologists often are faced with conflicting and contradictory points of view that mirror society's condemnation of homosexuality (Robertson, 1996). This paper is written from a self-psychological perspective to address the lack of a constructive body of literature that explains the unique treatment needs which impact gay men. Estimates of the prevalence of male homosexuality have generated considerable debate. A common assumption is that there are homosexual and non-homosexual men. However, scientists have long been aware that sexual responsiveness to others of the same sex, like most human traits, is continuously distributed in the population (Michaels, 1996). Still the presumption exists that such traits are stable within each man over time (Michaels, 1996). Conflating same-sex sexual experiences with a categorization of the man as homosexual is problematic, in that defining sexuality solely on the basis of experience excludes people who fantasize about sex with others of the same sex but never have sexual contact. Thus, most modern conceptions of sexual orientation consider personal identification, sexual behavior, and sexual fantasy (McWhirter, Sanders & Reinisch, 1990). Gay men's mental health can only be understood in the context of homosexuality throughout history, since religious and moral objections to sexual attraction between men have existed for centuries. Men who desired other men were regarded as sinful and depraved if not ill or abnormal, and same sex contacts were not distinguished from lewd behaviors (Weeks, 1989). Although most people, regardless of sexual orientation, have experienced some feelings of personal rejection, rarely do heterosexuals become targets for disapproval based on the nature of their attractions and behaviors relative to the same and to the other sex. For lesbians, bisexuals, and gay men, however, homosexuality becomes the focus of aspects of themselves that make them feel hated and hateful (Isay, 1989). While gay men and lesbians are often considered together because of the same-sex nature of their relationships and the similar issues that they may experience in their treatment within society, there are many issues where they might be best studied separately. Issues involving with health, parenthood, sexuality and perceived roles and status in society, for example, are often related more to gender than to any shared concept of a 'gay and lesbian community'. Many issues surrounding lesbians and lesbian culture will have more to do with women's issues, and some issues involving with gay men will have more to do with the gay male subculture and with masculinity. The author of this paper has limited experience in working with lesbian and bisexual individuals, and although it is likely that some of the concepts articulated in this paper could translate to working with lesbian and bisexual individuals, further research is indicated to examine the beneficence of utilizing a Self Psychological orientation in psychotherapy with lesbian women and bisexual individuals. This paper presents an overview of the literature including historical treatments of homosexuality, the history of Self Psychology, key principles in Self Psychology, research on Self Psychology, identity development models for gay men, and Self Psychological perspectives on identity development related to gay men. The literature review is followed by a section on treatment implications for psychologists seeking to treat gay men, including case vignettes based on work from my own practice. I have preserved the anonymity of clients by changing demographics, and rearranging and combining presenting issues and historical backgrounds among the case examples.

Clinical pathway intervention compliance and effectiveness when used in the treatment of patients with severe sepsis and septic shock at an Intensive Care Unit in Spain

The purpose of this quasi-experimental study was to assess levels of compliance with the intervention bundles contained in a clinical pathway used in the treatment of patients with severe sepsis and septic shock, and to analyze the pathway’s impact on survival and duration of hospital stays. We used data on 125 patients in an Intensive Care Unit, divided into a control group (N=84) and an intervention group (N=41). Levels of compliance increased from 13.1% to 29.3% in 5 resuscitation bundle interventions and from 14.3% to 22% in 3 monitoring bundle interventions. In-hospital mortality at 28 days decreased by 11.2% and the duration of hospital stay was reduced by 5 days. Although compliance was low, the intervention enhanced adherence to the instructions given in the clinical pathway and we observed a decline in mortality at 28 days and shorter hospital stays.

New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Modern diagnosis and treatment of diseases of children; a treatise on the medical and surgical diseases of infancy and childhood, with special emphasis upon clinical diagnosis and modern therpeutics.

Mode of access: Internet.

A manual of psychological medicine and allied nervous diseases : containing the description, etiology, diagnosis, pathology and treatment of insanity, with especial reference to the clinical features of mental diseases and the allied neuroses and its medico-legal aspects with a carefully prepared digest of the lunacy laws in the various states relating to the care, custody and responsibility of the insane /

Includes bibliographical references and index.

Clinical diagnosis and treatment of disorders of the bladder, with technique of cystoscopy,

Mode of access: Internet.

Index of diagnosis (clinical and radiological) for the canine and feline surgeon, with treatment.

Mode of access: Internet.